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Primary Immunodeficiencies

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Primary Immunodeficiencies Overview of the Primary Immunodeficiencies: Pure T Cell Disorders Pure B Cell Disorders Severe Combined Immunodeficiency (SCID ... – PowerPoint PPT presentation

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Title: Primary Immunodeficiencies


1
Primary Immunodeficiencies
2
PNP
ADA
ADA
ZAP 70
PNP
3
Overview of the Primary Immunodeficiencies
  • Pure T Cell Disorders
  • Pure B Cell Disorders
  • Severe Combined Immunodeficiency (SCID)
  • Combined Immunodeficiencies
  • Phagocyte Deficiencies
  • Complement Deficiencies

4
Patterns of Infection in Immunodeficiencies
  • B Cell recurrent sinopulmonary and GI infections
    beginning after 3-4 mo.
  • T Cell and Severe Combined Immunodeficiency
    (SCID) opportunistic infections beginning early
    in infancy (thrush, diarrhea, failure to thrive)
    Milder forms termed Combined Immunodeficiency
    (CID)
  • Phagocyte deficiencies deep tissue infections
    with high-grade bacterial pathogens
  • Complement some infections, primarily with
    encapsulated organisms and Neisseriae

5
T Cell Immunodeficiencies
  • Pure T Cell Deficiencies
  • DiGeorge syndrome
  • T cell receptor deficiencies
  • Zap 70 deficiency

6
DiGeorge Syndrome
  • Conotruncal cardiac malformation
  • Hypoparathyroidism
  • Thymic hypoplasia leading to variable
    immunodeficiency
  • Other features
  • Characteristic facies
  • Deletion in 22q11 in gt 80
  • Affected gene(s) is a transcription factor in the
    T-box family called Tbx1

7
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8
DiGeorge Syndrome Cardiac Abnormalities
  • Interrupted aortic arch 27
  • Truncus arteriosus 25
  • Tetrology of Fallot 22

9
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10
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11
Severe Combined Immunodeficiency Syndromes (SCID)
  • X-linked SCID (?c deficiency)
  • Jak3 kinase deficiency
  • Adenosine deaminase deficiency
  • Purine nucleoside phosphorylase deficiency
  • Bare lymphocyte syndrome
  • RAG1 and RAG2 deficiency

12
Common Features of Severe Combined
Immunodeficiency (SCID)
  • Failure to thrive
  • Onset of infections in the neonatal period
  • Opportunistic infections
  • Chronic or recurrent thrush
  • Chronic rashes
  • Chronic or recurrent diarrhea
  • Paucity of lymphoid tissue

13
Severe Combined Immunodeficiency Common
Laboratory Features
  • Hypogammaglobulinemia
  • Absence of antibody responses to immunizations
  • Absent mitogen responses
  • Low or absent T cells
  • Often low or absent B cells

14
Severe Combined Immunodeficiency Treatment
  • Bone marrow transplantation, preferably from a
    histocompatible sibling
  • Gene therapy

15
X-Linked SCID Common Cytokine Receptor Gamma
Chain (gc) Deficiency
  • Most common form of SCID (40)
  • Very low T cells and NK cells with low to normal
    numbers of B cells
  • Responsible gene ?c the common subunit of
    receptors for IL-2, IL-4, IL-7, IL-9, and IL-15

16
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17
B Cell Immunodeficiencies
  • Brutons (X-linked) Agammaglobulinemia
  • Autosomal Recessive Hyper-IgM Syndrome
  • B Cell Receptor Deficiencies
  • Common Variable Immunodeficiency (CVID)
  • Selective IgA Deficiency
  • IgG Subclass Deficiency

18
IgG Subclass IgA-D CVID Polar Ends of a
Common Disease?
  • IgA deficiency frequently coexists with IgG
    subclass deficiency, especially IgG2 and IgG4
  • Linkage to Class III region of HLA
  • 50 incidence of IgA-D in children of patients
    with CVID
  • Occasionally IgA deficient patients have been
    noted to progress to CVID

