Part 14. Immunologic System and Disorders

정리

Part XIV. The Immunologic System and Disorder

Chapter116 T-, B-, NK-cell systems

# body defense against infections

   1. physical barriers ; skin, mucous membrane, mucous blanket, ciliated epithelial cell

   2. immune system

       a. phagocytic cells ; T, B, NK cell

       b. complememt protein

Lymphopoiesis In The Fetus

Source Of Lymphoid Cells And Process Of Organogenesis

; human immune system arises in gut-associated tissue

 Fig. 116-1

; primary lymphoid organ

    - thymus, bone marrow

; secondary lymphoid organ

    - spleen, lymph node, tonsil, Peyer's patches, lamina propria

; CDs (clusters of differentiation)

Table 116-1

; ILs (interleukins)

Table 116-2

T-Cell Development And Differentiation

# 태생 4

    ; ectoderm of 3rd brachial cleft + endoderm of 3rd branchial pouch 에서

    --> primitive thymic rudiment 형성

# 태생 7-8

    ; Rt. + Lt. rudiment move caudally

  --> fuse in midle line

# 태생 8

    ; fetal liver 에서 유래한 blood-born T-cell precursor perithymic mesenchyme 나타남

    ; *identify by CD7, CD34

# 태생 8-8.5

    ; CD7+ cells found intrathymically

  ; some cells coexpress CD4+, CD8+

  ; some bear single T-cell receptor (TCR) chains

# TCR

    ; heterodimer of two chain, either α and β or γ and δ.

  ; coexpress on the cell surface with CD3

    ; TCR gene rearrangement by large, ononcontiguous blocks of DNA(V(variable), D(diversity), J(joining))

           - require RAG-1 & RAG-2(recombinase activating genes)

# Immature cortical thymocytes *positive or negative selection 의해 maturation or die

# 태생 11-12

    ; T-cell thymus 에서 spleen, lymph nodes, apendix 이동

    ; 12주때에 proliferate in response to plant lectins(phytohemagglutinin & concanavalin A)

# 태생 14-15

    ; lymph node paracortical area, spleen periarterioloar area, thoracic duct lymph 분포

# *태생 20

    ; antigen-binding T cells 발견된다.

B-Cell Deveolpment And Differentiation

; 태생 7주까지는 fetal liver

; 태생 8

    - fetal liver 에서 CD34+ stem cell clavicle bone marrow seeding

; 태생 10

    - long bones seeding

Staging(Fig. 116-2)

1. antigen independent stages

    ; pro-B cell

           / first descendent of stem cells

           / *CD34, CD10

           / IL-7, IL-3 receptors

    --> pre-pre-B cell

           / immunoglobulin gene rearrangement

           / CD34, CD10, CD19, CD40, CD73, CD22, CD24, CD 38

           / loss of IL-7 receptor

    --> pre-B cell

           / cytoplasmic μ chains

           / no sIgM

           / IL-4 receptors

           / *loss of CD34, CD10

    --> immature-B cell

           / expression of *sIgM

           / loss of IL-3 receptor, CD38

    --> mature or virgin B cell

           / coexpression of sIgM & *sIgD

           / *CD23

2. antigen dependent stages

    ; 항원에 의해 자극받은 mature B-cell에서 시작

    ; sIg + memory B cell & plasma cell

    ; five immunoglobulin isotype

           - IgG, IgM, IgA, IgD, IgE

           - IgG & IgM

                   / *only complement-fixing isotypes

                   / *important in blood, internal body fluid

                   / *IgM intravascular compartment 에만 존재

                   / subclass of IgG

                           : IgG1, IgG2, IgG3, IgG4

                           : *IgG2 anti-polysaccharide antibody activity

           - IgA

                   / GI, respiratory, urogenital tract secretion .

           / subclass of IgA : IgA1, IgA2

           - IgE

                   / internal and external body fluid 존재

                   / *host defence against parasite

           - IgD

                   / 중요성 모름     

Natural Killer(NK)-Cell Development

     bone marrow precursoe cell 에서 유래

     functional capacity ; non-MHC restricted cytotoxicity

     T or B cell 달리 antigen receptor gene rearrange 일오나지않음

     all NK cell ; CD56 (+)

     90% 이상의 NK cell CD 16

     CD 57 ; 50-60%

     CD7 and CD2 ; 70-90%

     CD8 ; 30-40%

     lymphcyte 10% 정도가 NK cell 이며 cord blood 에서는 낮은 비율로 존재

Postnatal Lymphopoiesis

T-Cells And T-Cell Subsets

B Cells And Immunoglobulins

NK Cells

Lymphoid Organ Development

Assessment Of T-, B-, And NK-Cell Function

B-Cell Function

# simple screening test

    ; presence & titers of antibodies to type A and B red blood cell polysaccharides

T-Cell Function

# candida albican skin test

    ; *cost-effective test

    ; intradermal injection with 0.1ml of 1:1,000 dilution

    ; positive

           - erythma and induration more than 10mm at 48hr

    ; if negative

           - at 72hr, intradermal injection with 0.1ml of 1:100 dilution

# TCRs stimulation test

    ; phytohemagglutinin, concanavalin A, pokeweed mitogen

# measurements of cytokine production

Inheritance Of Abnormalities In T-, B-, And NK-Cell Deveolopment

Prenatal Diagnosis And Carrier Detection

Chapter 117. Primary B-Cell Diseases

 # introduction

   primary immuno deficiency diseases ; B-cell dysfunction  most frequent

   Selective absence of serum and secretory IgA is the most common defect

   incidences ranging from 1:333 to 1:16,000

   원인 - deletions of genes encoding immunoglobulin heavy chains

Table 117-1

117.1 X-Linked (XLA Or Bruton) Agammaglobulinemia

Clinical Manifestations

    ; most boys afflicted with XLA

    ; well during first 6-9mo due to maternally transmitted IgG antibodies

    ; *thereafter repeatedly acquire infections with extracellular pyogenic organisms

        - penumococci, streptococci, and Haemophilus

           - *rarely chronic fungal infections, pneumocystis carinii pneumonia

    ; Viral infections

        - normally handled

           - exception) hepatitis viruses and enteroviruses

           - *chronic progressive, fatal, central nervous system infections with echoviruses

    ; mycoplasma infection

Diagnosis

    ; serum concentrations of IgG, IgA, IgM, IgE

       - below the 95% confidence limits for appropriate age- and race-matched controls

      (usually <100 mg/dL total immunoglobulin) 시에 의심.

  ; *hypoplasia of adenoids, tonsil, and peripheral lymph node

           - germinal center not found

        - rare plasma cell

Genetics

    ; q22 on long arm of X chromosome

           - encode B-cell protein tyrosine kinase or Bruton tyrosine kinase (or BTK)

    ; BTK

           - member of the Src-related nonreceptor tyrosine kinase family many hematopoietic cells 에서 signal transduction 관여함.

all B-lineage cells, including pre B cells 에서 과량 표현되고, T lineage 에서는 발견되지않음

모든 단계의 B-cell differentiation 관여하는 것으로 여겨짐

all male with known XLA

- low to undetectable BTK mRNA and kinase activity.

Carriers 진단

a. nonrandom X-chromosome inactivation in B cells in restriction fragment length polymorphism (RFLP) studies of hamster-human B-cell hybrids

b. differences in methylation patterns

  Prenatal diagnosis of affected male fetuses

   ; using closely linked probes and RFLP analysis.

Pathophysiology

  polymorphonuclear functions ; normal

  but intermittent neutropenia is observed

  per centage of T cells  increased, ratios of T-cell subsets normal, T-cell function  intact.     thymus  morphologically normal

  XLA is reported in association with growth hormone deficiency.

  여아에서의 발생 보고도있으나 이와 같은 AR inheritance 기전은 모름

117.2 Common Variable Immunodeficiency (CVID)

; 'acquired" hypogammaglobulinemia similar clinically to XLA

; XLA 유사한점 - infections and bacterial pathogens

; XLA 다른점

    - echovirus meningoencephalitis is rare

  - sex distribution almost equal

    - age of onset is later

  - infections are less severe

Clinical Manifestations

    ; *autoantibody formation, normal-sized or enlarged tonsils and lymph nodes

    ; *splenomegaly - 25%

  ; *spruelike syndrome with or without nodular follicular lymphoid hyperplasia of intestine

    ; thymoma, alopecia areata, hemolytic anemia, gastric atrophy, achlorhydria, pernicious anemia

    ; lymphoid interstitial pneumonia, pseudolymphoma, amyloidosis, noncaseating granulomata of the lungs, spleen, skin, and liver

    ; *본질환의 여자 환자중 40-50 lymphoma 발생율 438 높다.

Pathophysiology

  a. serum immunoglobulin and antibody deficiencies; XLA 만큼 심함

  b. T-cell and T-cell subsets

    ; normal percentages 이나 어떤환자에서는 T-cell dysfunction 나타남

Genetics

 this disorder occurs in first-degree relatives of patients with selective IgA deficiency

 some patients with IgA deficiency later become panhypogammaglobulinemia

 --> IgA deficiency common genetic basis 임을 시사

 --> discovery of a high incidence of C4-A gene deletions and C2 in the class III (MHC) on chromosome 6

# drug (phenytoin, D-penicillamine, gold, sulfasalazine) 유전적 경향이 있는 환자에서 질환의 발현을 촉진

117.3 Selective IgA Deficiency

# isolated absence or near absence (i.e., *< 10mg/dL) of serum and secretory IgA

  ; *common well-defined immunodeficiency disorder

Clinical Manifestations

 1. 주로 respiratory, gastrointestinal, urogenital tracts infection

    no clear evidence of susceptibility to viral agents.

 2. serum concentrations of other immunoglobulins ; normal

    but IgG2 (and other) subclass deficiency is reported

    IgM ; elevated

    often have IgG antibodies against cow milk and ruminant serum proteins

      --> false-positive results in immunoassay for IgA 유발함.

 3. sprue like syndrome ;  may or may not respond to a gluten-free diet

   high incidences of autoantibodies and autoimmune diseases

   incidence of malignancy ; increased

   Serum antibodies to IgA ; 44% of patients with selective IgA deficiency 에서 보고됨

 4. IgE isotype 존재하면 IgA containing blood product 투여시 이로인해  severe or fatal     anaphylactic reactions 발생함.

    환자에게는 five times washed (in 200 mL volumes) normal donor erythrocytes           blood products from other IgA absent individuals 투여 가능함.

 5. IVIG (which is >99% IgG)  not indicated

    IgG antibodies 정상적으로 존재하므로 

       IVIG -  anaphylactic reactions 유발 가능

Genetics And Pathophysiology

 1. basic defect ; unknown (see Tables 117-1 and 117-2)

   suggests autosomal inheritance

 2. environmental factors ; CVID 유발하는 동일 약제에 의해 IgA deficiency 발생 가능

117. 4 Transient Hypogammaglobulinemia Of Infancy (THI)

 X-linked agammaglobulinemia or CVID 와는 달리  human type A and B erythrocytes    항체 형성 가능하며, diphtheria tetanus toxoids 대한 항체 형성도 가능함. 

 (see Table 1 17-1)

 IVIG therapy  not indicated

117.5  Igg Subclass Deficiencie.S

 normal IgG serum concentration 이나  one or more subclasses of IgG deficiency 있는 경우임

  -->eg. absent or very low concentrations of IgG2

          IgG2 deficiency have an evolving pattern of immunodeficiency (such as CVID)

 IVIG ; contraindicated

 

 117.6 Immunoglobulin Heavy and Light Chain Deletions

  gene deletion  으로 인해 total absence of IgG1, IgG2, IgG4, and/or IgA1 이나 증상인     우가 16 명의 환자에서 보고됨 (see Tables 117-1 and 117-2)

117. 7 X-Linked Lymphoproliferative Disease (XLP)

 1. XLP = Duncan disease

 2. recessive trait

 3. Epstein-Barr virus (EBV) infection 대한 미흡한 immune reaction 특징적임

   (see Table 117-1).

