Disorders of Immunity Immunodeficiency Diseases

1. Disorders of ImmunityImmunodeficiency Diseases Professor Sudheer Kher

2. Classification of Primary Immune Deficiency Syndromes Disorders of Phagocytosis Chr. Granulomatous Disease Myeloperoxidase Deficiency Chediac- Higashi Syndrome Leucocyte G6PD Deficiency Job’s Syndrome Tuftsin deficiency Lazy Leucocyte Syndrome Hyper IgE Syndrome Actin binding protein deficiency Shwachman’s disease • Disorders of • Complement • Complement • Component deficiencies • Complement • Inhibitor deficiencies Disorders of Specific Immunity Combined Immuno Deficiencies B & T Cell Defects Humoral Immuno Deficiencies B Cell Defects Cellular Immuno Deficiencies T Cell Defects

3. Immunodeficiency Diseases • Patient unable to fight off infection • Hall marks • Repeated infections • Opportunistic infections

4. Immunodeficiency Diseases • Most are defects in T cells or B cells • T cells, Macrophage defects = Fungal, Viral, protozoal infections • B cells, Complement defects = Bacterial infections

5. Immunodeficiency Diseases • Congenital • Acquired

6. Congenital • B cell deficiency • IgA deficiency • DiGeorge’s Syndrome • Severe Combined Immunodeficiency (SCID)

7. B Cell deficiency • Agammaglobulinemia • Hypogammaglobulinemia

8. IgA deficiency • Most common immune deficiency disorder • Genetic condition • Failure of IgA synthesis • Patients have repeated, recurrent sinus, lung, GI infections

9. DiGeorge’s Syndrome • Thymic hypoplasia • Severe decrease in T-cell production & function • Defects in face, ears, heart.

10. Severe Combined Immunodeficiency • Thymus development arrested at ~ 6-8 weeks gestation. • Deficiency, defective maturation of stem cells that produce B & T cells. • Little to no antibody production.

11. SCID • Two types • Autosomal recessive • X-linked disease recessive

12. SCID • Recurrent, frequently overwhelming infections • Particularly respiratory and gastrointestinal • Most die in first few years of life, usually by one year of age • Death usually due to opportunistic infection

13. Acquired • Nutritional • Iatrogenic (drugs, radiations) • Trauma (prolonged hypoperfusion) • Stress • Infections (HIV) • Malignancies

14. Immune Deficiency Therapies • B-cell deficiency : Gamma globulin • SCID : Bone marrow transplant, enzyme replacement • DiGeorge’s Syndrome : Fetal thymus transplant • Gene therapy

15. Inherited Functional Disorders • Disorders of Granulocyte Function • Job’s syndrome – directional motility is impaired – recurrent boils and abscesses • Lazy Leukocyte Syndrome – random and directed movement are defective – cells fail to respond to inflammatory stimuli – mild symptoms of low grade fever, recurrent infections (gums, mouth, ears) • Chediak-Higashi – abnormal granule release

16. Inherited Functional Disorders • Congenital C3 deficiency – inability to ingest microorganisms- repeated severe infections with encapsulated bacteria • Chronic Granulomatous Disease – inability to kill catalase positive organisms – recurrent pyogenic infection • Leukocyte Glucose-6-Phosphate Dehydrogenase Deficiency – similar to CGD Myeloperoxidase Deficiency-benign – slow bacterial killing, but complete

17. B Cell Disorders • Infantile sex-linked agammaglobulinemia Recurrent bacterial infections All classes of immunoglobulin are low All lymphocytes are T cells Treat with antibiotics and gamma globulin • Common Variable hypogammaglobulinemia One or a combination of immunoglobulins is missing Inability of B cells to mature/function as plasma cells Excessive production/activity of T suppressor cells

18. Monocyte-Macrophage Disorders • Mucopolysaccharidoses – deficiencies in specific enzymes to degrade mucopolysaccharides (Hurley syndrome, Hunter syndrome: gargoylism) • Lipidoses: lipid storage diseases – macrophages become overloaded with lipids (Gaucher, Niemann-Pick, Tay-Sachs)

20. Mouse found on Mars!