1. By: Oki Suwarsa, dr, MKes, SpKK(K)
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. PRIMARY IMMUNODEFICIENCY
Infection
Mutation
Polymorphisms
Polygenic
Tumors
Gene therapy
Immunoglobulins

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

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
Dua atau lebih gejala dalam satu tahun
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. SECONDARY IMMUNODEFICIENCY
Infection
HIV
Stress
Nutrition
Tumors
vaccines
Immunomodulation
Extremes of age
Drugs

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:
Wiskott-Aldrich syndrome
Trias: eksim, trombositopenia, imunodefisiensi
Ataksia-teleangiektasia
Ataksia serebelar, teleangiektasia okulokutaneus
Sindrom DiGeorge
Delesi kromosom 22q11
Malformasi jantung, hipotiroid, hipokalsemi, wajah dismorfik, gangguan perkembangan timus

46. Thank You