Primary immunodeficiencies


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Immunological Disorders can be classified into 3 distinct categories.They are Hypersensitivity, Autoimmunity and Immunodeficiency.Here in this presentation we talk about Immunodeficiency disorders.Get more on our blog :

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Primary immunodeficiencies

  1. 2. ZAP 70 ADA ADA PNP PNP
  2. 3. <ul><li>“ Pure” T Cell Disorders </li></ul><ul><li>“ Pure” B Cell Disorders </li></ul><ul><li>Severe Combined Immunodeficiency (SCID) </li></ul><ul><li>Combined Immunodeficiencies </li></ul><ul><li>Phagocyte Deficiencies </li></ul><ul><li>Complement Deficiencies </li></ul>
  3. 4. <ul><li>B Cell: recurrent sinopulmonary and GI infections beginning after 3-4 mo. </li></ul><ul><li>T Cell and Severe Combined Immunodeficiency (SCID): opportunistic infections beginning early in infancy (thrush, diarrhea, failure to thrive); Milder forms termed Combined Immunodeficiency (CID) </li></ul><ul><li>Phagocyte deficiencies: deep tissue infections with high-grade bacterial pathogens </li></ul><ul><li>Complement: some infections, primarily with encapsulated organisms and Neisseriae </li></ul>
  4. 5. <ul><li>“ Pure” T Cell Deficiencies: </li></ul><ul><ul><ul><li>DiGeorge syndrome </li></ul></ul></ul><ul><ul><ul><li>T cell receptor deficiencies </li></ul></ul></ul><ul><ul><ul><li>Zap 70 deficiency </li></ul></ul></ul>
  5. 6. <ul><li>Conotruncal cardiac malformation </li></ul><ul><li>Hypoparathyroidism </li></ul><ul><li>Thymic hypoplasia leading to variable immunodeficiency </li></ul><ul><li>Other features: </li></ul><ul><ul><ul><li>Characteristic facies </li></ul></ul></ul><ul><ul><ul><li>Deletion in 22q11 in > 80% </li></ul></ul></ul><ul><ul><ul><li>Affected gene(s) is a transcription factor in the T-box family called Tbx1 </li></ul></ul></ul>
  6. 8. <ul><li>Interrupted aortic arch 27% </li></ul><ul><li>Truncus arteriosus 25% </li></ul><ul><li>Tetrology of Fallot 22% </li></ul>
  7. 11. <ul><ul><ul><li>X-linked SCID (  c deficiency) </li></ul></ul></ul><ul><ul><ul><li>Jak3 kinase deficiency </li></ul></ul></ul><ul><ul><ul><li>Adenosine deaminase deficiency </li></ul></ul></ul><ul><ul><ul><li>Purine nucleoside phosphorylase deficiency </li></ul></ul></ul><ul><ul><ul><li>Bare lymphocyte syndrome </li></ul></ul></ul><ul><ul><ul><li>RAG1 and RAG2 deficiency </li></ul></ul></ul>
  8. 12. <ul><ul><ul><li>Failure to thrive </li></ul></ul></ul><ul><ul><ul><li>Onset of infections in the neonatal period </li></ul></ul></ul><ul><ul><ul><li>Opportunistic infections </li></ul></ul></ul><ul><ul><ul><li>Chronic or recurrent thrush </li></ul></ul></ul><ul><ul><ul><li>Chronic rashes </li></ul></ul></ul><ul><ul><ul><li>Chronic or recurrent diarrhea </li></ul></ul></ul><ul><ul><ul><li>Paucity of lymphoid tissue </li></ul></ul></ul>
  9. 13. <ul><ul><ul><li>Hypogammaglobulinemia </li></ul></ul></ul><ul><ul><ul><li>Absence of antibody responses to immunizations </li></ul></ul></ul><ul><ul><ul><li>Absent mitogen responses </li></ul></ul></ul><ul><ul><ul><li>Low or absent T cells </li></ul></ul></ul><ul><ul><ul><li>Often low or absent B cells </li></ul></ul></ul>
  10. 14. <ul><ul><ul><li>Bone marrow transplantation, preferably from a histocompatible sibling </li></ul></ul></ul><ul><ul><ul><li>Gene therapy </li></ul></ul></ul>
  11. 15. <ul><ul><ul><li>Most common form of SCID (40%) </li></ul></ul></ul><ul><ul><ul><li>Very low T cells and NK cells with low to normal numbers of B cells </li></ul></ul></ul><ul><ul><ul><li>Responsible gene:  c – the common subunit of receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 </li></ul></ul></ul>
  12. 17. <ul><li>Bruton’s (X-linked) Agammaglobulinemia </li></ul><ul><li>Autosomal Recessive Hyper-IgM Syndrome </li></ul><ul><li>B Cell Receptor Deficiencies </li></ul><ul><li>Common Variable Immunodeficiency (CVID) </li></ul><ul><li>Selective IgA Deficiency </li></ul><ul><li>IgG Subclass Deficiency </li></ul>