 4. defective gene in XLP ; Xq25-26 region near DXS42 and DXS37 (see Table 117-2)

 5. affected males acquire EBV infection 있기까지는 건강해 보임

 6. 진단 ;  RFLP 이용한 linkage analysis

 7. 임상적 특징

  a. mean age of presentation is less than 5 yr.

  b. the most common form of presentation (75%) ; severe fatal (80%) EBV infection

     <-- extensive liver necrosis caused by polyclonally activated alloreactive cytotoxic T              cells

117.8 Treatment Of B-Cell Defects

# only effective Tx

    ; antibiotic + regular administration of antibodies

# IVIG

    ; 사용전 반드시 broad antibody deficiency 임을 확인

  ; *HIV is inactivated by the ethanol used in preparation of ISG and IVIG

  ; detergent is also added to eliminate hepatitis viruses

  ; hepatitis C virus infections 보고되었음.

  ; dose : IVIG 400 mg/kg/mo

  ; side effect

           - systemic reactions, rarely anaphylactic

           - anaphylactic reactions caused by patient IgE antibodies to IgA in the IVIG

           - *CVID or IgA deficiency 환자에서 주로 발생

             /CVID 진단되는 모든환아는 반드시 anti-lgA antibodies 검사를 실시하여야함.

Chapter 118. Priamry T-Cell Disease

 

; defects in T-cell function more severe than  antibody deficiency disorders

Table 118-1

Table 118-2

118.1 Thymic Hypoplasia (DiGeorge Syndronle)

# thymic hypoplasia

    ; dysmorphogenesis of 3rd and 4th pharyngeal pouches

  ; hypoplasia or aplasia of the thymus and parathyroid glands

# Other Amonaly

    ; *great vessels (right-sided aortic arch), esophageal atresia, bifid uvula, congenital heart disease (atrial and ventricular septal defects), short philtrum of the upper lip, hypertelorism, an antimongoloid slant to the eyes, mandibular hypoplasia, and low-set, often notched ears

# 신생아 시기의 hypocalcemic seizure attack 으로 먼저 질환 의심

# fetal alcohol syndrome 유사한 facial features and conotruncal heart lesions

Clinical Manifestations

# partial DiGeorge syndrome

    ; little trouble with infections and grow normally

    ; more frequent than total aplasia

# complete DiGeorge syndrome

    ; SCID 유사함.

  ; susceptibility to infections

       - low-grade or opportunistic pathogens : fungi, viruses, Pneumocystitis Carrinii

    ; *susceptibility to graft-versus-host disease (GVHD) from non-irradiated blood transfusions

    ; serum immunoglobulins usually near normal

           - *IgA may be diminished and IgE elevated

    ; CD3-positive T cells variably decreased in number

  ; increased percentage of B cells

Genetics

    ; familial occurrence is rare

    ; *submicroscopic chromosomal deletions at 22q11

Treatment

 complete DiGeorge syndrome

  a. thymic tissue transplants

  b. unfractionated HLA-identical bone marrow transplantation.

118.2 X-Linked Immunodeficiency with Hyper IgM (Hyper IgM)

; *very low serum conccntrations of IgG and IgA + markedly elevated of polyclonal IgM

Clinical Manifestations

    ; X-linked agammaglobulinemia 유사한 증상

    ; symptomatic during 1st-2nd year of life

    ; recurrent pyogenic inlections

           - otitis media, sinusitis, pneumonia, and tonsillitis

    ; lymphoid hyperplasia

           - *XLA 구별점

    ; thymic-dependent lymphoid tissues and T-cell functions ; normal

    high titers of IgM antibodies to blood group substances and to salmonella O antigen

    ,but very low titers or no IgM antibody are noted in others

  ; *autoimmune disorders more higher than other antibody-deficiency syndromes

    ; hemolytic anemia, thrombocytopenia

    ; transient, persistent, or cyclic neutropenia

    ; *normal numbers of B lymphocytes

Genetics

 # abnormal gene ; Xq26

   gene product ; gp39 or CD40L

    --> ligand for CD40 on B cells

   mutations in the CD40L on activated T cells--> hyper IgM

118.3 Defective Expression Of The T-Cell Receptor-CD3 Complex (Ti-CD3)

118.4 Defective Cytokine Production

#Type

    1. inability to produce IL-2

    2.defective transciption of several lymphokine genes

118.5 CD8 Lymphocytopenia

; *absence of CD8 single-positive thymocytes due to mutations in gene encoding ZAP-70, non-src family protein tyrosine kinase

118.6 T-Cell Activation Defects

 blood T-cell number and phenotype ; normal

 but fail to proliferate or produce cytokines

Chapter 119. Combined B-And T-Cell Disease

; severe, frequently opportunistic infection --> death in infancy

Table 119-1

Table 119-2

119.1 Combined Immunodefuciency (CID Or Nezelof Syndrome)

; *recurrent or chronic pulmonary infection, failure to thrive, oral or cutaneous candidiasis, chronic diarrhea, recurrent skin infection, severe varicella in infancy, gram negative sepsis, UTI

Laboratory Finding

    ; neutropenia, eosinophilia

  ; serum immunoglobulin

           - normal or elevated

           - *some selective IgA deficiency, marked elevation of IgE, elevated IgD

    ; *impaired antibody fromation capacity

    ; delayed cutaneous anergy to antigens, lymphopenia, low or absent lymphocyte proliferation to mitogens

    ; *confused with AIDS

  ; CD-3 positive T-cell severe deficiency

           - normal proportion of CD4, CD8 positive cell

119.2 Purine Nucleoside Phosphorylase (PNP) Deficiency

    ; Nezelof 증후군 환자중 33 명이 PNP 결핍을 보였음

  ; point mutation ; chromosome 14q13.1

119.3 Cartilage Hair Hypoplasia

 1. 임상특징 : short and pudgy hands, redundant skin,

             hyperextensible joints of hands and feet,

             fine, sparse, light hair and eye brows

 2. 방사선학적 특징 : bones - scalloping and sclerotic or cystic changes in the metaphyses                 flaring of costochondral junctions of the ribs

 3. severe and fatal varicella infections

   ; progressive vaccinia, vaccine-associated poliomyelitis

119.4 Severe Combined Immunodeficiency (SCID)

# Characteristics

    ; absence of T-cell and B-cell fucntion from birth

  ; great genetic diversity

# death usually in the 1st yr & almost before the end of 2nd yr

Clinical Manifestations

    ; 생후 수개월내 diarrhea, pneumonia, otitis, sepsis, cutaneous infections 반복

    ; candida albicans infection, pneumocystis carinii, varicella, measles, parainfluenzae 3,            CMV, EVB, bacillus Calmette-Guerin, death

 3. profound Iymphopenia, delayed cutaneous anergy

   Serum immunoglobulin concentrations ; diminished to absent

                                         no antibody formation

   T cells and subsets ; extremely low or absent

Pathology

  1. very small thymuses (less than 1g)

     ; fail to descend from neck, few thymocyte, lack of corticomedullary distinction

  2. tonsils, adenoids, and Peyer's patches  absent or extremely underdeveloped

Treatment

  bone narrow transplantation

119.5 Autosomal Recessive SCID

  X-linked form Clinically, functionally, and histopathologically 과유사

  다른점 ; lower percentages of B cells

          higher percentages of NK cells.

119.6 Adlenosine Deaminase (ADA) Deficiency

; 15% of SCID

Etiology

    ; point and deletional mutations in ADA gene on chromosome 20ql3-ter

           --> *accumulation of adenosine, 2'-deoxyadenosine, 2'-O-methyladenosine

           --> *lymphocyte toxicity

       -->immunodeficiency

Clinical Manifestation

    ; other distinguishable features

        - rib cage abnormalities : similar to rachitic rosary

    - multiple skeletal abnormalities of chondro-osseous dysplasia

           / predominantly costochondral junctions, apophyses of iliac bone, vertebral body

Treatment

    ; bone marrow transplantation

  ; enzyme replacement therapy

        - polyethylene glycol modified bovine ADA (PEG-ADA), s.c. once weekly

       - BMT 실시하면 GVHD 가능성 높아 BMT 실시할 수있으면 이는 금기

    ; *gene therapy

119. 7 X-Linked Severe Combined Immunodeficiency (XSCID)

 (1) most common form of SCID in the United States (Table 119-1)

 (2) 다른형의 SCID 다른점

   1. higher B-cell percentage

   2. numbcr and function of NK cclls ; low or absent

 (3) gene in XSCID

   --> Xq13 ; encode gamma chain of IL-2 receptor (IL-2Rγ)

       * IL-2 ; T-cell growth factor

                key role in intracellular signaling in T cells

119.8 Reticular Dysgenesis

# 특징

  ; *말초혈과 골수에서 lymphocytes granulocytes 완전 소실

    --> overwhelming infections

# 치료 ; BMT

119.9 Defective Expresion of Major Histocompatibility Complex (MPC) Antigen

 (1) 3 forms

   1. class I MHC antigen deficiency (bare Iymphocyte syndrome)

   2. class II MHC antigen deficiency

   3. deficiency of both class I and II MHC antigens

119.10 Omenn Syndrome (=Combined Immunodeficiency With Hypereosinophilia)

; combined immunodeficiency with hypereosinophilia, AR

Clinical Manifestation

    ; fatal condition, susceptoble to infection, T-cell infiltration of skin, gut, liver, spleen

    ; *exfoliative dermatitis, lymphadenopathy, hepatosplenomegaly, intractable diarrhea

Laboratory Finding

    ; persistent leukocytosis with eosinophilia

  ; *elevated serum IgE, low IgG, IgA, IgM

119.11 Immunodeficiency with Thrombocytopenia and Eczema (=Wiskott-Aldrich Syndrome)

 # *X-linked recessive syndrome

   ; *atopic dermatitis, thrombocytopenic purpura with normal-appearing megakaryocytes, susceptibility to infection

Clinical Manifestations

; thrombocytopenia due to intrinsic platelet abnormality

      -> infancy bleeding from circumcision site or bloody diarrhea 나타남

; *atopic dermatitis, recurrent infections during first yr

    - 원인균

           / pneumococci, other bacteria having polysaccharide capsules

    - otitis media, pneumonia, meningitis, and/or sepsis

  - later, infections with Pneumocystis carinii, herpesvirus

; 10 이전에 사망함.

     causes of death ; infection ,bleeding

     12% incidence of fatal malignancy

Pathophysiology And Diagnosis

; impaired humoral immune response to polysaccharide antigens

; low serum IgM, elevated IgA and IgE, and a normal or slightly low IgG

; normal IgG2 subclass concentrations

; analyses of blood lymphocytes

    - reduced of CD3, CD4, CD8 Lymphocyte

; cutaneous anergy

Genetics

  abnormal gene ; proximal arm of the X chromosome at Xpll.22-11.23

  --> gene proline-rich cytoplasmic protein coding

       protein lymphocytic and megakaryocytic lineages 국한되어 표현됨

       protein Wiskott-Aldrich syndrome protein (WASP)이라함

  --> important regulator of lymphocyte and platelet function

   carriers 진단 ; nonrandom X-chromosome inactivation

119. 12 Ataxia-Telangiectasia

  # complex syndrome

   ; neurologic, immunologic, endocrinologic, hepatic, cutaneous abnormalities

Clinical Manifestations

  * most prominent clinical features

    a. progressive cerebellar ataxia ; 걷기 시작할때 부터 나타나 10-12세경 wheelchair

    b. oculocutaneous telangiectasias ; 3-6 세경

    c. chronic sinopulmonary disease ; recurrent, bacterial infection, 80 % 에서 나타남

    d. high incidence of malig nancy

    e. variable humoral and cellular immunodeficiency

Pathophysiology And Diagnosis

 * patients heterozygous carriers

  ; increased sensitivity to ionizing radiation

   defective DNA repair

   frequent chromosomal abnormalities

 * chromosomal breakage ; chromosomes 7 and 14

   --> coding for the T-cell receptor and immunoglobulin heavy chains

 * malignancy ; lymphoreticular type

 

 * humoral immunologic abnormality

   a. selective absence of IgA ; 50-80%

   b. hypercatabolism of IgA

   c. IgE ; low  IgM ; the low molecular weight variety

      IgG2 or total IgG ; decreased

     specific antibody titers ; decreased or normal

   d. moderately reduced percentages of CD3-and CD4 positive T cells

      normal or increased percentages of CD8 +

Genetics

 * autosomal-recessive

119.13 Hyperimmunoglobulinemia E (Hyper IgE) Syndrome

; *recurrent severe staphylococcal abscesses and marked elevated level of serum IgE

