IMMUNODEFICIENCY

1. IMMUNODEFICIENCY By: Oki Suwarsa, dr, MKes, SpKK(K)

2. IMMUNODEFICIENCY •  Risk of opportunist infection & tumors • Divided in two types: • Primary immunodeficiency : • Relatively rare • Genetic basis • Secondary immunodeficiency: • More common • Caused by lesion outside the immune system

3. Repeated/unusual infection  immunodeficiency • Type of infection  cause & degree of immunodeficiency • Repeated bacterial infection  defective antibody • Respiratory infection caused by Pneumococcus or Haemophilus spp.  bronchiectasis • Gram - & fungi  abnormal phagocytes • Meningococcal meningitis  defective complement • Defective T cells or macrophages  infection of intracelullar organisms : protozoa, virus, intracellular bacteria (mycobacteria & salmonella)

4. Reactivation of herpes virus infection  T cell immunodeficiency • Herpes virus induce tumors, kaposi’s sarcoma, non-Hodkin’s lymphoma  T cell dysfunction • the degree of T cell immunodeficiency  pattern of mycrobial infection • Mild  Mycobacterium tuberculosis (virulent) spreads outside the lungs • Severe  infection of mycobacterium of low virulence, found in environment (Mycobacterium avium) or vaccine

5. Features of immunodeficiencies affecting T & B lymphocytes

6. Immunodeficiency caused by defect in B & T cells maturation

7. Immunodeficiency caused by defects in B & T cell activation

8. Defect of lymphocyte maturation

9. Defect in lymphocyte activation

10. Infection Tumors Primary immunodeficiency Gene therapy Mutation Polymorphisms Immunoglobulins Polygenic PRIMARY IMMUNODEFICIENCY

11. Causes of primary immunodeficiency • Mutation : • Rare, affect any part of immune system • Severe disease • Polymorphisms : • Common traits, affect any part of the immune system • Moderate increased risk of infection • Polygenic disorders : • Relatively common, affect mainly antibody • Severe disease

12. Repeated or unusual infection suggests immunodeficiency

13. Defects in innate immune system are characterized by extracellular pathogen infections

14. Mutations and immunodeficiency • 12 important mutations  immunodeficiency • > Mutation  severe combined immunodeficiency (SCID) • Affecting both B & T cells • Autosomally inherited  RAG deficiency • X linked  γ-chain deficiency & hyper-IgM syndrome • The Di George syndrome  translocated of chromosome 22, not inherited

15. T cell defects

16. Polymorphisms & immunodeficiency • Polymorphisms : alleles of the same gene occurring at a single locus in 1% population • HLA alleles  polymorphic  affect the outcome of infection (hepatitis B, hepatitis C & HIV) • Polymorphisms promoter of TNF genes   risk cerebral malaria & septic shock • Polymorphisms chemokines & their receptors   risk HIV • Polymorphisms in MBL & complement   risk infections

17. Polygenic disorder • Caused by interaction of several genes with environmental factors • Common variable immunodeficiency (CVID) & deficiency of IgA & IgG  common polygenic disorder, affecting Ab • IgA deficiency  1:600 people • Celiac disease  more common in IgA deficiency • CVID  commonest immunodeficiency  treatment • CVID  recurrent infection of respiratory tract, start in early adult • Autoimmunity is common in CVID & frequently includes pernicious anemia & thyroid disease, arthritis & immune thrombocytopenia

18. Diagnosis SCID should be considered if: • Unusual or recurrent infection • Failure to thrive & diarrhea • Unusual rashes • A family history of neonatal death or of consanguinity • A very low total lymphocyte count (below 1 x 109/L)

19. Avoid serious infection: • Avoid live vaccine : BCG, measles, mumps, rubella & polio • Use prophylaxis against opportunist infections : Pneumocystis carinii pneumonia • Suspect SCID  exclude HIV  refer to spesialist to confirm diagnosis  definitive treatment (often bone marrow transplant)

