Primary immunodeficiency disorders

Explaining all about immunodeficiency disorders

1. Speaker - Dr Rajesh kumar PRIMARY IMMUNODEFICIENCY DISORDER

2. IMMUNODEFICIENCY DISEASES PRIMARY: SECONDARY : Usually hereditary 6 months to 2 years of life Less common Arise as complications of cancer, infection, malnutrition, immunosupression , irradiation, or chemotherapy More common Diseases caused by the absence or failure of normal function of one or more elements of immune system.

3. PRIMARY IMMUNODEFICIENCY DISEASES These are the diseases caused by inherited mutations in genes involved in lymphocyte maturation or function, or in innate immunity. DEFECTS IN INNATE IMMUNITY: - phagocytic cell defect -complement system defect -defect in pattern recognition receptor DEFECTS IN ADAPTIVE IMMUNITY: - lymphocyte maturation defect - lymphocyte activation defect - associated with systemic diseases

4. COMPONENTS OF INNATE & ADAPTIVE IMMUNITY

5. PHAGOCYTIC CELL DEFECTS

6. LEUKOCYTE ADHESION DEFICIENCY Type 1 : M utation in beta chain of CD11/CD18 integrin Type 2 : M utation in fucosyl transferase Type 3 : D efect in integrin activation molecule kindling-3

7. CHRONIC GRANULOMATOUS DISEASE Defect in genes encoding components of phagocyte oxidase 2 variants: X linked: D efect in membrane bound component i.e. gp91phox Autosomal recessive : D efect in cytoplasmic component i.e. P47phox, p67phox

8. CHEDIAK-HIGASHI SYNDROME Autosomal recessive, involving LYST gene . Defective fusion of phagosome and lysosome . Leucocyte abnormalities → neutropenia and giant granules Melanocyte abnormalities → albinism Also affects nervous system and platelets.

9. DEFICIENCIES OF COMPLEMENT PATHWAYS

10. NORMAL COMPLEMENT CASCADE

11. DEFICIENCIES OF PATTERN RECOGNITION RECEPTOR SIGNALING MyD88 adaptor protein deficiency → infection with Pneumococci and Salmonella. IL1R-associated kinase-4 deficiency → Gram- positive bacterial infection including Streptococcus pneumoniae and Staph aureus. TLR3 deficiency → recurrent Herpes simplex virus encephalitis

12. DEFECTS IN ADAPTIVE IMMUNITY

13. SEVERE COMBINED IMMUNODEFICIENCY

14. X-linked SCID:- Autosomal Recessive SCID:- Most common form (50-60% cases) Mutation in common gamma-chain subunit of cytokine receptors Defect in IL-7 receptor signaling , required for T cell proliferation Ineffective IL-15 receptor signaling → deficiency of NK cells Most common enzyme deficiency → adenosine deaminase Accumulation of deoxyadenosine & deoxy-ATP, which are toxic to immature lymphocytes. Other associated mutations:- Recombinase activating genes(RAG) gene JAK3 (intracellular kinase)

15. Common Cytokine Receptor Gamma-Chain Signaling Pathways

16. X-LINKED ( BRUTON ) AGAMMAGLOBULINEMIA Failure of B-cell precursors (Pro-B cells & Pre-B cells) to develop into mature B cells. Caused by mutation in Bruton tyrosine kinase (BTK) gene at Xq21.22 Serum levels of all classes of immunoglobulins are decreased. HP-No germinal centre in lymph node and spleen. Plasma cells are absent from the tissues. Does not manifest upto 6 month due to presence of maternal immunoglobulin. Commonly affected by H.influenzae , S.pneumoniae , S.aureus .

17. Overview of B-cell development and defects causing antibody deficiency.

18. DiGeorge Syndrome (thymic hypoplasia) Failure of development of 3 rd & 4 th pharyngeal pouch . Deletion of Chr 22q11. TBX1 gene depleted. Features- thymic hypoplasia → Tcell deficiency → fungal & viral infections

19. 2. Parathyroid hypoplasia → hypocalcemic tetany 3. Congenital defect of heart & blood vessels 4. Dysmorphic facies

20. Bare lymphocyte syndrome Mutation in transcription factors required for class II MHC expression. No development of CD4+ T cell → defect in cellular immunity. Humoral immunity also affected.

21. HYPER- IgM SYNDROME Production of IgM without IgA , IgG , or IgE antibodies. 2 patterns:- a) X-linked recessive (70% cases) : mutation in CD40L gene (located on Xq26) b) Autosomal recessive : mutation in CD40 or activation induced deaminase (AID)

22. Clinical features :- Recurrent bacterial infections due to lack of opsonizing IgG antibodies. Increased susceptibility to Pneumocystis jiroveci . IgM antibodies act against blood cells→ autoimmune hemolytic anaemia, neutropenia or thrombocytopenia.

