1. MICR 304 Immunology & Serology
Lecture 16
Immunodeficiency Diseases
Chapter 12.7-

2. Overview of Today’s Lecture
Inherited immunodeficiencies
Immunoglobulins
Complement
Phagocytes
T cells
Acquired immunodeficiencies
Artificial
AIDS

3. Immunodeficiencies
Caused by defects of one or more components of the immune system
Recurrent infections
Often opportunistic microbes

4. Susceptibility for Infections
Defects in complement, phagocytes, antibodies:
Extracellular bacteria, pyogenic infections
Defects in T-cells:
Fungal and viral infections, infections with intracellular pathogens

5. Compare and Contrast Inherited and Acquired Immune Deficiencies
Inherited defects of the immune system
Alterations in genes involved in immunity
Symptomatic from infancy on
Acquired defects of the immune system
Various causes
Typically develop later

6. Our most Important Defense Weapons
Complement: to opsonize, initiate inflammatory response, and to kill
Antimicrobial peptides: to kill and to modulate immune response
Phagocytes: to remove microbes, prevent further spread, to kill and in some cases to initiate adaptive immune response
Antibodies: to neutralize, opsonize, and to agglutinate
Granuloma formation: a concerted action to wall off and ultimately kill intracellular microbes
NK cells and CTLs: to remove infected (or maligne) host cells via apoptosis and indirectly kill microbial invaders
TH and regulatory T cells: to orchestrate the immune response

7. Evaluation of the Immune System

8. Inherited Immune Defects Discussed Today
Complement
C1 Inhibitor deficiency, C5-9 deficiency
Phagocytes
Chronic granulomatous disease
Leukocyte adhesion deficiency
Antibodies (B-cells)
X-linked ammaglobulinemia
X-linked hyper IgM syndrome
T- cells
X-linked gc SCID
B+T cells
ADA deficiency

9. Complement System
C1INH
DAF
Proctectin
Factor I

10. Complement Deficiencies
Lack of active complement factors:
C3 damage: wide range of pyogenic infections (S. aureus, S. pyogenes etc)
Overall and in particular with C5-9 deficiency increased Neisseria infections
10,000 x risk increase
Lack of control proteins
C1 Inhibitor: angioneurotic edema
Decay accelerating factor: spontaneous hemolytic attacks
Factor I: consumption of complement, lack of complement

11. Phagocyte Defects Chronic Granulomatous Disease
NADPH oxidase defect
Many different gene mutations
No superoxide radical production
Host forms granulomas to eliminate pathogens
Leukocyte adhesion deficiency
Mutations in sialyl lewis (ligand for selectin) or intergrins
Prevents leukocyte migration to the locus of infection

12. Diagnostics in Chronic Granulomatous Disease
Aspergillus pneumonia in CGD patient
Pneumonia
Altered NBT Test
Normal
Patient
Carrier
Nitro blue tetrazolium is reduced by NADPH oxidase to yield an insoluble blue formazan salt.

13. X-Linked Agammaglobulinemia (XLA)
Failure to produce antibodies
Increase in infections with pyogenic bacteria e.g. S. pyogenes and chronic viral infections e.g. hepatitis B
Mutations in X-chromosome
One of the common: Bruton’s Disease
Mutation in Bruton’s tyrosine kinase (Btk)
Signal transduction defect in pre-B cells
No stimulation in response to Ag
Arrest of B-cell development
B-cells rarely found in peripheral blood

14. Consequences of Btk Mutation
In normal males, only X-chromosome is active
In affected male no B-cell development
In female carriers, only B-cells that have randomly inactivated the defect chromosome mature
All mature B-cells have the nondefective x-chromosome activated
Non-random X chromosome inactivation only in B cells
Signal transduced via Btk

15. Onset of XLA
When maternal antibodies fade

16. Absence of Immunoglobulins in Serum from XLA Patients

17. Absence of B-Cells in XLA
Flow cytometer analysis
CD19: B-cell marker
CD3: T-cell marker

18. Refresher: B-Cell Activation by T-Cells

19. Hyper IgM Syndrome
Normal B and T cell development but lack of IgG, IgA, and IgE
B-cell activation by T-cells is disrupted
CD40 ligand deficiency in T-cells prevents activation of otherwise normal B-cells
X-linked
Also defective in cell mediated immunity
Mutations in CD40 in B cells
Mutation of NFkB pathways in B-cells (NEMO)
AID deficiency
No isotype switch after antigen recognition
Lymphoid tissues are devoid of germinal centers
Selected syndromes

