1. Immunodeficiency diseases

2. Which are collectively called immunodeficiency diseases.
Definition:
Defects in one or more components of the immune system lead to serious and often fatal disorders.
Which are collectively called immunodeficiency diseases.

3. Two major types of immunodeficiency diseases
Secondary immunodeficiencies
immunodeficiency resulting from infections and other diseases
immunodeficiency resulting from iatrogenic causes
immunodeficiency due to aging or malnutrition
Primary immunodeficiency
Inherited immunodeficiencies

4. General Features:
The principal consequence of immunodeficiency is an increased susceptibility to infection.
Patients with immunodeficiencies are also susceptible to certain types of cancer.
Immunodeficiency may result from defects in lymphocyte maturation or activation or from the effector mechanisms of innate and adaptive immunity.

5. Secondary immunodeficiencies
Immunodecifiency caused by infectious agents
Many bacterial, viral and parasitic agents compromise the host immune functions, most prominent among them is HIV infection
Immunodeficiency resulting from aging and malnutrition
A number of immune functions become less efficient with aging
Immunodeficiency during malignancy and other diseases, immunosuppressive drugs

6. Immunologic defects caused by HIV infection

7. HIV
Structure
Life cycle
See the three videos

8. CD4+ T cell numbers during HIV infection

9. CD8+ T cell numbers during HIV infection

10. NK cell function among AIDS patients (% cytotoxicity)

11. The cellular and immunological picture - The course of the disease
HIV and AIDS
The cellular and immunological picture - The course of the disease

12. The cellular and immunological picture The course of the disease
HIV and AIDS
The cellular and immunological picture
The course of the disease
1. Acute Infection
High virus titer (up to 10 million viruses per ml blood)
Mild symptoms
Fall in CD4+ cells but recovers
Rise in CD8+ cells but recovers
Macrophages infected

13. HIV and AIDS 2. A strong immune response
Virus almost disappears from circulation
Good cytoxic T cell response
Soluble antibodies appear later against both surface and internal proteins
Most virus at this stage comes from recently activated and infected CD4+ cells (half life about a day)
CD4+ cell production compensates for loss due to lysis of cells by virus production and destruction of infected cells by CTLs

14. HIV and AIDS Latency of virus and of symptoms
3. A latent state
Latency of virus and of symptoms
Virus persists in extravascular tissues
Lymph node dendritic cells
Resting CD4+ memory cells (last a very long time - a very stable population of cells)
Resting CD4+ cells carry provirus

15. HIV and AIDS 4. The beginning of disease
Massive loss of CD4+ cells
CD4+ cells are the targets of the virus (direct cytopathic effects)
Destruction by immune response (ADCC, CTL killing, unmaturation)
Dendritic cells present antigen and virus to CD4 cells just as they are activated
Epitope variation allows more and more HIV to escape from immune response just as response wanes
Apoptosis of CD4+ cells
HIV patients with high T4 cell counts do not develop AIDS

16. HIV and AIDS 5. Advanced disease - AIDS
CD8+ cells destroy more CD4+ cells
CD4 cell loss means virus and infected cells no longer controlled
As CD4+ cells fall below 200 per cu mm virus titer rises rapidly and remaining immune response collapses
CD8+ cell number collapses
Opportunistic infections
Death in ~2 years without intervention
Good correlation between loss of CD4+ cells and onset of symptoms

17. Functional defects among AIDS patients
Susceptibility to opportunistic infections
Pneumocystis, toxoplasma, cryptococcus, herpes,CMV, Mycobacterium avium
Neoplasms, cachexia
kidney failure (HIV nephropathy),
CNS degeneration (AIDS encephalopathy)

19. Treatment Highly Active Anti- Retroviral Therapy
HAART: Two nucleoside analog RT inhibitors and 1 protease inhibitor
Now also: Two nucleoside analog RT inhibitors and 1 non nucleoside
See a video

21. Drug resistance

22. Vaccine
Very difficult
But still being in development

23. Developmental defect in primary immunodeficiencies
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24. Primary immunodeficiency diseases
Stem cell defect
Reticular dysgenesis

25. Primary immunodeficiency diseases
T and B cell defect
severe combined immunodeficiency
X-linked
IL2 receptor γ-chain (50%)
Autosomal (20%)
adenosine deaminase (ADA)
purine nucleoside phosphorylase (PNP)
RAG1 and RAG2 defects

26.    
IL-4R
IL-9R
IL-15R
IL-2R

27. Severe combined immunodeficiency
Lack of Thymic shadow (x-ray) and T and B cells
Lack of all Ig classes and subclasses
No primary follicles and germinal centers
Lymphoid hypo-cellularity of tonsil and Peyer’s patch
Extreme susceptibility to bacterial, viral, parasitic infections
Live vaccines are hazardous