23. COMMON VARIABLE IMMUNODEFICIENCY Hypogammaglobulinemia, generally affecting all the antibody classes, but sometimes only IgG. Relatives have high incidence of selective IgA deficiency. Normal or near- normal B cells, but unable to differentiate into plasma cells. Mutations: Receptor for a cytokine BAFF ICOS ( inducible costimulator )

24. Features:- Typically present with recurrent sino -pulmonary pyogenic infections. Recurrent Herpes virus infections (20% cases) Persistent diarrhoea due to Giardia lamblia . Affects both sexes equally and onset is late Hyperplastic B cell zones Increase incidence of autoimmune disease and lymphoid malignancy

25. ISOLATED IgA DEFICIENCY Extremely low level of both serum and secretory IgA . Impaired differentiation of naive B lymphocyte to IgA producing plasma cell. Molecular basis not known. Probably due to defect in receptor for BAFF. Mucosal immunity mostly affected. Recurrent sino -pulmonary infections & diarrhoea. Increase incidence of allergy & autoimmune disorders.

26. X LINKED LYMPHOPROLIFERATIVE SYNDROME Mutation in gene encoding SLAM associated protein. Diminished NK & T cell activation. Inability to eliminate EB virus leading to fulminant Infectious mononucleosis.

27. WISKOTT ALDRICH SYNDROME X linked disease. Triad of thrombocytopenia, eczema and recurrent infections .

28. Mutation in gene for WASP located at Xp11.23 WASP protein involved in cytoskeleton dependent responses including cell migration & signal transduction. Features :- Normal thymus but loss of T lymphocyte in peripheral blood and lymph node. No antibody production to polysaccharides and poor response to protein antigens. IgM ↓↓, IgG – Normal, IgA & IgE -↑↑ Increased incidence of B cell lymphoma.

29. ATAXIA TELANGIECTASIA Autosomal recessive Mutation of gene encoding ATM on Chr. 11 ATM protein is a sensor of DNA damage → activates P53 to activate cell cycle checkpoints → apoptosis in cells with damaged DNA. ATM contributes to the stability of DNA double-strand break complexes during V(D)J recombination.

30. Characterized by 1) ataxia 2) vascular malformation 3) neurological deficit 4) increase incidence of tumor and immunodeficiency Both T & B cell affected. Humoral immunity predominantly affected. Defective production of IgA & IgG2.

31. APPROACH TO PATIENTS WITH SUSPECTED IMMUNODEFICIENCY Detailed history Physical examination Investigations

32. KEY HISTORY History of infections: location, organism, frequency, response to therapy, hospitalization Family history – consanguinity History of allergy Developmental delays

33. 10 warning signs of Immunodeficiency 1 Eight or more new ear infections within one year Recurrent deep skin or organ abscess 6 2 Two or more serious sinus infections within one year Persistent thrush in mouth or elsewhere on skin after age one. 7 3 Two or more months on antibiotics with little effect Need for I/V antibiotics to clear infections 8 4 Two or more pneumonias within one year Two or more deep seated infections 9 5 Failure of an infant to gain weight or grow naturally Family history of primary immunodeficiency 10

34. PHYSICAL FINDINGS Failure to thrive Abnormal facial features Skin and mucosa: eczema, petechiae , abscess, pyoderma , telangiectasia , delayed umbilical cord separation Respiratory tract: bronchial breath sound, fine crepitations

35. INVESTIGATIONS CBC:-Absolute lymphocyte count -Absolute neutrophil count -Platelet count Peripheral smear Delayed-type hypersensitivity skin tests Chest x-ray

36. serum immunoglobulins lymphocyte subset analysis by flowcytometry antibody response to -known exposure -known immunizations

37. enzyme assays: ADA,NADPH OXIDASE chemotaxis assays nitroblue tetrazolium slide test dihydro rhodamine flowcytometry Complement level:C3,C5,CH50 biopsies: skin,lymphnode,thymus cytogenetic analysis: FISH for 22q11 mutation analysis: CD40L,JAK3,ZAP70

38. Nitroblue Tetrazolium Slide Test Neutrophils make reactive oxygen species which reduces colorless NBT dye into a blue colored formazan salt In CGD these reactive oxygen species are not formed, so dye is not reduced to blue color

39. TREATMENT SUPPORTIVE THERAPY- antibiotics REPLACEMENT THERAPY- IV immunoglobulins , enzymes DEFINITIVE THERAPY- fetal thymic grafts, bone marrow transplantation GENE THERAPY

40. Thank You