20. AID Deficiency
Mutation in gene for activation induced cytidine deaminase
Subform of hyper IgM syndrome
Defective B cells with lack of isotype switch
More susceptible to severe bacterial infections but not to opportunistic infections e.g. P. carinii pneumonia

21. Severe Combined Immunodeficiencies
B and T cell function is affected
Causes can be primary T cell defects or T and B cell defects
Without T cells lack of
T cell dependent antibodies
Cell mediated immune responses
Immunological memory
Severe opportunistic infections
Adenoviruses
EBV
Candida albicans
P. carinii

22. Major Causes of SCID

23. X-Linked SCID with Common Gamma Chain Mutation
Common gamma chain of the following cytokine receptors affected:
IL2, IL4, IL7, IL9, IL15, IL21
Predominantly T-cell defect
No T-cell development, no NK cells
B cell numbers are normal but not their function
Lack of macrophage activation and B-cell activation
X-linked

24. Refresher: Selected Cytokines
Major Effects
IL2
T cell proliferation
IL4
B cell activation, IgE switch, TH2 differentiation
IL7
Growth of pre-B cells and pre-T cells
IL9
Mast cell enhancing activity, TH2 stimulation
IL15
Stimulates growth of T cells, NK cells, enhances CD8 memory T cell survival
IL21
Induces proliferation of B, T, and NK cells

25. Autosomal SCID: ADA Deficiency
Adenosine deaminase deficiency
Alterations in purine degradation
Accumulation of nucleotide metabolites
In particular toxic for T-cells, also B-cells
General lack of T and B-cell function

26. Refresher: T-Cells and Granuloma Formation
Functional T cells are essential in clearing infections with intracellular pathogens.

27. Acquired Immune Deficiencies
Natural: newborns
Immune suppressive therapy
Cyclosporin (transplantation)
Steroids (autoimmune diseases, chronic inflammation)
Tumor patients
Neutropenia during therapy
Cytokine production (TGF-b, IL10)
Chronic Disease
Infections
Measles
HIV and AIDS

28. Transient Immunoglobulin Deficiency in Newborns

29. HIV Infection is Pandemic

30. HIV Virus
Retrovirus
Infects CD4+ cells: TH cells, dendritic cells, macrophages, monocytes
Requires co-receptor: chemokine receptor
Tropism depends on chemokine receptor
CCR5: DC, MP, CD4 T Ly
R5 virus
Mutations protect against HIV infection
CXCR4: activated T Ly
X4 virus

31. Dendritic Cells Transport HIV to Lymphnodes

32. Typical Course of Untreated HIV Infection

33. Immune Response to HIV

34. HIV Associated Diseases
T- cell defect
Lack of macrophage activation
Intracellular opportunistic infections
Lack of effective CTLs
Development of virus- associated tumors

35. Tumors Associated with HIV Infection
Remember
T-helper cells activate NK cells
New Herpes viridae are involved that are not eliminated
Lymphoma, Kaposi sarkoma

36. Diagnostics of Immune Deficiencies
Complement: CH50 test
Phagocytes: NBT test, phagocytosis and killing tests
Antibodies: immune electrophoresis
B-cells: pokeweed stimulation, induced antibody response
T cells: unspecific lymphocyte stimulation with phytohemagglutin, skin tests

37. Therapeutic Approaches for Immune Deficiencies
Symptomatic
Ig treatment
Bone marrow transplantation
Gene therapy
Remove bone marrow
Insert new gene into collected cells
Re-implant bone marrow
Antiviral therapy

38. Bone Marrow Grafting is Problematic
Can be prevented by T-cell depletion of donor marrow

39. Often requires up to 40 pills a day.
HIV Therapy
Reverse Transcriptase Inhibitors
Protease Inhibitors
Virus decoys (material to which virus binds instead of to cells)
Boosting immune system
Often requires up to 40 pills a day.