Clinical Manifestations

; from infancy

; *recurrent staphylococcal abscesses of skin, lungs, joints, and other sites

; persistent pneumatocoeles

; *pruritic dermatitis

    - not typical atopic dermatitis

; Laboratory Finding

    - *high serum IgE ; elevated serum IgD ; normal concentrations of IgG, IgA, IgM

  - blood and sputum eosinophilia

; Immunologic Abnormalities

    - poor antibody and cell-mediated responses to neoantigens

    - low anamnestic antibody responses

    - *paradoxically low levels of IL-4-stimulated IgE synthesis in vitro

    - *imbalace of TH1 and TH2 type cells

           / TH1-like deficiency, TH2-like excess

    - decrease percentage of T cell with memory (CD45RO) phenotype

Treatment

 a. penicillinase-resistant penicillin 장기 투여

 b. IVlG

 c. Op. indication

   ; superinfected pneumatoceles

     or pneumatocele 6 개월 이상 지속시

119. 14 Treatment of Celluar Immunodeficiency

 1. fatal T-cell or combined T, B-cell defect 경우

   -> transplantation of MHC compatible or haploidentical parental bone marrow

   -> major risk : graft-versus-host disease

   * haploidentical (half-matched) BMT

      donor marrow 에서 post-thymic Tcell 제거시키는 기술의 향상으로 가능해짐

      : soybean lectin incubation

        --> sheep erythrocyte rosette depletion 혹은

             incubation with monoclonal antibodies to T cells plus complement

# less severe forms of cellular immunodeficienc 경우

  ; Nezelof syndrome, Wiskott-Aldrich syndrome, cytokine deficiency, MHC antigen deficiency

  ; *immunosuppressive agents 치료후 HLA-identical BMT

# enzyme replacement therapy

   ; ADA deficient patient-> polyethylene glycol-modified bovine ADA (PEG-ADA)

    subcutaneously once weekly

   but , ADA treatment of choice BMT

Chapter 120. The Complement System

Complement

Table 120-1

Nomenclature

 1. classic pathyway :  C1423

 2. menbrane attack complex : C56789

 3. Cl : 3 subcomponents -> Clq, Clr, and Cls

 4. component cleavage 생긴 fragments enzymes 기능을 가지고있으며 are             small letters (a, b, c, d, or e) 표기

    component activation ( active enzyme) 되면 bar 표기함

 5. alternative pathway : B and D

    -> control proteins I and H -> downregulate both pathways

 6. C3 (C3b) ; component of  classical and alternative pathways

General Concepts

  * classical path way ; antigen-antibody-C142356789

    alternative pathway;  activator-(antibody)-C3bBDC356789

Sequence Of Activation

Figure 120-1

 (1) classic pathway

     Ag-Ab interaction --> C1q Fc non-antigen-binding part fix

     --> Cl tricomplex configuration change

     --> Cls active enzyme Cl esterase

     --> C4, C2 activation and fixation

      ; C4a - anaphylactoxic 으로 작용. mast cell 작용하여 chemical mediator 분비시킴

        C2-kinin - vascular permeability and edema

     --> AgAbC14b

      ; 4b - neutrophil, monocyte, erythrocyte 부착 가능하게함.

     --> C3 cleavage, generation of C3b (most crucial biologic activity)

      ; classid pathway C3 convertase C142 의해

     --> C3b   B lymphocytes, erythrocytes, phagocytic cells (neutrophils, monocytes, and           macrophages) complement receptor 1(CR1) Ag-Ab complex 부착 가능하게           . phagocytic cell 에서는 phagocytosis 일어나게함.

         그러므로 C3 deficiecy 에서는 severe pyogenic infections 발생

         *  factor I (C3b inactivator)

         * C3a - anaphylactoxin activity

     --> activated C423 C5 clevage

        ; C5a ; powerful anaphylactoxin

     --> C14b2a3b5b C6 binding

     --> C5b6 C423에서 떨어져나오고 C5b67 형성

     --> C5b6789 ; membrane attack complex

     --> cell lysis   

     

    * C-reactive protein (CRP) :

          reacts with C carbohydrate from microorganisms

          --> antibody 대신 Clq fixing

          --> initiate reaction of the entire sequence

    * CRP 이외에도 antibody 없이 C1 직접 반응할 수있는 agent

         : certain bacteria, mycoplasma, and RNA viruses, uric acid crystals,

           lipid A component of bacterial endotoxin, certain intracellular organelles

 

    * Control mechanisms of classic pathway

      a. Cl inhibitor (Cl INH) ;  inhibits Cls enzymatic activity

                              --> inhibitionof cleavage of C4 and C2

      b. relative instability of activated C2

      c. anaphylatoxin inactivator

      d. Factor I ; inactivate C4b and C3b

                   control mechanism 으로 중요

      e. Factor H ; accelerate inactivation of C3b

      f. cell membranes protein(CRl, membrane cofactor protein, decay accelerating factor)

         ; promote the disruption of C3 and C5 convertases

      g. other cell membrane-associated proteins (C8 binding protein and CD59)

         ; bind C8 or both C8 and C9

           --> interfering with insertion of the membrane-attack complex (C5b6789)

Altenative Pathway

  C3b 의해 activated <- C3b generated by

                            1. classical pathway activity

                            2. leukocyte proteases released by degranulation

                            3. activation of thrombin or plasmin

                            4. C3 created by low grade, spontaneous reaction of 

  --> factor B attached to C3b

  --> cleaved to Bb by D (Bb = active proteolytic enzyme)

  --> 이렇게 형성된 C3bBb C3 convertase 작용하여 amplification loop 통해 C3b

       more generation

 

 * materials promote alternative pathway activation

   ; teichoic acid from bacterial cell wall

     endotoxic lipopolysaccharide

     immunoglobulin aggregates, especially of IgA class

 * controlors

   ; factors I and H - inhibitory

     P - C3Bb stabilizer

Participation In Host Defense

 1. C1 and C4 ; antibody 의한 virus neutralization 촉진

    C3b ; antibody concentrations 낮을 경우 C3b viral Ag-Ab fixation 되어

         neutralization 개선

   complement : particularly important in the early phases of a viral infection when                             antibody is limited

 2. C1q ; opsonization (promote phagocytosis)

 3. C4a, C3a, and C5a ; bind to mast cells

                 --> trigger release of histamine and other mediators

                 --> vasodilatation, swelling, redness of inflammation

   C5a ; monocytes cytokines (TNF, IL-1) release 촉진

         major chemotactic stimulus for neutrophils, monocytes, and eosinophils

  fixation of C3b to a target cell --> cell lysis 촉진 via ADCC

 4. B- and T-lymphocyte-mediated specific immunity 관여함.

   a. C3b- and C3d-coated particles ; bind to B Iymphocytes

                           --> enhance  primary antibody response

   b. C3a ; suppress antibody formation

   c. C5a and Clq ; enhance response

 5. activation of entire complement sequence

    ; lysis of virus-infected cells, tumor cells, and most types of microorganisms

Chapter 121. Diseases of the Complement System

121.1 Primary Deficiencies of Complement Components

★♣Table 121-1

Primary Deficiency Of C1q

    ; *SLE or SLE-like syndrome without typical SLE serology

 (2) Clr, Clr/Cls, C4, C2, and C3 deficiencies

     ; high incidence of vasculitis syndromes

      especially SLE or the SLE-like syndrome

C5, C6, C7, Or C8 Deficiency

    ; *recurrent neisserial infections

Genetic Deficiency Of C3

    ; *recurrent, severe pyogenic infection due to pneumococci, meningococci

Properdin Deficiency

    ; *X-linked trait

121.2 Deficiencies of Plasma, Membrane, or Serosal Complement Control Proteins

Factor I Deficiency

    Factor I : essential regulator of both pathways.

    deficiency :

           prolonged existence of C3b in the C3 Convertase of the alternative pathway,                  C3bBb → constant activation of the alternative pathway

                      cleavage of more C3 to C3

Factor H Deficiency

     Factor H : assists in dismantling the alternative pathway C3 convertase

     deficiency : factor I deficiency 비슷한 현상

                   Levels of C3,factor B,total hemolytic activity,alternative pathway activity

                   low or undetectable

     증상:sustained systemic infection(특히 meningococci)

         glomerulonephritis(almost half the cases)

Deficiency Of C4 Binding Protein

     C4 binding protein level 정상의 25%

     no typical disease presentation

Preperdin Deficiency

     predisposition to meningococcal meningitis

     striking history of male deaths due to meningitis

     serum hemolytic complement activity is normal

     presence of specific antibody should avoid the need for the alternative pathway

     and properdinn

Hereditary Angioedema

    ; *inability to synthesize normally functioning Cl inhibitor (Cl INH)

           - 85% : markedly reduced concentrations of inhibitor (5-30% of normal)

    - 15% : normal or elevated concentrations but nonfunctional protein

    ; autosomal dominant traits

    ; pathogenesis

           - activation of Cl

                   --> uncontrolled Cl activity

         --> breakdown of C4 and C2

         --> release of a vasoactive peptide (kinin) from C2

                   --> *kinin vasodilatory effect

    ; Clinical Manifestation

           - *episodic, localized, nonpitting edema

           - *no urticaria, itching, discoloration, redness, severe pain

           - intense abdominal cramping, vomiting or diarrhea

                   / due to swelling of the intestinal wall

           - laryngeal edema : fatal

    - Attack 2-3일간 지속되다가 차츰 사라짐

    - sites of trauma, after vigorous exercise, with menses,; or with emotional stress.               Attacks:생후 2년내에 시작되며 보통 late childhood,adolescence까지는 심하지                      .

Acquired C1 INH Deficiency

    ; *B-cell Iymphoproliferative disorder

           - autoantibody to the inhibitor.

Membrane Complement Control Proteins

    ; complement receptor I (CRI)

  ; membrane cofactor protein

  ; decay accelerating factor (DAF)

           - prevent the formation of the full C3-cleaving enzyme, C3bBb(triggered by C3b deposition)

    ; membrane inhibitor of reactive Iysis (CD59)

  ; C8 binding protein (C8bp)

        - prevent the full development of the membrane attack complex that creates the hole

Paroxysmal Nocturnal Hemoglobinuria

          hemolytic anemia

          erythrocyte surface위에 DAF, CD59, and C8bp 표현되지 않는 질환

          somatic mutation in a hematopoietic stem cell of the PIG-A gene on the X                   chromosome. PIG-A gene product 적어도 40종류의 protein(including DAF,                              CD59, C8bp) cell membrane anchor하는                                                  glycosylphosphatidylinositol이다.

Genetic Isolated CD59 Deficiency

: mild PNH-like disease

                                        DAF expression 정상

Genetic Isolated DAF Deficiency

: hemolytic anemia 야기하지 않는다.

Partial Deficiency Of CR1

           immune complex disease risk

           SLE환자나 환자의 asymptomatic family members에서 발견된다.

Serosal Fluids Complement Control Protein(Protease)

      기능:chemotactic activity of C5a/interleu kin 8 (IL-8)( important chemotacti factors for                                                              neutrophils)

FMF(familial Mediterranean fever)

         peritoneal and synovial fluids 내에 complement control protein protease genetic            defect

         증상:recurrent episodes of fever

             painful inflammation of joints and pleural and peritoneal cavities.

121.3 Secondary Disorders of Complement

Deficiency Of IgG

    ; severe combined immunodeficiency disease, hypogammaglobulinemia

    ; *no prevention of rapid catabolism of C1q

Nephritic Factor(NeF) Containing Disorders

    ; NeF

           - *IgG Ab to C3bBb(C3-cleaving enzyme of alternative pathway)

           - protects the enzyme from inactivation

                   --> increased consumption of C3

    ; Pyogenic infections(including meningitis)

           - serum C3 level 정상의 10%이하로 떨어지는 경우

    ; chronic membranoproliferative glomerulonephritis, partial lipodystrophy, acute postinfectious nephritis, systemic lupus erythematosus

Deficiencies Of All Plasma Components Of The Complement System.