19
Common Variable Immunodeficiency
  • Panhypogammaglobulinemia, usually with
    lymphadenopathy and splenomegaly
  • Absence of clear abnormalities in T and B cell
    subsets
  • Chronic/recurrent respiratory infections,
    diarrhea, especially due to Giardia
  • Tendency to develop autoimmunity and lymphoid
    malignancies
  • Linkage to HLA Class III Region in 2/3 of
    patients
  • One gene identified ICOS (B7h) (activation
    antigen on T cells)

20
IgG Subclass and IgA Deficiencies Patterns of
Illness
  • Chronic/recurrent upper respiratory infections,
    especially sinusitis
  • Tendency to develop respiratory and
    gastrointestinal allergies and autoimmunity

21
Combined Immunodeficiencies
  • Wiskott-Aldrich Syndrome thrombocytopenia,
    eczema, immunodeficiency
  • Ataxia-Telangiectasia DNA repair disorder
  • X-linked Hyper-IgM Syndrome inability to make
    other Ig isotypes
  • X-linked Lymphoproliferative Disorder
    immunodeficiency following EBV infection
  • Hyper-IgE with Infections markedly elevated IgE
    with deep-seated bacterial infections
  • Chronic Mucocutaneous Candidiasis chronic
    superficial fungal infections
  • Genes identified

22
Phagocyte Deficiencies
  • Chronic granulomatous disease (CGD)
  • Leukocyte adhesion deficiency (LAD I)
  • Chediak-Higashi syndrome
  • IL-12/IFN? pathway deficiencies
  • Chronic or cyclic neutropenia

23
Chronic Granulomatous Disease
  • Inability of phagocytes to generate hydrogen
    peroxide due to mutations in one of four proteins
    comprising the NADPH oxidase
  • Severe tissue infections with catalase positive
    organisms, esp. Staph aureus, Serratia
    marcescens, mycobacteria, and fungi such as
    Aspergillus

24
Chronic Granulomatous Disease Diagnosis
  • Nitroblue tetrazolium (NBT) test or, more
    recently, flow cytometric tests using fluorescent
    dyes such as dihydrorhodamine (DHR)

25
Chronic Granulomatous Disease Treatment
  • Prophylaxis with antibiotics (bactrim and
    itraconazole) and gamma interferon
  • Bone marrow transplant with HLA identical sibling
  • Gene therapy (?)

26
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27
DHR Flow Cytometric Assay
Patient
Father
Mother
28
CGD patient with skin infections due to Serratia
marcescens
29
Leukocyte Adhesion Deficiency I
  • Severe tissue infections due to absence of
    adhesion molecules (b-integrins CD11/CD18) on
    leukocytes
  • Inability to make pus due to entrapment of
    phagocytes within the vasculature
  • Lethal within the first decade of life without
    bone marrow transplant

30
Omphalitis in LAD I patient
31
Chediak-Higashi Syndrome
  • Abnormal large granules in a variety of cells
    leading to
  • hypopigmentation/partial albinism
  • severe immunodeficiency
  • neurologic abnormalities
  • mild bleeding tendencies
  • Defective gene CHS1 located on 1q42-43, protein
    product involved in granule trafficking

32
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33
IL-12/IFN? Pathway Defects
  • IL-12 receptor
  • IL-12
  • IFN?R1 and IFN?R2
  • STAT-1
  • Pattern of infections overwhelming infection
    with intracellular pathogens, esp. atypical
    mycobacteria

34
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35
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36
Complement Deficiencies
  • Rule I In any inherited deficiency of a
    component of the classical pathway, total
    hemolytic activity (CH50) will be close to zero
  • Rule II In any inherited deficiency of a
    component of the alternate pathway, total
    hemolytic activity (AH50) will be close to zero

37
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