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Primary immunodeficiency

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Primary immunodeficiency

  1. 1. Primary Immunodeficiency Nishitha A 4TH Term
  2. 2. Objectives WHAT WILL I LEARN TODAY? Immunodeficiencies: Definition, cause and types Primary Immunodeficiencies: Definition, types, diagnosis and therapy Examples:SCID, XLA, DiGeorge’s syndrome, Ataxia- teleangectesia, Wiskott- Aldrich syndrome, CGD
  3. 3. Immunodeficiency • Immune system’s ability to fight infectious diseases is completely absent or compromised. • Types: Primary Immunodeficiency Secondary Immunodeficiency
  4. 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. 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. 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. 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. 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. 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. 10. Bubble Boy
  11. 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. 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. 13. Thymic Dysplasia
  14. 14. . Cell-Mediated/T cell Immunity
  15. 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. 16. DiGeorge’s syndrome • Also called thymic hypoplasia • Congenital disorder • Abnormalities in structure derived from 3rd and 4th pharyngeal pouches • Predominantly T cell defect • Charactersitics: Neonatal tetany(absence of parathyroid) • Therapy: Thymic transplants
  17. 17. • Cleft palate • Antimongoloid eyes • Short philtrum with fish-mouth appearance , • Micrognathia • Low set pixie-like ears • Short palpebral fissures Facial features of children with DiGeorge syndrome
  18. 18. DiGeorge Syndrome
  19. 19. DiGeorge syndrome
  20. 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. 21. Ataxia
  22. 22. telangiectasia
  23. 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. 24. Eczema Histological Pictutre:
  25. 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. 26. CGD patient with skin infections due to Serratia marcescens
  27. 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. 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. 29. Other Primary ID’s • Selective IgA deficiency • Common variable Immunodeficiency • X-linked lymphoproliferative disease • Job’s syndrome
  30. 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. 31. Diagnosis of Primary Immunodeficiencies • Histopathology • Immunohistochemistry • Monoclonal Antibodies • Cell separation by flow cytometry • Insitu Hybridisation
  32. 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