    ; *newborn infants, malnutrition, anorexia nervosa, severe chronic cirrhosis of liver & hepatic failure

Defective Function Of Alternative Pathway

    ; *sickle cell disease, 10% of splenectomy, β-thalassemia major, nephrotic syndrome

Immune Complexes & Consumption Of Complement

    ; Systemic lupus erythematosus, lepromatous leprosy, subacute bacterial endocarditis, infected ventriculojugular shunts, malaria, infectious mononucleosis, dengue hemorrhagic fever, acute hepatitis B

    ; dermatitis herpetiformis, celiac disease, primary biliary cirrhosis, reye syndrome

Direct Activation Of Alternative Pathways

    ; *bacteremic shock, iv injection of iodinated roentgenographic contrast medium

    ; *burn, cardiopulmonary bypass, plasma exchange, hemodialysis

    ; *EPP, PCT

121. 4 Diagnosis Of Disorders Of The Complement System

CH50 (Testing for total hemolytic complement activity)

    ; useful screening procedure for disease of complement system

    ; *classic pathway & membrane attack complex 관여

    ; not detect deficiency of alternative pathway components B or D, properdin

low both C4 & C3

    ; activation of classic pathway by immune complexes

low C3 and normal C4

    ; activation of alternative pathyway

    ; useful in distinguishing nephritis due to NeF(nephritic factor)

121.5 Treatment Of Disorers Of The Complement System

; no specific therapy

; serious complications 대한 치료

# Hereditary Angioedema

    ; *danazol

           - *Cl inhibitor level증가시켜서 attack 예방

         - short-term prophylaxis for oral surgery

           - 수술전 1주간 투여

           - *소아에서는 권장되지 않음

    ; purified Cl INH

           - acute attacks/long-term prophylaxis.

           - 연구중

다른 complement system disease에서는 supportive management만이 available관련된 complication(collagen vascular disease,infection) 의심되는 경우 진단적 노력이 필요하고 초기에 치료를 하는 것이 필요하다.

# onset of unexplained fever

    ; cultures, antibiotic therapy

# vaccination

    ; patient & contacts

    ; pneumococci, Haemophilus influenzae, and Neisseria meningitidis

Chapter 122. The Phagocytic System

122.1 Normal Physiology Of The Phagocytic Inflammatory Response

principal phagocytes:neutrophils   acute inflammation and microbial killing

                   monocytes chronic inflammation.

                   Eosinophils phagocytic microbial killing

                              allergic/certain parasitic responses.

                   Fixed tissue macrophages of liver, spleen, lung, and bone marrow

Differentiation pathways of hematolymphoid cells

     pluripotent stem cell progenitor in the bone marrow

     -- cytokine 영향으로 specific lineages differentiation (Fig.122-1)

cytokines

   costimulation : stem cell factor, (IL)-3, IL-l, IL-6, IL-12, (GM-CSF).

   Multipotent myeloid-erythroid progenitors : erythropoietin for erythrocyte development

                                            IL-5 for eosinophil development

                                            IL-9 and IL-II for megakaryocyte development                                               M-CSF for monocyte macrophage development                                              G-CSF for granulocyte development

Neutrophilic granulocytes BM내에서 10-12일동안 증식/성숙한다.

           myeloblast promyelocyte myelocyte

           end cells

             ːno longer capable of mitosis

              : mature further into metamyelocytes, bands, and segmented PMNs

           5일간 BM내에 저장되어 있다가 circulation내로 release된다.

           migrate to tissues (live for 1-2 days) (Fig. 122-2).

           BM내의 PMNs endotoxin,TNF,IL-1,activated complement 같은 염증반응                 개체에 의해 circulation내로 release된다.

Steroid neutrophilia : release of a marginated pool

                     increased production

adrenaline and other adrenergic agonists : adenylate cyclase 활성화시켜 neutrophil                                                       demargination 일으킨다.

 

A variety of chemotactic factors are derived from cells or plasma. The activation of complemenl generales CSa, clolling generates thrombin, cell membrane phospholipids generale platelet-activating faclor, stimulated T Iymphocytes provide Iymphocyte-derived chemotactic factor, activaled macrophages and Iymphocytes release IL-8, and activaled PMNs generale leukotriene B4. The ability of the various chemoattractant mol ecules to activate leukocyte responses is mediated by specific receptors, which, when occupied by a specific chemotactic factor, activate phospholipase C to produce inosilol triphos phate (IP3) and diacylglycerol. IP3 in turn increases intracellu lar calcium-dependent responses associated with phagocyte activation, such as protein kinase C for phosphorylation of several important intracellular proteins required for cell activa tion and the assembly of actin and associated contractile pro teins. The increased expression of a group of adherence pro teins, for example, iC3b, and the assembly of actin and associated contractible proteins enable the phagocyte to attach to endothelial surfaces and move in a crawling amoeboid way to the site of infection or inflammation. The pathway is paved by an increasing gradient of chemoattractants that culminate in either a full expression of phagocytic activation or engage ment of opsonized microbes.

 Microbes are opsonized (prepared for ingestion) by heat stable and heat-labile factors in human serum that include immunoglobulin G and C3. Human leukocytes have three distinguishable receptors for each of the four immunoglobulin G subclasses (IgGI~) and four receptors for C3 (CRI~). CRI and CR3 are distinct opsonin receptors on neutrophils, mono cytes, and macrophages that bind C3b and iC3b, respectively, and facilitate phagocytosis of microbes and other particles or cells opsonized by them. In contrast to the IgG receptors, FcR, and the CRI receptors (which do not require divalent cation for their ligand binding), CR3 requires 0.5 mM concentrations of calcium and magnesium ions for iC3b binding. The in vivo importance of the CR3 receptor for host defense will be dis cussed later. The trigger for ingestion by phagocytes of CRI-

 

 

and CR3-bound microbes or cells appears to involve phosphor ylation of the receptor by activaled protein kinases. Adhesive proleins found in plasma and lissue matrices (such as fibro nectin, laminin, and the protein kinase C stimulant phorbal myristate acetate) have been shown to trigger phagocytic cell ingestion. Ingestion is an active process accompanied by fur ther assembly and disassembly of contractile elements as the pseudopode envelopes its prey as it forms a phagosome. Gran ules fuse with the phagosomal membrane and discharge their contents into it. In neutrophils, specific granules interact with the phagosome earlier than do azurophilic granules. This pro cess of degranulation occurs in all phagocytic cells and pro motes the killing or digestion of microbes. On the other hand, treatment of cells with cytochalasin B disrupts assembled mi crofilaments, blocks ingestion, and renders the phagocytes se cretory. Under such conditions, full activation induces release of the granule contents to the outside of the cell. Soluble chemotactic stimuli at sites of inflammation can induce exten sive granule secretion, escalating the inflammatory process. In addition, the microbicidal and cytotoxic system of phagocytes includes the secretory products of the respiratory burst, super oxide anion, hydrogen peroxide, hydroxyl radical, and longer acting hypochlorous acid and chloramines (Fig. 122-3). The azurophilic granule constituent myeloperoxidase participates in the amplification of this system by halides such as iodide and chloride. This system may also inhibit chemotactic factors and Iysosomal granule components that may attenuate the inflammatory process. The respiratory burst is discussed in more detail in Chapter 129 in terms of the etiology and patho genesis of chronic granulomatous disease.

122.2 Other Types of Inflammatory Leukocytes

NEUTROPHILS

 predominating type of granulocyte.

 nuclei : 3-5 segments

 most important phagocytic cells against bacterial infection

EOSINOPHILS

 large coarse granules of prominent red color (with Romanowsky stain)

 nucleus with one or two segments.

 circulating leukocyte 5%이하

 Eosinopenia : (1) acute stress --  adrenocorticoids/epinephrine 자극

              (2) acute inflammatory states

 Eosinophilia : parasitic infections

              allergic phenomena

              dermatologic conditions

              gastrointestinal disorders

              Hodgkin's disease

              immune deficiency diseases

              during convalescence from viral diseases.

              Loffler syndrome

              eosinophilic leukemia.

BASOPHILS

 coarse, deep blue granules : 많은 양의 heparin histamine 함유

 total leukocytes 0.5%

 증가하는 경우 : chronic myelogenous leukemia

                 ulcerative colitis

                 juvenile rheumatoid arthritis

                 iron deficiency

                 chronic renal failure

                 radiation therapy

LYMPHOCYTES

 blood leukocytes 30-50%

 actively motile but not phagocytic.

 Marked absolute Iymphocytosis

      certain acute infections : pertussis, infectious mononucleosis

                              acute infectious lymphocytosis

 Moderate relative Iymphocytosis

      childhood exanthems

      viral illnesses, brucellosis, typhoid/paratyphoid fevers

      allergic reactions, leukemia, thyrotoxicosis, Addison disease

 Profound lymphopenia

      Thymic alymphoplasia

 

MONOCYTES

 large lobulated nucleus

 abundant gray cytoplasm

 fine azurophilic granules

 leukocytes 1-5%

 BM내에 monocytes reserve pool 없기 때문에 mature monocyte neutrophil보다 blood     stream 며칠 빨리 나타난다.

 relative monocytosis : BM aplasia hypoplasia 회복기

                       recovering of chemotherapeutic agents.

 moves more slowly than the neutrophil.

 tissue macrophage : 2년간 macrophage기능을 수행

                    scavenging of debris

                       ingesting bacteria

                       adept handling microorganisms and parasites

                       (Legionella pneumophila, Listeria monocytogenes, Toxoplasma gondii)    Monocytes 증가하는 경우

     tuberculosis

     systemic mycosis

     bacterial endocarditis

     chronic inflammatory bowel disease

     certain protozoan infections

     isolated neutropenia.

 

QUANTITATIVE DISORDERS OF THE NEUTROPHILS

   at birth : neutrophil 우세

   1st few days of life동안 감소

   During infancy : constitute 20-30%

   5 yr : lymphocyte neutrophil 비율이 비슷해진다.

   사춘기에 이르러서 성인에서와 같이 neutrophil 70% 차지하게 된다.

   neutrophil absolute count : 1,500-2,500/mm3

Chapter 123. Neutrophilia

  neutrophil bonc marrow production

  movement in and out of the bone marrow com partments into the circulation.

  neutrophil destruction.

 

1. BM peripheral marginating pool에서의 circulation으로의 release증가

2. tissue egress impairment blood neutrophil survival증가

3. expansion of the circulating ncutrophil pool

# Acute neutrophilia

    ; *physical exercise, epinephrine-induced reaction(panic response)

    ; neutrophil marginating pool로부터 ciiculating pool로의 neutrophil 이동하기 때문

# Slower onset of acute neutrophilia

    ; glucocorticosteroid administration, response to inflammation or infection(endotoxin)

    ; Maximal response 4-24시간내에 일어난다

  ; BM내의 neutrophil circulation내로 release되기 때문

# Chronic neutrophilia

    ; continuous stimulation of neutrophil production

           - prolonged administration of glucocorticoids

    - chronic inflammatory reactions

    - chronic anxiety

    ; inhibition of marrow feedback mechanisms하기 때문

# Leukemoid reactions(reactive leukocytosis)

  ; blood picture leukemia 비슷

  ; CML 차이점

           - ALP activity leukemoid reaction에서는 증가되어 있다.

  ; sepsis, systemic mycotic/protozoal infections, hepatic failure, diabetic acidosis, azotemia, malignancy involving the bone marrow.

    ; hematologic disorder

           - chr.hemolytic anemia, hemorrhage, transfusion reactions, postsplenectomy reactions, myeloprolilerative disorders

Chapter 124. Neutropenia

   정의 : deficiency of circulating neutrophils and band forms

         absolute neutrophil count (ANC) < 1,500 / μl

   원인 :

       BM에서의 생산의 이상

       circulation에서 exaggerated loss

   acquired cause 의한 일시적인 neutropenia 수일에서 수주동안 지속

   immune, congenital, or genetic cause 의한 chronic state 경우는 내지는 평생동안    지속할 수도 있다.

   neutropenia chronic state에서 감염의 여부는 ANC BM내의 neutrophil reserve 비례

Table 124-1

124.1 Transient Neutropenia

Viral

 childhood에서 일시적인 neutrophilia 가장 흔한 원인

    neutropenia 야기하는 virus

        hepatitis A and B

        respiratory syncytial virus

        influenza A and B

        measles, rubella, varicella

    24-48hr내에 neutropenia 나타나고 3-6일동안 지속

    viral infection에서 neutropenia 일으키는 기전

         virus-induced redistribution of neutrophils (circulating poolmarginating pool)

        sequestration in the spleen,reticuloendothelial organs

        damaged tissue uptake증가

Nutritional

    vitamin B12, folic acid, copper deficiency

Bacterial

    Staphylococcus aureus

    brucellosis tularemia rickettsia

    salmonella typhi, Shigella sonnei  

    Mycobacterium tuberculosis

    Marked neutropenia overwhelming sepsis에서 일어날 있다.