20. Diagnosis • Chronic or recurrent bacterial respiratory infection  Indication for testing  measure of IgG, IgA & IgM • If total Ig normal  measure IgG subclasses & spesific Ab against Haemophilus & Pneumococcus spp. • If all test normal  check complement or neutrophil function • Patient with atypical viral, protozoal or mycobacterial infection  rule out T cell immunodeficiency • Patient with suspected cellular immunodeficiency  measure lymphocyte numbers • Genetic testing  PCR

21. Sepuluh tanda imunodefisiensi Duaataulebihgejaladalamsatutahun Jeffrey Modell Foundation

22. Empat atau lebih infeksi telinga dalam setahun Dua atau lebih infeksi sinus berat dalam setahun Pada bayi terjadi kegagalan peningkatan berat badan dan gagal tumbuh Dua bulan atau lebih pemakaian antibiotik dengan sedikit efek Dua episode atau lebih pneumonia dalam setahun

23. Kandidiasis persisten di mulut atau di mana saja usia >1 tahun Abses berulang pada kulit dan organ dalam Riwayat keluarga dengan imunodefisiensi primer Kebutuhan penggunaan antibiotik intravena untuk mengatasi infeksi Dua atau lebih infeksi dalam termasuk septikemia

24. Treatment • Aim of treatment  prevent infection • Mild cases  prophylactic antibiotics • More severe Ab deficiency  immunoglobulin replacement therapy (intravenous or subcutaneus) • T cell deficiency  bone marrow transplant (BMT) • If BMT isn’t option  gene therapy

25. Congenital disorders of innate immunity

26. vaccines Infection Tumors Immunomodulation Secondary immunodeficiency vaccines HIV Immunomodulation Stress Nutrition Extremes of age Drugs SECONDARY IMMUNODEFICIENCY

27. Secondary immunodeficiency • Can be severe : • HIV infection • Myeloma • Some drug treatments

28. Acquired immunodeficiencies

29. HIV Infection • Most important caused of secondary immunodefiency  affecting over 30 million people • Monitoring infection : • Immunological monitoring  CD4 cell counts  form part of assessment schemes for progression of HIV infection (CDC) • CD4 < 200 /l  high risk PCP  prophylaxis • CD4 < 100 /l  consider CMV & atypical mycobacteria • Virological monitoring  viral load

30. HIV infection and viral mutations

32. Structure of HIV-1

33. HIV-1 genome

34. HIV life cycle

35. Mechanism of HIV entry into a cell

36. Progression of HIV infection

37. Clinical course of HIV disease

38. Clinical features of HIV infection

39. Cellular reservoirs of HIV

40. Candidate HIV vaccines

41. Other secondary immunodeficiency • Nutrition • Deficiency of zinc & magnesium  impairs cell mediated immunity, particularly TH1-cytokine secretion • Loss of fat  low levels of leptin  mild immunodeficiency • Physiological stress • The immune system in the first year of life • Spesific immune system remain immature • Neonates have high number of T cells  all naive  not respond to Ag • Transient hypergammaglobulinemia of infancy  delay in maturation of Ig, especially IgG2 (maternal Ab ↓)

42. Other secondary immunodeficiency • The aging immune system • Elderly  thymic function ↓  more infection • Miscelaneous factors • B cell malignancy • Myeloma & chronic lymphocytic leukemia  ↓ Ab  common caused of immunodeficiency in elderly • Thymoma  rare tumor  cause immunodeficiency

43. Other secondary immunodeficiency • Drugs  Common caused • Eliminating offending drug  improve immune response • Immunosupression  side effect steroids, cytotoxic drugs & immunosupressive regimens • Kidney disease • Nephrotic syndrome • Renal protein loss • ↓ blood level of IgG & IgA, normal IgM • Severe diarrhea  lost igG via the gut • Renal failure & diabetes  secondary phagocyte defect

44. Infection • Malaria & congenital rubella  Ab deficiency • Measles  defects in cell mediated imunity  could reactivate tuberculosis

45. Combined immunodeficiency • Syndrome:

46. Thank You