Primary immunodeficiency

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1. Primary Immunodeficiency Nishitha A 4 TH Term

2. Objectives WHAT WILL I LEARN TODAY? Immunodeficiencies : Definition, cause and types Primary Immunodeficiencies : D efinition, types, diagnosis and therapy Examples: SCID , XLA, DiGeorge’s syndrome, Ataxia- teleangectesia , Wiskott -Aldrich syndrome, CGD

3. Immunodeficiency I mmune system’s ability to fight infectious diseases is completely absent or compromised . Types: Primary Immunodeficiency Secondary Immunodeficiency

4. Immunodeficiency Cause for Immunodeficiency: Human Immune system: Very specific Dependent on memory of cells and lymphocytes that recognise foreign antigen and infected cells respectively. Any alterations in these functions Immunodeficiency.

5. Classification Most are genetically determined Less common May arise as complications of cancers, infestations, malnutrition, or side effects of immunosuppression, Irradiation and chemotherapy. More common Primary Immunodeficiency Secondary Immunodeficiency

6. Primary Immunodeficiencies A group of disorders characterized by an impaired ability to produce normal immune response. Cause: mutations in genes involved in the development and function of immune organs, cells, and molecules. Genetically determined. Usually diseases of infancy & childhood.

7. Primary Immunodeficiency Most important feature: High Incidence in Males: Why ? 6 X-linked ID’s have been described: 5 - Affect Lymphocytes 1- Affect Phagocyte

8. Table 1. Characteristic infections of the primary immunodeficiencies component primary pathogen primary site clinical example T-cells intracellular, bacteria viruses, protozoa, fungi, non-specific SCID, DiGeorge B-cells pneumococcus, streptococcus, haemophilus lung, skin, CNS IgG, IgM deficiency IgG, IgM deficiency enteric bacteria and viruses GI, nasal, eye IgA deficiency phagocytes Staphylococcal, Klebsiella Pseudomonas, lung, skin, regional lymph node Chronic granulomatous disease (CGD) complement neisseria, Haemophilus, pneumococcus, streptococcus CNS lung skin C3, Factors I and H, late C omponents

9. Severe Combined Immunodeficiency(SCID) Synonyms: Glanzzman -Rinker syndrome, Bubble Boy Disease, Thymic Alymphoplasia Genetic disorder characterised by absence of T-lymphocytes. Impairment of both cellular & humoral response Specific defects in antigen presentation & functional immune molecules.

10. Bubble Boy

11. SCID-Types Main Types: Autosomal recessive (- ve T & B cells) X-linked recessive(+ ve B cells) Other important types: Nezelof Syndrome SCID associated with ADA & PNP deficiency.

12. Features of SCID Absent tonsils Small or absent lymph nodes Absent thymic shadow Lymphopenias Decreased Number of T cells Severe agammaglobulinemia ( Swiss type of agammaglobulinemia ) No IG’s usually present

13. Thymic Dysplasia

14.                                                                                                .   Cell-Mediated/T cell Immunity

15. Bruton’s X-linked Agammaglobuinemia Primarily B-cell defect Boys-more affected Severe reduction in γ -globulins IG’s, circulating and marrow B-cells. Probable cause: Molecular defect at Xq22.Mutation of bruton tyrosine kinase. Therapy: IV IG’s.

16. DiGeorge’s syndrome Also called thymic hypoplasia Congenital disorder Abnormalities in structure derived from 3 rd and 4 th pharyngeal pouches Predominantly T cell defect Charactersitics : Neonatal tetany (absence of parathyroid) Therapy: Thymic transplants

17. Cleft palate Antimongoloid eyes S hort philtrum with fish-mouth appearance , M icrognathia Low set pixie-like ears Short palpebral fissures Facial features of children with DiGeorge syndrome

18. DiGeorge Syndrome

19. DiGeorge syndrome

20. Ataxia-telangiectasia Autosomal recessive Incidence: 25:10,00,000 Characteristics: Progressive cerebellar ataxia, ocular and cutaneous telangiectasias , severe sino -pulmonary infections, progeric changes, sclerodermoid changes Thymus: fetal-like histological pattern. Translocation between 14 and 7

21. Ataxia

22. telangiectasia

23. Wiskott -Aldrich Syndrome X-linked condition Incidence: 4:10,00,000 Severe eczema, recurrent infections, Bloody diarrhea, chronic otitis T cells appear bald :? Platelets: Decreased in number, small Failure to recognise polysaccharide antigens . Defect: Failure in expression of sialophorin .

24. Eczema Histological Pictutre :

25. Chronic Granulomatous Disease Incidence: 1:10,00,000 Defect: Inability of phagocytes to produce superoxide ineffective reduction of O2. Failure to express respiratory burst associated with phagocytosis . Central necrosis and granulomatoid response in lung, liver, bone , skin and lymph nodes. Presence of numerous pigmented macrophages.

26. CGD patient with skin infections due to Serratia marcescens

27. Chediak -Higashi Syndrome Rare autosomal disorder Abnormal large granules in leucocytes leading to: hypopigmentation /partial albinism severe immunodeficiency neurologic abnormalities mild bleeding tendencies Defective gene: CHS1

28. Leucocyte -Adhesion defect Autosomal recessive disorder Inability of phagocytic cells to adhere to endothelial cells and migrate to infected sites Characteristics: delayed cord dehiscence and scar formation, recurrent diarrhea and respiratory symptoms, leucocytosis Defect in CD18 gene Treatment : Bone marrow transplantation

29. Other Primary ID’s Selective IgA deficiency Common variable Immunodeficiency X-linked lymphoproliferative disease Job’s syndrome

30. Complement deficiencies Involves 19 proteins: 11-classical, 3-alternate, 5-regulatory Alteration in the expression of these proteins Autoimmune & Immunodeficiency diseases Classical AI affecting vessels & glomeruli Alternate Pyogenic infections Regulatory Hereditary Angioneurotic edema

31. Diagnosis of Primary Immunodeficiencies Histopathology Immunohistochemistry Monoclonal Antibodies Cell separation by flow cytometry Insitu Hybridisation

32. Therapy Supportive therapy- antibiotics Replacement therapy- IV immunoglobulin infusion, ADA-rich RBC infusions Definitive therapy- Fetal thymic grafts, bone marrow transplantation Stem-cell therapy Gene therapy

33. Thank you