Drug Induced

    dose-dependent bone marrow suppression

    haptene-associated induction of antineutrophil antibody.

    종류 : Phenothiazines

          semisynthetic penicillins

          nonsteroidal anti-inflammatory agents

    예후 : drug stop 수일내에 blood내에 monocytes immature neutrophils 나타나기 시작한다.

 

124.2 Neonatal Neutropenia And Maternal Hypertension

 

심한 pregnancy-induced hypertension 가진 산모에서 태어난 아기의 50%에서 neutropenia 나타난다.

감염의 risk 높지는 않으나 preterm infants에서 흔하다.

Neutrophil production cord blood serum에서 발견되는 placenta factor 의해 inhibition된다.

124.3 Neonatal Neutropenia With Sepsis

  term infants에서 나타나는 neutropenic episode 대부분 infection 관련

  preterm infants 경우는 infection과도 연관이 있고 noninfectious cause와도 연관되어 자주    나타난다.

  Hcmatologic predictors of sepsis in the neonate

      elevated immature:mature neutrophil ratio(>0.35)

     ANC < 500/uL.

  depleted storage reservoir in the bone marrow (PMNs,band forms,metamyelocyte BM cell    7%이하인 경우) : vulnerable to over whelming sepsis, meningitis, and death.

   치료 : Granulocyte transfusions ----  sepsis neutropenia있는 newborn에서 효과

          High-dose gamma globulin

          recombinant C-CSF

124. 4 Benign Chronic Neutropenia

Autoimmune Neutropenia Of Infancy.

      the most common form of chronic childhood neutropenia.

   mature neutrophil depletion

   compensated increase in immature granulocytes in the bone marrow

   median age : 8 mo

   3:2 female predominance.

   fever 동반되는 경우가 많다.

   P/Ex infection 의심할 만한 소견외에는 nonspecific

   ANC 심한 감소에도 불구하고 benign course 취한다.(<500/μl)

   median duration of neutropenia : 20 mo

                                   95% 4세까지 recover

   BM 소견 : late metamyelocyte,band stage에서 분화가 멈춘 상태

   Treatment : high-dose gamma globulin

               recombinant human G-CSF

               infection standard antibiotic Tx

Neutropenia Associated With Primary Immune Disease

      frequent occurrence in congenital and acquired forms of immune deficiencies

                                 agammaglo bulinemia

                                 hypogammaglobulinemia

                                 hypergammaglobulinia

                                 T-cell defects

                                 natural killer cell defects

                                 autoimmune diseases

      positive family history of neutropenia

      recurrent bacterial infections

      poor growth

      Tx : underlying cause 교정과 infection 대한 aggressive treatment 필요

Autoimmune Neonatal Neutropenia (ANN)

      산모의 태아의 neutrophil Ag 대한 alloantibody transplacental transfer후에 일어남

      기전 : Rh hemolytic disease에서와 같이 산모의 prenatal sensitization fetal neutrophil                Ag 대한 IgG 유도시킨다.

   ANN   pathogenesis

       : liver,spleen,lung,BM내의 mφ에 의해 Ab-coated neutrophil phagocytosis 기인

   경과 : neutropenia 수주 내지는 6mon 지속된다.

   diagnosis : maternal neutrophil-specific alloantibodies 존재유무

   Treatment : High-dose gamma globulin

               Transfusion of paternal neutrophils

Neonatal Maternal Autoimmune Neutropenia.

   autoimmune diseases 산모에서 태어난 아기가 일시적으로 neutropenia 가진다.

   duration : 모체에서 전달된 Ig G Ab 제거하는 기간에 비례한다.

             수주 내지 수개월

   asymptomatic

124.5 Congenital Neutropenias

Genetic Infantile Agranulocytosis (Kostmann's Disease).

; rare autosomal recessive disease

; *neutropenia at birth & frequent bacterial infection

    --> death in most patients by 3yr

; *asso. with HLA-B12

; BM morphology - maturational arrest of neutrophil precursors at the promyelocyte stage

; Treatment

    - *G-CSF 3.5-12 ug/kg/24hr dose

Cyclic Neutropenia (Cyclic Hematopoiesis)

; *regular 18-21 day cyclic fluctuations in the number of blood neutrophil, monocyte, eosinophil, lymphocyte, PLT, reticulocyte count

Clinical Manifestation

    ; recurrent fever, malaise, mucosal ulcers, severe periodontal infections, oral ulcerations, skin infections, life-threatening infection during the nadir of neutropenia

    ; defective BM transplantation함으로써 recipient에게 cyclic hematopoiesis transfer

     hematopoietic stem cell defect 있음을 암시

Treatment

G-CSF 투여가 많은 case에서 fever episode,mouth,skin infection빈도를 줄임

Familial Benign Neutropenia

    AR,AD 형태로 유전

    in Jews from Yemen and Ethiopia

    intramedullary destruction of the neutrophils

    morphologic abnormalities of their nuclei.

    cytoplasmic vacuoles/thin strands connecting the nuclear lobes(myelokathexis)

Chediak-Higashi Syndrome

    autosomal recessive disorder

    partial albinism, photophobia, nystagmus

    decreased pigmentation of the hair and eyes

    increased susceptibility to infection (see Chapter 127).

Glycogen Storage Disease Type Ib

    특징 : Recurrent infections and neutropenia

    classical von Gierke glycogen storage disease (GSDla)/GSDlb: 심한 간비대

                                                                성장 장애

    GSD1b : GSDla와는 달리 glucose 6-phosphatase activity in vitro에서는 존재하지만 in                  vivo에서 glc-6 phosphate에서 glucose 방출되지 않는다.

    porto caval shunt후에 neutrophil level improve되고 recurrent infection 감소한다.

    inflammatory bowel disease

    oral lesions

    perianal abscesses

    G-CSF or GM-CSF 투여가 neutropenia,recurrent infection,enteric inflammation 호전에       과가 있다. GM-CSF보다 G-CSF S/E 적다.

Shwachman-Dlamond syndrome

    ; AR

  ; *pancreatic insufficiency, neutropenia

    ; *metaphyseal dysostosis

    ; growth failure

    ; anemia,thrombocytopenia

    ; bone marrow

           - myeloid hyperplasia

  ; defective chemotactic response of peripheral blood neutrophils

    ; high risk for leukemia

    ; Treatment

           - G-CSF administration

Metaphyseal Chondrodysplasia (Cartilage-Hair Hypoplasia)

    특징 : skeletal abnormalities, sparse and light colored hair,

           immunologic defect of T Iymphocytes.

           disseminated varicella infection and death from pneumonia.

           Macrocytic anemia with reticulocytopenia

           lymphopenic

           neutropenia(25%)

     gene mapping : chromosome 9

     Bone marrow transplantation

Cardioskeletal Myopathy (Ibarth Syndrome)

     특징 : dilated cardiomyopathy

           growth retardation

           neutropenia

           skeletal myopathy

     임상 경과 : early infancy동안 CHF발생

                recurrent infections associated with neutropenia

                growth retardation

                Weakness of skeletal muscles (sparing of extraocular and bulbar muscles)         EM : endomyocardium, skeletal muscle

           bone marrow granulocyte precursors,

           liver, kidneys

           등에서 mitochrondrial abnormalities 보임

     Neutropenia

     bone marrow : myelocyte stage에서 arrest

     gene mapping : Xq2.8.

Dyskeratosls congenlta

     congenital X-linked multisystem disorder

     임상 특징 : skin pigmentation, dystrophic nails, leukoplakia

                 neutropenia, bone marrow failure, life-threatening infection

     Tx : GM-CSF, BMT

Onychotrichodysplasia And Neutropenia

     AR

     특징 : hypoplasia of the fingernail, sparse hair, neutropenia.

           moderate degrees of mental retardation.

           recurrent infections.

           skin/mucous membranes. clinical infection

Neutropenia Related To Cancer And Acquired Immunodeflclency Syndrome (AIDS)

      특징 : Neutropenia

             primary malignancy (leukemia, Iymphoma, metastatic tumor,neuroblastoma)

              확진 : BM biopsy

      검사소견 :  PB : erythroblastic response with nucleated erythrocytes

                       tear drop red cells

                       young myelocytes/metamelocytes.

Chapter 125. Adhesion Deficiency Disorders

; Characteristics

    - recurrent or progressive skin, mucous mem brane, and subcutaneous infections

    - diminished pus formation

    - poor wound healing

    - *delayed separation of the umbilical cord

Etiology

# Type I LAD

    ; *defective expression of three α-β heterodimeric glycoprotein molecules

           - *MAC-1, LFA-1, p150,95

# Type II LAD 

    ; endothelial cell selectin 대한 ligand 작용하는 carbohydrate structure (neutrophil cell surface 존재하는 sialyl-Lewis X) genetic defect

Epidemiology

    North America, Europe, North Africa, Iran, and Japan

    AR

Pathogenesis

    leukocyte surface위의 adhesive glycoproteins,carbohydrate expression 감소로 여러가지      symptom 나타난다.

Clinical Manifestations

    ; *delayed separation or infection of umbilical cord in neonatal periods

           - *earlist sign

    ; Wound healing impaired

 Skin and subcutaneous infections

 Small (<1 cm) indolent or necrotic abscesses or cellulitis

 Perirectal abscesses/lesions on the extremities large ulcers with plaque formation gangrenous bullous areas

      Infections of the ears, nose, and mouth

         Recurrent otitis media, pharyngitis, and ulcerative stomatitis

         Severe gingivitis

         alveolar bone loss/severe periodontitis.

      Systemic infection with life-threatening sepsis

      Recurrent bronchopneumonia/aseptic meningitis

      예후 : severely affected patients 75%정도에서 5세전에 사망

            moderate phenotype  12 - 32세에 50% 사망

Laboratory Findings And Diagnosis

    ; *persistent neutrophilia

           - 15,000 - 160,000/uL, 50-90% PMNs

           - *hallmark

      Mild to moderale anemia

      Inflammatory skin windows : 24hr study에서 inflammatory cell accumulation 일어나                                     않는다.

      abnormal chemotaxis, adherence to endothelial monolayers,

      abnormal granulocyte aggregation

      normal platelet aggregation/adherence

      tetanus, influenza 같은 polypeptide Ag 대한 specific Ab 생산의 deficiency

      cf) pneumococcus,H.influenzae 같은 polysaccharide Ag 대한 Ab형성은 not impaired

      Cultures gram-positive (Staphylococcus aureus)

                  gram-negative (Escherichia coli, Pseudomonas species, Klebsiella)

                  fungi (Candida, Aspergillus)

Differential Diagnosis

Table 125-1

     chronic/recurrent pyogenic and fungal infections 생각해야 질환

        phagocyte-antibody immunity질환

        Severe forms of agranulocytosis(congenital neutropenia)

        deficiency of phagocyte

        NADPH oxidase (chronic granulomatous disease)

        neutrophi granule defects(specific, azurophilic, and Chediak-Higashi syn drome [CHS]),          agammaglobulinemia/hypo and dysgammaglobulinemias

        Job syndrome

     chemotactic defects 있는 neutrophil disorders :

        skin, soft tissue, mouth and mucous membranc infections

     neutrophil bactericidal/fungicidal deficiencies :

        subcutaneous sites, Iymph nodes, lung, liver, abdominal viscera, bone abscess 형성

        (Table 125-1).

     LAD neutrophilia 감별해야 질환

        (1) reactive leukemoid reaction

        (2) chronic myeloproliferative disorders (CML)

Treatment

     Aggressive use of antibiotics

     puncture site surgical wounds 적절한 local treatment/debridement

     granulocyte transfusions : long-term management에는 효과가 없다.

     BMT

Genetic Counseling

     Prenatal diagnosis of LAD : gestation 20wks blood sampling

Chapter 126. Neutrophil Granule Defects

# Two distinct sets of granules

    1. peroxidase-positive azurphils

    2. peroxidase-negative specific granules

Table 126-1

Etiology

*Three Phenotype Genetic Disorders

    1) myeloperoxidase (MPO) deficiency of azurophilic granule

  2) specific granule deficiency (SGD)

  3) Chediak-Higashi syndrome (CHS)

Pathogenesis.