  13. 18. <ul><li>IgA deficiency frequently coexists with IgG subclass deficiency, especially IgG2 and IgG4 </li></ul><ul><li>Linkage to Class III region of HLA </li></ul><ul><li>50% incidence of IgA-D in children of patients with CVID </li></ul><ul><li>Occasionally IgA deficient patients have been noted to progress to CVID </li></ul>
  14. 19. <ul><li>Panhypogammaglobulinemia, usually with lymphadenopathy and splenomegaly </li></ul><ul><li>Absence of clear abnormalities in T and B cell subsets </li></ul><ul><li>Chronic/recurrent respiratory infections, & diarrhea, especially due to Giardia </li></ul><ul><li>Tendency to develop autoimmunity and lymphoid malignancies </li></ul><ul><li>Linkage to HLA Class III Region in 2/3 of patients </li></ul><ul><li>One gene identified: ICOS (B7h) (activation antigen on T cells) </li></ul>
  15. 20. <ul><li>Chronic/recurrent upper respiratory infections, especially sinusitis </li></ul><ul><li>Tendency to develop respiratory and gastrointestinal allergies and autoimmunity </li></ul>
  16. 21. <ul><li>Wiskott-Aldrich Syndrome: thrombocytopenia, eczema, immunodeficiency </li></ul><ul><li>Ataxia-Telangiectasia: DNA repair disorder </li></ul><ul><li>X-linked Hyper-IgM Syndrome: inability to make other Ig isotypes </li></ul><ul><li>X-linked Lymphoproliferative Disorder: immunodeficiency following EBV infection </li></ul><ul><li>Hyper-IgE with Infections: markedly elevated IgE with deep-seated bacterial infections </li></ul><ul><li>Chronic Mucocutaneous Candidiasis: chronic superficial fungal infections </li></ul><ul><li>Genes identified </li></ul>
  17. 22. <ul><li>Chronic granulomatous disease (CGD) </li></ul><ul><li>Leukocyte adhesion deficiency (LAD I) </li></ul><ul><li>Chediak-Higashi syndrome </li></ul><ul><li>IL-12/IFN  pathway deficiencies </li></ul><ul><li>Chronic or cyclic neutropenia </li></ul>
  18. 23. <ul><li>Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase </li></ul><ul><li>Severe tissue infections with catalase positive organisms, esp. Staph aureus, Serratia marcescens, mycobacteria, and fungi such as Aspergillus </li></ul>
  19. 24. <ul><li>Nitroblue tetrazolium (NBT) test or, more recently, flow cytometric tests using fluorescent dyes such as dihydrorhodamine (DHR) </li></ul>
  20. 25. <ul><li>Prophylaxis with antibiotics (bactrim and itraconazole) and gamma interferon </li></ul><ul><li>Bone marrow transplant with HLA identical sibling </li></ul><ul><li>Gene therapy (?) </li></ul>
  21. 27. Patient Mother Father DHR Flow Cytometric Assay
  22. 28. CGD patient with skin infections due to Serratia marcescens
  23. 29. <ul><li>Severe tissue infections due to absence of adhesion molecules (  -integrins CD11/CD18) on leukocytes </li></ul><ul><li>Inability to make pus due to entrapment of phagocytes within the vasculature </li></ul><ul><li>Lethal within the first decade of life without bone marrow transplant </li></ul>
  24. 30. Omphalitis in LAD I patient
  25. 31. <ul><li>Abnormal large granules in a variety of cells leading to: </li></ul><ul><ul><li>hypopigmentation/partial albinism </li></ul></ul><ul><ul><li>severe immunodeficiency </li></ul></ul><ul><ul><li>neurologic abnormalities </li></ul></ul><ul><ul><li>mild bleeding tendencies </li></ul></ul><ul><li>Defective gene: CHS1 located on 1q42-43, protein product involved in granule trafficking </li></ul>
  26. 33. <ul><li>IL-12 receptor </li></ul><ul><li>IL-12 </li></ul><ul><li>IFN  R1 and IFN  R2 </li></ul><ul><li>STAT-1 </li></ul><ul><li>Pattern of infections: overwhelming infection with intracellular pathogens, esp. atypical mycobacteria </li></ul>
  27. 36. <ul><li>Rule I: In any inherited deficiency of a component of the classical pathway, total hemolytic activity (CH50) will be close to zero </li></ul><ul><li>Rule II: In any inherited deficiency of a component of the alternate pathway, total hemolytic activity (AH50) will be close to zero </li></ul>