the primary immunodeficiencies
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The Primary Immunodeficiencies. Prescott Atkinson, MD PhD Professor and Director Division of Pediatric Allergy, Asthma & Immunology University of Alabama at Birmingham. Overview of the Primary Immunodeficiencies:. “Pure” T Cell Disorders “Pure” B Cell Disorders - PowerPoint PPT PresentationTRANSCRIPT
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The Primary Immunodeficiencies
Prescott Atkinson, MD PhDProfessor and Director
Division of Pediatric Allergy, Asthma & Immunology
University of Alabama at Birmingham
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Overview of the Primary Immunodeficiencies:
“Pure” T Cell Disorders “Pure” B Cell Disorders Severe Combined
Immunodeficiency (SCID) Combined Immunodeficiencies Phagocyte Deficiencies Complement Deficiencies
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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 (cellulitis, abscesses, osteomyelitis) and mucositis/gingivitis
Complement: some infections, primarily with encapsulated organisms and Neisseriae
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T Cell Immunodeficiencies:
“Pure” T Cell Deficiencies: DiGeorge/Velocardiofacial syndrome T cell receptor deficiencies Zap 70 deficiency
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DiGeorge/Velocardiofacial
Syndrome Conotruncal cardiac malformation Hypoparathyroidism Thymic hypoplasia leading to variable immunodeficiency Other features:
Cleft palate in VCF syndrome Characteristic facies Deletion in 22q11 in > 80% Small percentage with mutations in chromodomain
helicase-DNA binding protein 7 (CHD7) on chromosome 10, associated with much more severe congenital malformations (CHARGE syndrome) and complete absence of thymus (Sanka M et al 2007)
Affected gene(s) on chromosome 22 is a transcription factor in the T-box family called Tbx1
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DiGeorge Syndrome: Cardiac Abnormalities
Interrupted aortic arch 27% Truncus arteriosus 25% Tetrology of Fallot 22%
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Severe Combined Immunodeficiency Syndromes
(SCID) X-linked SCID (c deficiency) Jak3 kinase deficiency IL-7R deficiency CD45 deficiency Adenosine deaminase deficiency Bare lymphocyte syndrome (MHC
Class I/II deficiency) RAG1/RAG2 deficiency T cell receptor deficiencies
– CD3, , or Zap 70 deficiency IL-2R (CD25) deficiency
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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
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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
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Severe Combined Immunodeficiency Treatment
Bone marrow transplantation, preferably from a histocompatible sibling
Gene therapy
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B Cell Immunodeficiencies: Bruton’s (X-linked) Agammaglobulinemia
(Bruton’s tyrosine kinase (btk) deficiency) Autosomal Recessive Hyper-IgM Syndrome
AID (activation-induced cytidine deaminase) UNG (uracil DNA glycosylase)
B Cell Receptor and Signaling Deficiencies: heavy chain mutations Pseudo-light chain deficiency (5/V-preB) CD79B (Ig) deficiency BLNK deficiency
Common Variable Immunodeficiency (CVID) (TACI, BAFF-R, CD19, ICOS)
Selective IgA Deficiency IgG Subclass Deficiency
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IgG Subclass – IgA-D – CVIDPolar 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
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Common Variable Immunodeficiency
Panhypogammaglobulinemia, usually with lymphadenopathy and splenomegaly
No clear abnormalities in T and B cells 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
Four genes identified: ICOS (B7h), BAFF-R, CD19, and TACI (co-stimulatory molecules on T and B cells)
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IgG Subclass and IgA Deficiencies
Patterns of Illness
Chronic/recurrent upper respiratory infections, especially sinusitis
Tendency to develop respiratory and gastrointestinal allergies and autoimmunity
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Combined Immunodeficiencies Wiskott-Aldrich Syndrome: eczema,
thrombocytopenia, immunodeficiency (WAS) Ataxia-Telangiectasia: DNA repair disorder,
isotype switch defect (ATM) Hyper-IgM Syndrome: isotype switch defect, T cell
dysfunction (CD40, CD40-L, NEMO) X-linked Lymphoproliferative Disorder: fulminant
infectious mono, hypogammaglobulinemia, lymphoma (SH2D1A/SAP, XIAP)
Chronic Mucocutaneous Candidiasis: chronic superficial fungal infections, autoimmunity (AIRE)
Hyper-IgE syndrome: markedly elevated IgE with bacterial & fungal infections (STAT3)
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Hyper-IgE Syndrome Coarse facies, joint hypermobility, retention of
primary dentition Dominant negative mutations in STAT3 Diffuse defects in cytokine receptor responses Markedly elevated IgE with relatively normal
immunoglobulins and antibody responses Peripheral eosinophilia Invasive infections with extracellular bacteria and
fungi Absent TH17 cells
Milner J et al Nature 2008
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NEMO Deficiency Hypohidrotic ectodermal dysplasia and
infections Hypotrichosis or atrichosis Hypohidrosis or anhidrosis leading to
heat intolerance hypodontia or anodontia with conical
incisors Increased serum IgM and low IgA and/or
IgG Infections, often with opportunistic
pathogens such as atypical mycobacteria
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Other Cellular Immunodeficiencies:
Defective NK and CTL function: Familial Hemophagocytic Lymphohistiocytosis
Defects in the interferon-gamma (IFN)/interleukin-12 (IL-12) pathway
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Familial Hemophagocytic Lymphohistiocytosis (FHL): Defective NK and cytotoxic T cell (CD8+ T
cell) killing leading to infiltration of the liver, spleen, bone marrow, and central nervous system by activated T cells and macrophages
Defective genes: perforin (PRF1) (up to 50%), Munc13-4 (UNC13D) (20-30%), syntaxin 11 (STX11) (10-20%)
Diagnosis: flow cytometry for intracellular perforin, functional killing assays
Therapy: Immunosuppression with prednisone or
cyclosporine Bone marrow transplant
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Defects in the interferon-gamma (IFN)/interleukin-12 (IL-12) pathway :
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IL-12/IFN Pathway Defects
IL-12R1 IL-12p40 IFNR1 and IFNR2 STAT-1
Pattern of infections: overwhelming infection with intracellular pathogens, esp. atypical mycobacteria
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Numerous acid-fast organisms and poor granuloma development in the liver of a Tunisian child with BCG infection
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Phagocyte Deficiencies: Chronic granulomatous disease (CGD) (gp91-phox, p22-
phox, p47-phox, p67-phox) Leukocyte adhesion defects
LAD I (integrin CD11/CD18) LAD II (GDP-fucose transporter SLC35C1)
Granule defects – defects in phagocyte, NK cell, platelet, neuron function (albinism, infection, bleeding, FHL) Chediak-Higashi syndrome (Lysosomal trafficking
regulator, LYST) Griscelli syndrome (Ras-associated protein RAB27A) Hermansky-Pudlak syndrome – adapter protein 3
(APS2) Chronic or cyclic neutropenia (neutrophil elastase)
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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
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Chronic Granulomatous Disease: Diagnosis
Nitroblue tetrazolium (NBT) test or, more recently, flow cytometric tests using fluorescent dyes such as dihydrorhodamine (DHR)
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Patient
Mother
Father
DHR Flow Cytometric Assay
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CGD patient with skin infectionsdue to Serratia marcescens
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Leukocyte Adhesion Deficiency I Severe tissue infections due to absence of
adhesion molecules (-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
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Omphalitis in LAD I patient
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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
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