      MPO-deficiency 있는 환아에서는 대개 무증상이다.

      neutrophil-specific granule deficiency : Defensins(potent bactericidal protein in                                                            azurophilic granules) 결핍

azurophilic granule constituents, for exam ple, cathepsin G and elastase, are normal.

      CHS : cathepsin G / elastase 결핍

Clinical Manifestation

Hereditary MPO deficiency

   no obvious clinical sequelae

   심한 candidiasis 경험하는 환아는 대부분 DM이나 comprimised host defense 가진다.

Congenital Specific Granule Deficiency.

    recurrent infections of the skin and lung

    large indolent skin ulcers

    repeated episodes of bronchopneumonia/lung abscesses.

    lymphadenitis, otitis, and mastoiditis

    Staphylococcus aureus/gram-negative microbes/Candida albicans

Laboratory Findings And Diagnosis.

    SGD : bilobed nuclei in more than 80% of the neutrophils

           specific granule부족으로 인한 cytoplasmic granularity 감소

           absence of alkaline phosphatase/presence of azurophilic granule peroxidase.                    lactoferrin is abscent

    myeoperoxidase deticiency : peroxidase activity 감소

    CHS : Wright stain에서 giant granule

Treatment

    MPO deficiency 환자는 특별한 치료가 필요없다

    SGD : functional phagocytic defect 치료와 동일

           intravenous antibiotics/drainage of abscesses

Chapter 127. Chediak-Hagashi Syndrome

; rare AR

Etiology

; unknown

; *abnormal membrane fluidity --> uncontrolled granule fusion

    - *inability of neutrophil to move

    - *inability to concentrate serotonin into platelet

    - *inability to concentrate hydrolytic enzymes into lysosome

Pathophysiology

# *Partial Albinism (Hair And Skin)

    ; giant melanosome in melanocytes

           --> failure to dispense pigment

# *Central And Peripheral Neuropathies

    ; giant granules in schwann cells

# Neutropenia

    ; giant granules in cytoplasm of leukocytes

           --> die within BM

# Infection Susceptibility In Chediak-Higashi Syndrome :

    ; skin, respiratory tract, and mucous membranes

    ; by neutropenia, defective chemotaxis, degranulation, bacterial activity in remaining neutrophil

# poor function in Ab dependent-cell-mediated cytolysis of tumor cells

    ; giant granules in lymphocytes

# comprimized NK cells

# *BT prolongation in spite of normal PLT count

    ; impaired platelet aggregation

    ; asso. with *deficiency of granules containing adenosine diphosphate, serotonin

# Accelerated Phase(Peculiar Propensity For Lymphohistiocytic Proliferation)

# Viral-Mediated Hemophagocytic Syndrome

Clinical Manifestations

; onset of symptoms in early childhood.

; *photophobia, rotary nystagmus, red reflex, partial albinism, recurrent gingivitis, and periodontitis.

; hair color

  - from blond to dark brown

; *Staphylococcus aureus, β-hemolytic streptococci

    - *common

; prolonged bleeding times

    - normal platelet counts

    - due to platelet aggregation defect

; motor and sensory neurologic defects

    - ataxia, muscular weakness, decreased molor neuror conduction

    - abnormal EEG, seizures

; *Death

    - any age owing to acceleratated phase

    - 85% of patient

; precipitating event inititing accelerated phase

  - Epstein-Barr virus, other lymphotrophic viruses infection

    - lymphoma-like picture

           /widespread enlargement of lymphnode, hepatosplenomegaly

Laboratory Findings And Diagnosis

; abnormal chemotaxis, reduced killing

    - due to delayed fusion of the abnormal granules

    - *reduced iC3b receptor expression

; increased release of superoxide (02) similar to myeloperoxidase-deficient neutrophils

; prolonged BT

    - due to platelet aggregation defects owing to a lack of a storage pool of ADP

; poor function in tests of antibody-depelldellt tumor cell Iysis and natural killer cell activity

; Confirm Dx

    - large lysosomal granules in leukocytes and giant melanosomes in melanocytes

Treatment

   stable phase : proper management of infections

   Ascorbic acid : clinical status,phagocytic function improve시킨다.

   antibiotics : acute infections 효과가 있지만 예방적 사용은 효과가 없다.

   Corticosteroids, vincristine, and cyclophosphamide : control of the accelerated phase

   acyclovir 500 mg/m2 3/day + prednisone 2 mg/kg/24hr

       : fever, pancytopenia, coagulopathy 일시적으로 경감시킬 있다.

   Bone marrow transplantation

CHAPTER 128. Disorders of Cell Motility and Chemotaxis

Table 128-1

* chemotactic disorder 시의 infection organism

   a. staphylococcous aureus ; the most common

   b. 그외 gram-positive, gram-negative, fugi

 * infection site

   skin, gingiva, mucosa, regional l.n. respiratory infection

   but sepsis uncommon

CHAPTER 129. Chronic Granulomaous Disease

; *common inherited disorder of phagocytic function

Etiology

    ; respiratory burst 장애

   -> NADPH oxidase complex ( Fig.129-1)

       a. 2 cytochrome b.membrane subunit

       b. FAD

       c. soluble cofator

       d. protein ras-2

    -> respiratory burst

        : oxygen ---> superoxide anion

          --> hydrogen peroxide, hydrogen radical

          --> microbial killing, tissue damage

# Inheritance

   Table 129-1

# CGD gene

   X chromosome proximal to muscular dystrophy gene

   and distal to ornithine transcarbamylase gene on Xq21

Pathology

 lung, skin, lymph node, liver, spleen, bone granuloma or abscess

  * granuloma ; phagocytes, giant cell, pigmented lipid-laden histiocyte 구성

Clinical Manifestation

    ; *chronic recurrent pyogenic infection during first 2yr

           - milder form : teeage or adulthood

    ; *lymphadenopathy - almost all cases

    ; recurrent enlargement of cervical LN

    ; *later hepatomegaly and splenomegaly

    ; hepatic or perihepatic abscesses or granuloma

    ; *chronic or recurrent pneumonia with unusual microbes : e.g. Serratia marcescens

    ; *subcutaneous abscesses, recurrent skin furunculosis, eczematoid dermatitis, impetigo

    ; granuloma formation

           --> obstruction of the esophageal outlet, pyloris, or urethra

    ; granulomatous colitis ; persistent diarrhea

    ; *perianal abscesses or rectal fistulous tracts

    ; osteomyelitis

         - small bones of the hand and feet

    ; mucous mcmbrane infection ; less common

Laboratory Findings And Diagnosis

 * CGD ; normal chemotaxis, phagocytosis, degranulation

          do not generate superoxide anion--> do not kill catalase-positive microbes

# common infectious organism

  ; Staphylococcus aureus

  ; Klebsiella, Aerobacter, Escherichia coli, Shigella, Salmonella, Pseudomonas

    ; Serratia marcescens

    ; Candida albicans, Aspergillus and other fungi

# Not Common Organism

    ; *catalase-negative peroxide-producing organisms

           - *Streptococcus, H. influenzae

# NBT test (nitroblue tetrazolium test)

    ; screening test for adequate superoxide anion during phagocytic activation

# ferricytochrome reduction method

    ; quantitation of rate of superoxide generation

# CBC

    ; neutrophilic leukocytosis during infections

  ; anemia of chronic infection

# ESR ; elevated

# immunoglobulins ; normal to increased

# abnormal chest X-ray ; 90% of patients

# liver-spleen scans and bone scans ; presence of liver abscesses and osteomyelitis,

# ultrasound, endoscopy, contrast studies

    ; *gastric antral obstructions

# cystourethrograms ; granulomatous involvement of the bladder

Differential Diagnosis

Treatment

 1. long term trimethoprim-sulfamethoxasole (TMP-SMZ) prophylaxis

 2. acute episodes of infection

   a. appropriate intravenous antibiotics

   b. short-term(average 1 wk) granulocyte transfusion

      ; especially gram-negative bacteria infection

 3. gastric outlet obstruction and granulomatous cystitis

    ; antimicrobial therapy and prednisone

# *γ-interferon

  ; increase generation superoxide anion

    ; 0.05 mg/m2 3 times per wk

 5. transfusion 반드시 kell antigen 유무 조사해야함.

    CGD 환아가 McLeod phenotype 혈액형 (lack Kell associated red blood cell Ag)

       , 심한 수혈 반응을 일을킬 수있기때문

 6. bone marrow transplantation ; limited success

 7. somatic gene therapy

Genetic Counseling

 1. cord blood, placental blood NBT slide test

 2. linkage analysis and restriction fragment length polymorphism of maternal DNA

 

Chapter 130. Disorder Of Neutrophil Oxidative Metabolism And Other Functions

Severe Glucose-6-Phosphate Dehydrogenase Deficiency(G-6-PD)

   a. caucasian

   b. neutrophils ; less than 5% G-6 PD activity

   c. CGD 임상증상 유사

Glutathione Reductase Deficiency

    a. hemolytic anemia

Glutathione Synthetase Deficiency

   a. glutathione ; potent antioxidant

   b. hemolytic anemia, recurrent otitis

Hyperimmunoglobulin E (Job Syndrome)

   a. high serum IgE

     recurrent serious infections of the skin and sinopulmonary tract

     chronic eczema

   b. onset ; first 8 wk of life

   c. deep-seated abscesses in subcutaneous tissue

     Pneumonia, osteomyelitis, arthritis, visceral abscesses

     allergic rhinitis, coarse facies, keratoconjunctivitis, asthma, stunted growth

   d. most common organisms ; S. aureus and Candida albicans

      but H. influenzae, S. pneumoniae, enteric gram-negative bacteria,

          and herpesvirus also common

   f. Lab/f

     : eosinophilia,

      marked elevation of serum IgE

   g. treatment

     : Intravenous gamma globulin prophylaxis

      abscesses drained surgically

      intravenous antibiotics or antifungal or antiviral agents

 Newborn Dysfunction Of Neutrophils

  * newborn neutrophil dysfunction 시사하는 소견  

    a. high incidence of sepsis and meningitis

      -> a/w severe neutropenia and depletion of marrow

    b. paucity of neutrophils in the alveoli of newborns

       -> dying of pneumonia

    c. common occurrence of skin infections with S. aureus and C. albicans

  * newborn neutrophil dysfuntion

    a. decreased leukocyte migration

    b. diminished chemotactic defect

Chapter 131. Inherited Leukocyte Abnormalities

  * neutrophils

    90% 2-4 segments

    5% unsegmented (bands)

    fewer than 5% five or more segments

Hereditary Hypersegmentation Of Neutrophils And Hereditar Giantneutrophil Leukocyte

    1. neutrophil hypersegmentation

     * autosomal dominant

    2. giant neutrophil

     * autosomal dominant

Hereditary Hyposegmentation (Pelger-Huet Anomaly)

    1. 특징

       failure in normal lobe development of granulocytic cells

       -->  mature neutrophil ; one or two lobes/nucleus and take on a round

                               dumbbell or peanut shape

     2. autosomal dominant

Alder-Reilly Anomaly

     1. autosomal recessive

     2. neutrophil granulations ; larger and stain more prominently

                               granules - lavender or blue

May-Hegglin Anomaly

      1. neutrophils and platelets 이상

      2. neutrophil ; irregular blue cytoplasmic inclusions similar to Dohle bodies

                    thrombocytopenia, bizarre giant platelets.