28. Hypocelluarity of the thymus in SCID

29. Hypocelluarity of the lymph node in SCID

30. Hypocelluarity of the tonsil in SCID

31. Hypocelluarity of gut lymphoid tissue in SCID

32. Immunodeficiencies involving T cells
Immunodeficiency of T cell
DiGeorge syndrome
T cell deficiency with some degree of B cell defect
Wiskott-Aldrich syndrome
Ataxia telangiectasia

33. DiGeorge syndrome Poor development or absence of thymus
T cells absent or low in numbers
A thymic graft can correct T cell defect
Other defects due to aberrant fetal development Abnormal facial features
Hypocalcemia due to defect in parathyroid
Congenital heart defects

34. DiGeorge syndrome
Low set, notched ears
Fish mouth

35. Hypocelluarity of thymus DiGeorge

36. Hypocelluarity of lymph node in DiGeorge

37. T cell immunodeficiency due to MHC defects
Deficiency resulting from MHC defect
Class-II MHC defect (class-II trans-activator or a transcription factor defect)
Class-I MHC defect (TAP protein defect)

38. MHC class II deficiency
Bare lymphocyte syndrome
Low or no expression HLA-DP, HLA-DR, HLA-DQ on B cells, macrophages and dendritic cells
At least three genetic defects, CIITA, RFX-J and RFXAP
T cells are near normal, CD4 cells decreased.
Lymphocytes proliferate normally to PHA ,but poorly to antigen
Immunoglobulin responses are poor

40. MHC class I deficiency
Less common and less severe than MHC class II deficiency
The defects is associated with the gene encoding TAP-1 or TAP-2 subunit of TAP complex
Patients may have chronic aspiratory infection.
A few patients gave both class I and class II MHC deficiencies

41. Ataxia telangiectasia
Immune defects
Reduced T cell-numbers and functions (PHA, con-A responses)
Low IgG and IgA
Non immune defects
Lack of coordination
Telangiectasis
Defective DNA repair mechanism
Break in TCR & Ig heavy chain genes

42. Wiskott-Aldrich syndrome
Immune defects
T cells normal in numbers; reduced functions
Low IgM, normal IgG and elevated IgA and IgE
Poor antibody response to polysaccharides
Poor polyclonal T-cell response to lectins
Non immune defects
Eczema and petechia （瘀点）
Thrombocytopenia and defective platelets
Defective WASP (Xp11.22)
Defective cytoskeletal organization

43. Immunodeficiencies involving B cells and or Ig
X-linked (Bruton’s) hypo-γ-globulinemia
Common variable hypo-γ-globulinemia
Selective IgA deficiency
Selective IgG deficiency
Hyper-IgM deficiency (mutation of CD40L)

44. X-linked (Bruton’s) hypo- γ -globulinemia
Low B cell numbers
Low immunoglobulin classes and subclasses
Defect in btk (Bruton’s tyrosine kinase) gene

45. Common variable hypogammaglobulinemia
Acquired in the 2nd or 3rd decade of life
All immunoglubulins decline
Cause unknown

46. Immunodeficiency of the non specific immune system
Phagocyte defects
Cyclic neutropenia
Chronic granulomatous disease
Leukocyte adhesion defect
Chediak-Higashi syndrome
Complement deficiencies

47. Phagocyte defects (1) Cyclic neutropenia
Poor regulation of neutrophils
Chronic granulomatous disease
Defect in NADPH oxidase (cytochrome-b558)
Poor NBT (nitroblue tetrazolium test) reduction

48. Phagocyte defects (2) Leukocyte adhesion defect
Defect in CD11a (LFA-1) or CD11b (mac-1)
Chediak-Higashi syndrome
Poor phago-lysosome fusion
Poor NK cell activity

49. Poor intracellular killing and NBT-reduction tests in CGD

50. Complement deficiencies
C3 deficiency
Due to poor C3 synthesis
Due to a deficiency of factor I or H
C1-C9 deficiency
Poor synthesis of individual components
C1-INH deficiency
Hereditary angioedema

51. C1-inhibitor deficiency: angioedema

52. Indicate whether each of the following statements is true or false.
If you think a statement is false, explain why.
a. DiGeorge syndrome is a congenital birth defect resulting in absence of the thymus.
b. X-linked agammaglobulinemia (XLA) is a combined B-cell and T-cell immunodeficiency disease.
c. The hallmark of a phagocytic deficiency is increased susceptibility to viral infections.
d. In chronic granulomatous disease, the underlying defect is in a cytochrome or an associated protein.

53. e. Injections of immunoglobulins are given to treat individuals with X-linked agammaglobulinemia.
f. Multiple defects have been identified in human SCID.
g. Mice with the SCID defect lack functional B and T lymphocytes.
h. Mice with SCID-like phenotype can be produced by knockout of RAG genes.
i. Children born with SCID often manifest increased infections by encapsulated bacteria in the first months of life.
j. Failure to express class II MHC molecules in bare-lymphocyte syndrome affects cell-mediated immunity only.