Chapter 132. Bone Marrow Transplantation

# BMT

  a. autologous BMT

  b. allogenic BMT

  c. 97 other source of marrow stem cell transplatation

     ; cord blood, peripheral stem cell, fetal liver

132.1 Clinical Indications

Acquired Diseases

Aplastic Anemia

# Indication

  ; *severe aplastic anemia who had HLA-matched family donor

         - *platelet < 20000, ANC < 500, reticulocyte < 1%

# 2 yr survival rate - 69%

   * higher incidence of graft rejection

     --> 예방 ; ATG + cyclophosphamide

   * disparate or matched unrelated donor 경우

     -->  more immunosuppressive therapy + radiation and/or chemotherapy 필요

     --> 이로인해 secondary cancer 빈도 증가함 (3.8-22%)

Acute Myelogenous Leukemia

   * 일반적인 BMT 시기

      first remission

   * disease free survival range for matched sibling marrow in first remission

     55%-83%

   * indication

     a. AML not enter remission

        ; HLA-identical family donor, midmatched family donor,

          matched unrelated donor 이용할수있다.

     b. AML who in first remission

        ; HLA-identical fimily dornor

     c. relapse or in second remission

        ; HLA-matched family dornor, unrelated donor, previously stored

          autologous marrow

     d. multiple relapse or resistant disease

        ; 2-3 antigen mismatched dornor transplantation 고려할 수있다.

     e. 예외

        AML M3 or promyelocytic leukemia

         all-trans-retinoic acid and consolidation CTx 반응잘하기 때문

Acute Lymphoblastic Leukemia

# high-risk for relapse ; 반드시 BMT 고려

Table 132-1

*  autologous BMT for  high risk ALL

     -> disease free survival ; 15-65%

         relapse rate : 30-70%

  *  HLA-matched sibling marrow transplants for high-risk ALL

     in first complete remission

      ;  disease-free survivals of 70-100%

         relapse rates of 0-10%

     no high risk patient

       ; relapse HLA-identical family donor transplantation 실시

        => ALL relapse HLA-identical sibling marrow transplantation 경우

            disease free survival 40%, chemotherapy 경우 disease free survival 10%

        => ALL relapse : allogeneic BMT - disease free survival 33-61%

                         autografts - 21-31%

  * infant leukemia

     a. first 12 mo of life 발생

     b. very poor prognosis

        ; conventional chemotherapy 5yr survival rate 20-30%

     c. cytogenetic abnormality

        ; chromosome 11q23 - 75%

          other - 1p32, 4q21, 19pl3 in ALL

                  1q21, 2p21, 6q27, 9p22, 10pl, 17q25, 19pl3 in AML

         most common translocation - t(4,11)(q21;q23)

     d. infant leukemia with normal 11q23

         ; good response to conventional chemotherapy

           disease free survival 80% at median follow-up of 46 mo

        infant leukemia with  rearranged 11q23

         ; very poor response with a 15% disease-free survival

     e. acute leukemia within the first 1-2 yr

        ; intense induction chemother followed by bone marrow transplantation

Myelodysplastic And Myeloproliferative Disorders

   1. MDS ; AML protocol 따라 치료

      * transplant outcome ; AML 유사

      * BMT 진단 초기에고려해야함

      * conventional chemotherapy , other nontransplant forms of treatment

         -> not significant impact of the natural progression

   2.myeloproliferative disord

      * 종류

         CML

         essential thrombocythemia (ET)

         polycythemia vera (PV)

         agnogenic myeloid metaplasia

         juvenile chronic myelogenous leukemia (JCML)

     * CML ; BMT choice

               HLA-identical sibling transplantation

                  ; 80% long-term disease free survival

               matched unrelated donor ; 45-50%

               진단 1년이내에 BMT 실시되어야함

      * juvenile chronic myelogenous leukemia

         ; clonal proliferation of immature myeloid precursor

          a/w neurofibromatosis type I, monosomy 7

          rapidly progression

          resistance to conventional CTx

          BMT is curative

          some case : 13-cis-retinoic acid 일시적인 완해 유도됨

                      --> 적당한 marrow donor 시간 확보 가능

Lymphomas

    * BMT indication for NHL and HD

       relapse 직후에 실시될 수있음

       little bulky disease 일수록 transplantation tolerabel

    * pretransplant salvage chemotherapy

       -->  benefit to reduce  tumor burden

    * HLA-idenlical sibling allogeneic transplant

       --> advantage of GVL effect

       --> reduced  relapse rate

     * peripheral blood stem cellr transplantation 

       --> autologous transplantation 보다 우수

Neuroblastoma

    ; *common extracranial solid tumor of children

     * 10 yr survival for stage I-II ; 80-90%

                      for slage III ; 63%

                      for disseminated disease (stage IV) ; 21%

 

     * disease-free (3 yr) survival rates

        for patients transplanted after progression ; 0-32%

        for tranplant before progression ; 25-56%

     * 현재까지 CTx BMT 대한 randomized trial 없다

Brain Tumors

    * most common solid tumors ; 20% of childhood malignancies

    * glioblastoma multiforme, anaplastic astrocytoma 등에 intensive Ctx

      BMT 대한 연구 진행중

Solid Tumors

    * CTx 반응 잘하나 very poor prognosis

      --> intension CTx BMT 고려할 수있는 경우

           a. high risk by histology

             (alveolar rhabdomyosarcoma, anaplastic Wilms'tumor)

           b. location

             (pelvis,trunk,or proximal extemity Ewing sarcoma,

             axial skeletal osteogenic sarcoma)

           c. widespread metastatic presentation  presentation

Genetic Diseases

Immunodeficiency Disorders

    1) SCID 

           ; HLA-identical unaffected sibling donor : disease-free survival >90%

             T-depleted mistached family donor : 69-76%

  2) Wiskott-Aldrich syndrome

    3) Digerorge syndrome

  4) Kostmann neutroepnia

  5) leukocyte adherence deficiency

    6) CGD

    7) Chediak-Higashi syndrome

    8) familial erythrophagocytic lymphohistiosis

    9) Duncan syndrome

    10) neutrophil actin deficien

  2-9. : matched sibling donor 경우 survival rate  68%

        mismatched donor 경우 survival rate  35%

  * CGD gamma globulin Tx   Kostmann neutropenia G-CSF 부터

    먼저 시도해보고, 반응이 없는 경우 BMT 고려

Fanconi Anemia

  * AR

  * aplastic anemia

    congenital anomalies, chromosome fragility,

    pancytopenia, myelodysplasia, AML

  * 진단 : mitomycin-C or diepoxybutane 등과 같은 DNA cross-linking agent                      chromosome fragility 증가되는 것으로 진단

 

  * transplant-related toxicities ; severe oral mucositis, hemorrhagic cystitis,

                                erythroderma, and GVHD

     --> conventional BMT conditioning regimen dose reduction 필요함

  * conditioning regimens + matched sibling transplants -> best outcome

    mismatched and unrelated donor transplants-> may be successful

Storage Diseases

Thalassemia

   * 3 risk factor influence outcome of BMT

      1. hepatomegaly

      2. portla fibrosis

      3.history of inconsistent iron chelation prior to transplant

Sickle Cell Disease

Other Congenital Anemias

# diamond-Blackfan syndrome or congenital pure red cell aplasia

     ; normochromic-macrocytic anemia with a normocellular marrow

       serum erythropoietin - elevated

       --> corticosteroids Tx 실패한 경우 BMT with HLA-identical sibling

            donor 실시

# congenital sideroblastic anemia

     ; ineffective erythropoiesis, hypochromic anemia, and elevated serum iron

      progresses to transfusion dependency--> total body iron overload

      --> secondary hemosiderosis --> hepatic and cardiac failure

132.2 Matching And Rejection

# MHC

  ; short arm of chromosome 6

        - 4,000 kilobases of DNA

       - genes for  cell surface glycoproteins termed  human leukocyte antigens (HLA)

# primary determinants for BMT

  ; *HLA-A, HLA-B(class I), HLA-DRB(class II)

           - class I gene ; determined by serotyping and

                          isoelectric focusing gel electrophoresis

           - class 11 gene ; identified by DNA typing

# Graft failure and graft rejection

Table 132-2

  1. HLA disparity ; most important variable

     # risk of graft failure

       HLA-identical sibling BMT  1-2%

       haploidentical BMT  3-15%

  2. alloimmunization ; 특히 aplastic amnemia 환자에서 관찰됨.

  3. conditioning regimen

      aplastic anemia - matched sibling donor : cyclophosphamide -->24% rejection rate

                            Cyclophosphamide + ATG --> 3% rejection rate

  4. elimination of donor T-cell

132.3 Graft-Versus-Host Disease (GVHD)

# donor lymphocytes in immunologically compromised host

         --> donor T-cell activation against host MHC anligens

     --> GVHD

     --> cell death mediated by

                - *cell-mediated cytotoxic activity

                - *complex cascade of lymphokines released by activated lymphocytes

# 분류

  1. acute form ; BMT 100 이내에 발생

  2. chronic form ; BMT 100 이후에 발생

# graft-versus-leukemia (GVL) effect

Acute GVHD

# ♥특징 ; erythroderma, cholestatic hepatitis, enteritis

Table 132-3

; typically about day 19 (median)

; *starts with a pruritic macular/papular rash

    - ears, palms, and soles

    --> progress to trunk

    --> confluent erythroderma with bullae formation and exfoliation

    - DDx) toxicity of immunosuppressive regimen, drug rash, viral or other infectious exanthems

; hepatic manifestations

  - cholestatic jaundice, elevated LFT

  - DDx) hepatitis, veno-occlusive disease, drug effect

; intestinal symptoms

    - abdominal pain, watery diarrhea with blood

# Factors Related To aGVHD

    ; histocompatibility differences between the donor and patient

  ; sex mismatching

  ; donor parity

  ; age

  ; active or relapsed malignancy at the time of BMT

  ; increasing doses of radiation

# prevention and treatment

  ; immunosuppressive agents

Chronic GVHD

   1. onset ; usually after day 100, but as early as day 60-70

   2. Sx ; resembles a multisystem autoimmune process

   3. recurrent infections (sepsis, sinusitis, pneumonia)

        <- encapsulated bacteria , fungal,  viral organisms

      transplant-related morbidity and mortality 관련됨

   4 risks for chronic GVHD

      a. age

      b. prior acute GVHD

      c. buffy coat transfusions

      d. parity of a female donor

   5. therapy

     a. additional immunosuppression ; prednisone and cyclosporine

132.4 Principles Of Immmunosuppression

*  BMT 경우 6-12 개월정도의 immunosuppression therapy 실시함

 PREPARATIVE REGIMEN

   1. cyclophosphamide ; most widly utilized immunossuppressant in BMT

   2. TBI ; excellent antineoplastic activity  and immunosuppressive quality

   3. 그외 ; combination of CPM and TBI, busulfan, etoposide,

       melphalan, carmustine(BCNU) ara-C, thiotepa, ifosfamide, carboplatin

 T-CELL DEPLETION

  * GVHD prevention 위한 preparation

    -> T-cell depletion by

        1. using monoclonal antibody

        2. physical separation technic (soy lectin agglutination)

  * T-cell depletion --> dramatic reduction of GVHD

                    --> 문제점 ; increased graft rejection and relapse

                         donor T-cell GVL effect 통해 residual host T-cell                               거에 중요한 역할을 하기때문

 METHOTREXATE

   * MTX given on days 1, 3, 6, and 11

      --> effective prevention of GVHD

   * side-effect

     mucositis

     renal impairment, fluid collection (pleural effusion) -> leukovorin rescue

 CYCLOSPORINE

   * action ; potent and specific immunosuppressive agent

      a. selectively inhibits translation of IL-2 mRNA by helper T cells

      b. may inhibit IL-l, lL-3, gamma-interferon synthesis

      c. higher dose ; inhibits IL-2 receptor formation

      cf) no myelosuppressive or anti-inflammatory effects

   * 대사 ; hepatic cytochrome P-450 enzyme system

        drug interactions

           a. cyclosporine levels increased

              : ketoconazole, erythromycin, methylprednisolone,

               warfarin, verapamil, ethanol, imipenem-cilastatin,

               metaclopramide, fluconazole

           b. cyclosporine levels decreased

              : phenytoin, phenobarbital, carbamazepine,

                valproate, nafcillin, and rifampin

   * toxic effect

    a. neurotoxicity ; tremors, paresthesias, headache, confusion, somnolence,

                     seizures, coma

    b. hyertrichosis, gingival hyperplasia

    c. anorexia, nausea, vomiting

    d. hepatotoxicity ; cholestasis, cholelithiasis, hemorrhagic necrosis

 

    e. endocrinopathies ; ketosis, hyperprolactinemia, hypertestosteronemia, gynecomastia,                       impaired spermatogenesis

    f. metabolic disorders ; hypomagnesemia, hyperuricemia, hyperglycemia,

                     hyperkalemia, hypocholesterolemia

    g. vascular derangements ; hypertension, increased sympathetic nervous system                           activation, vasculitic-hemolytic uremic syndrome-like illness,

                     atherogenesis

    h. nephrotoxicity ;  Renal toxicity is a significant limitation of cyclosporine use

                      increased creatinine, oliguria, hypertension,

                      fluid retention, vasoconstriction

                      renal tubular damage, hemolytic-uremic syndrome-like lesions

                      chronic nephrotoxicity (interstitial fibrosis, tubular atrophy)

                        --> reduction of the cyclosporine dose or

                             change to other immunosuppressant drugs

        * obesity  ; dose ideal body weight 기초하여

 FK506

   * experimental macrolide immunosuppressive drug

   * cyclosporine 유사

 CORTICOSTEROIDS

   * 다른 immunosuppressive agents 함께 사용

   * action

    1. interfere  T-lymphocyte proliferation by directly blocking activation of the genes         for IL-1 and IL-6

    2. block IL-2 action indirectly <- because IL-2 secretion depends on IL-1, IL-6

    3. antiinflammatory response

       ; lipocortin(= inhibitor of phosphlipaseA2) 형성

         -> reduce synthesis of inflammatory prostaglandins

    4. lyse small populations of activated lympllocytes

   * side effect

     1. serious opportunistic infections

     2. long-term complication

        a. growth failure

        b. cushingoid appearance

        c. hypertension

        d. cataracts

        e. gastrointestinal bleeding, pancreatitis

        f. psychosis

        g. hyperglycemia

        h. osteoporosis, aseptic necrosis of the femoral head

        i. suppression of pituitary adrenal axis

ANTITHYMOCYTE GLOBULIN (ATG)

  * heterologous antibodies againstl human thymocyte

  * resistant GVHD 치료에 사용

  * Toxicity

     fever, hypotension, rash-urticaria, tachycardia, dyspnea, chills, myalgias,

     serum sickness, potential anaphy laxis

  * skin teste 사용해야함

  * Tx of side effect

    a. diphenhydramine

    b. Tylenol (acetaminophen)

    c. hydrocortisone

 OKT3

  * murine monoclonal antibody against  T3 (CD3) surface glycoprotein on T cells

  * newer antibody BC3 ; more effective for treating GVHD and  fewer side effect

 AZATHIOPRINE

  * imidazole derivative of 6-mercaptopurine

  * action ; blocks DNA synthesis by inhibiting purine synthesis

           --> inhibit T-cell activation

               and decrease number of migrating mononuclear cells

  * toxic effect

     myelosuppression (neutropenia)

     hepatic venoocclusive disease, hepatitis, pancreatitis

     secondary malignancy

 THALIDOMIDE

  * high risk or refractory cGVHD 사용 가능

132.5 Late Effects Of Bone Marrow Transplantation

NEUROLOGIC FUNCTION

  1. neurologic sequelae contributing factor

    a. infections

    b. metalolic encephalopathy (resulting from hepatic dysfunction)

    c.drug/radiation therapy

 2. cyclosporine

    headache (most responsive to propranolol), tremor, confusion, visual disturbance, seizures,      frank encephalopathy

   --> drug d.c 하면 좋아짐

 3. Leukoencephalopa

  a. 임상증상 ; lethargy, slurred speech, ataxia, scizures, confusion, dysphagia,

               decerebrate posturing, coma or death

  b. transplant 전에 extensive intrathecal chemotherapy or cranial radiation

    실시한 경우에

  c. incidence  ; 7%

 

 

 SECONDARY MALIGNANCIES

   a. overall risk ; 6.7 times

   b. greatest risk ; within 1st yr

   c. half of secondary tumors ; non-Hodgkin Iymphomas,

              and two thirds of these are Epstein-Barr virus (EBV) positive

   d. other malignancies ;  leukemia, brain tumors, melanomas,  carcinomas of the skin,                 liver, lung, and thyroid

   f. risk factors

      use of ATG

      T depletion of donor marrow

      TBI in the preparative regimen

   g. EBV-related B-cell Iymphomas 치료

       infusions of donor T cells

 GROWTH AND DEVELOPMENT

  1. etiology  

    a. TBI ; growth depression and growth hormone deficiency

    b. radiation-containing regimens ; no pubertal growth spurt

    c. cGVHD and treatment with corticosteroid ; growth impairment

  2. Tx

    recombinant growth hormone

    --> but little or no growth spurt

  3. F/U

     annual Tanner scores and endocrine evaluation (GH,FSH,LH )

 THYROID FUNCTION

  cf) chemotherapy-only ; little effect on thyroid function

   1. TBI  with/without radiation involving thyroid gland

     -> compensated or overt hypothyroidism

   2. Tx ; thyroxine

   3. serial F/U of TFT 실시해야함

 

 IMMUNE RECONSTITUTION

   1. donor marrow infusion normal immune function 돌아오는데 수개월에서

     수년 걸림

     a. engrafting B cells mitogenic stimulation 대한 반응의 정상화 ; 2-3 mo

     b. IgM levels 정상화 ; 4-6 mo

     c. IgG levels ; 7-9 mo

     d. IgA ; 2 yr

     e. CD8 T cells 정상화 ; 4 mo

       CD4 T cells  ; 6-9 mo

        inverted CD4/CD8 ratio for  first 6-9 mo post-transplant

  2. factors that prolong interval

     a. T depletion of  marrow

     b. post-transplant immunosuppression

     c. chronic GVHD

 

  3. vaccination without cGVHD

    a. DT ; given 3-6 mo posttransplant

    b. inactivated (Salk) polio  ; 6-12 mo

    c. MMR) ;  1-2 yr

  4.  chronic GVHD 경우

      re-immunization 연기

     cGVHD 에서 호전될때까지 IgG supplementation

132.5 Late Effects of Bo11e Marrow

 

T~ansplantation

 

As more children are undergoing BMT for a widening spec trum of indications and an increasing number of these children become long-term survivors, late effects of the transplant pro cess have a lasting impact on the healtll and well-being of the individual. The pediatrician should be aware of possible de layed complications. including effects on growth and develop ment, neuroendocrine dysfunctioll, fertility~ second tunlors, chronic GVHD, cataracts, leukoencephalopatlly, and immune dysfunction .

 NEUROLOGIC FUNCTION. Infections. metalolic encephalopathy (resulting from hepatic dysfunction), and drug/radiation thcr apy may all contril ute to neurologic sequelae. Cyclosporine may produce headache (most responsive to propranolol), tremor, confusion, visual disturbance, seizures, and frank en cephalopathy. Most of these effects are reversible with discon tinuation of the drug. The incidellce of cataracts is roughly 80% in palients receiving single-dose TBI, 20-50% with frac tionated TBI, and 20% after chelllotllerapy-ollly regimens. A dry eye syndrome is often related to chronic GVHD and is treated with artificial tears and lul ricants. Leukoencephalopa thy is a clinical syndrome characterized by lethargy, slurred speech, ataxia, scizures, confusioll, dysphagia, and decerebrate posturing. It may present with minimal symptoms or can result in coma or death in its most severe form. Magnetic resonance imaging (MRI) and computed tomography (CT) scans reveal multifocal areas of white matter degeneration with necrosis. Leukoencephalopathy is almost exclusively observed in pa tients who have received extensive intrathecal chemotherapy or cranial radiation prior to transplant, with an overall inci dence of 7% in patients at risk.

 SECONDARY MALIGNANCIES. The overall risk of developing a sec ondary form of cancer is about 6.7 times that of the general population, with the greatest risk being within the I st yr. Roughly half of the secondary tumors are non-Hodgkin Iymphomas, and two thirds of these are Epstein-Barr virus (EBV) positive. Other malignancies observed include leukemia, brain tumors, melanomas, and a variety of carcinomas of the skin, liver, lung, and thyroid. Risk factors that are associated with second malignancies included the use of ATG, T depletion of the donor marrow, and TBI in the preparative regimen. EBV-related B-cell Iymphomas, which are aggressive and resis tant to most therapeutic interventions, have been successfully treated with infusions of donor T cells.

 GROWTH AND DEVELOPMENT. Long-term follow-up studies of pa tients who have received TBI-containing regimens reveal sig nificant growth depression and growth hormone deficiency. After 5 yr, TBI-treated patients were more than two standard deviations below the mean height for age and dropped to three to four standard deviations below the mean by 8 yr post transplant. This decrease in growth velocity is similar for boys and girls, and does not vary with the use of cranial radiation or different regimens of radiation (single vs. fractionated). Children receiving radiation-containing regimens also have no pubertal growth spurt. The pubertal growth spurt depends on the presence of adequate growth hormone and gonadal hormones, both of which may be low post-transplant. A major determinant of final height is the amount of growth done prior to puberty. Children receiving BMT before the age of 11 have a final height below the 1 0th percentile, while those

 transplanted after age 11 attain a height close to the average. Chronic GVHD and its treatment with corticosteroids may also contribute to growth impairment post-transplant. In an at tempt to avoid'TBI-related growth effects in children, chemo therapy-only regimens have been used such as busulfan/cyclo phosphamide. Early results of growth studies suggest that busulfan also interferes with growth. Preparative regimens us ing cyclophosphamide only for aplastic anemia have little ef fect on normal growth and development, implicating the role of busulfan in affecting growth and development in busulfan/ cyclophosphamide regimens. The use of radiation to the long bones and vertebral bodies for neuroblastoma also contributes to decreased growth velocity. Therapy with recombinant growth hormone after age 12 yr prevents a further decrease in growth velocity, but little or no catch-up growth is achieved. Annual growth hormone evaluation is essential in all children post-transplant. Current studies are aimed at identifying chil dren with growth hormone deficiencies at an earlier age and supplementing them with growth hormone to achieve a nor mal pubertal growth spurt. Gonadal hormones are essential for normal pubertal growth as well as secondary sexual charac teristic development. About three quarters of patients receiving TBI-containing regimens show delayed secondary sexual char acteristic development, resulting from primary ovarian or tes ticular failure. Laboratory evaluation reveals elevated follicle stimulating hormone (FSH) and luteinizing hormone (LH) with depressed estradiol and testosterone. These patients re quire careful follow-up with annual Tanner scores and endo crine evaluation. Supplementation of gonadal hormones is useful for primary gonadal failure, and is given along with growth hormone, to promote normal pubertal growth.

 THYROID FUNCTION. Chemotherapy-only preparative regimens have little effect on normal thyroid function. The use of TBI with or without additional conventional radiation involving the thyroid gland may result in compensated or overt hypothy roidism. Some patients, who have received single-dose TBI, develop compensated (28-56%) or overt (9-13%) hypothy roidism. The use of fractionated TBI has reduced the incidence of compensated (10-14%) and overt (<5%) hypothyroidism significantly. Risk factors for the development of hypothyroid ism appear t(? be related only to the use of radiation, with no influence of age, sex, or GVHD. The site of injury by radiation is at the level of the thyroid gland rather than at the pituitary or hypothalamus. Therapy with thyroxine is very effective for overt hypothyroidism, but treatment of compensated hypothy roidism is more controversial. Despite treating hypothyroidism, there remains a risk for thyroid carcinomas. Because the risk of hypothyroidism continues for many years, annual thyroid function studies are important.

 IMMUNE RECONSTITUTION. Chemo-radiotherapy for BMT results in complete eradication of host B- and T-cell immunity. After infusion of donor marrow, the recovery of the normal immune functions takes many months or years. The ability of newly engrafting B cells to respond to mitogenic stimulation is intact by 2-3 mo. Because the production of antibodies requires B and T-cell interaction, normal IgM levels are not observed until 4-6 mo post-transplant, IgG levels take 7-9 mo, and it may take 2 yr before normal IgA levels are achieved. T-cell recovery also takes many months. CD8 T cells recover by about 4 mo but CD4 T cells do not increase until 6-9 mo, resulting in an inverted CD4/CD8 ratio for the first 6-9 mo post-transplant. Factors that prolong this interval include T depletion of the marrow, post-transplant immunosuppression, and, chronic GVHD. Patients with cGVHD have a continued decrease in the number of cytotoxic T Iymphocytes and helper T cells, along with increased suppressor T cells. Re-immunization of an indi vidual will be successful only after adequate recovery of im mune function. For patients without cGVHD, diphtheria and tetanus toxoid (DT) immunizations may be given 3-6 mo post-

transplant, inactivated (Salk) polio after 6-12 mo, and measles,

 mumps, and rubella (MMR) after 1-2 yr. If chronic GVHD is

 present, re-immunization should be postponed and IgG sup-

 plemented until it resolves.