1. Dr. Gülderen Yanıkkaya Demirel
IMMUNODEFICIENCIES
Dr. Gülderen Yanıkkaya Demirel

2. What is Immunodeficiency?
A failing of one or more of the body’s defensive mechanisms resulting in morbidity or mortality.
Any part of the immune system can be deficient cells, proteins, signalling mechanisms…….
The body is susceptible to infection by organisms that meet with little or no resistance.
Or, in certain cases, other homeostatic systems in the body will be disrupted by the defect.
Severity is variable.
May be Primary or Secondary.

3. IMMUNODEFICIENCIES Primary (inherited) Secondary (to some other)
Physiological

4. Immunodeficiency (Defect in one or more components of immune system)
Types:
Primary: Mutation in genes controlling immune system
(e.g. Recurrent, severe infection in children)
Secondary: Acquired as a consequence of other diseases or environmental factors
(e.g. infection, malignancy, aging, starvation, medication, drugs)

5. Clinical features associated with immunodeficiency
Feature frequency present and highly suspicious:
Chronic infection
Recurrent infection (more than expected)
Unusual microbial agents
Incomplete clearing of infection
Incomplete response to treatment

6. Clinical features associated with immunodeficiency
Feature moderately suspicious
Diarrhea (chronic)
Growth failure
Recurrent abscesses
Recurrent osteomyelitis
Feature associated with specific immunodeficiency disorder
Telangiectasia
Partial albinism

7. CLASSIFICATION of PRIMARY IMMUNDEFICIENCIES
Combined T cell and B cell immunodeficiencies
Predominantly antibody deficiencies
Other well defined immunodeficiency syndromes
Diseases of immune dysregulation
Congenital defects of phagocyte number, function or both
Defects in innate immunity
Autoinflammatory disorders
Complement deficiencies

8. Primary Immunodeficiencies
Stem Cell
Reticular Dysgenesis
Lymphoid
Progenitor
Myeloid
Progenitor
Severe combined
Immunodeficiency
SCID
Congenital
Agranulocytosis
Pre-B
Monocyte
Pre-T
Neutrophil
x-linked
agglobulinemia
xLA
Mature B
Thymus
Leukocyte
Adhesion
Deficiency
DiGeorge
Syndrome D
Chronic
Granulomatous
Disease (x or D)
Mature T
Plasma
Cell
Memory B
WAS
Common Variable Hypogglobulinemia
/ x-linked hyperIgM syndrome/Selective Ig deficiency
WAS=Wiskott-
Aldrich Syndrome x
Bare Lymphocyte
Syndrome

9. Phagocyte Deficiencies:
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Chediak- Higashi syndrome
IL-12 / IFN pathway deficiencies
Chronic or cyclic neutropenia

10. Leucocyte Adhesion Defect (LAD)

12. Defects in T cell-B cell interactions
Btk=Bruton tyrosine kinase
Defect (XLA)
IL-2Rg defect
IL-2Rg
IL-2, 4, 7, 9, 15 B J
Btk
XHM
CD40
CD40L
JAK3
defect Ag
JAK-3 Ag
RAG
1/2
RAG1/2
MHC II
TCR Ig
Bare Lymphocyte
Syndrome (MHC II- ve)
CD4
T cell
B cell
RAG=Recombinase activating gene defect (SCID)
JAK=Janus kinase

13. Adaptive Immunity Deficiency
T cell deficiency
Susceptible to intracellular bacterial infection
Susceptible to viral, parasitic and fungal infection
B cell deficiency
Susceptible to extracellular bacterial infection
Severe Combined Immunodeficiency Disease (SCID)
T and B cell functions defective
Usually fatal
Transplacental/milk transmission of Abs
TCR gene rearrangement lacking
Myeloid and erythroid components intact

19. Ig Levels vs Age

20. Overview of B-Cell Development

21. Hyper IgM syndrome

22. Serum levels of immunoglobulin in Hyper IgM syndrome
IgG↓
IgM ↑↑
IgA↓
IgE↓

23. Hyper IgM syndrome Defect in CD40 ligand T cell B cell Ig Class switch

24. Selective IgA Deficiency
Selective IgA deficiency is the most common ID disorder The prevalence is about 1:700.
Pathogenesis : block in B cell differentiation is due to intrinsic B cell defect or abnormal T cell help such as production of cytokine (TGF-B,IL-5) or in B cell responses to these cytokines.

25. IgA Deficiency
Clinical feature: Recurrent sinopulmonary infection, gastrointestinal disorders, allergy, cancer and autoimmune disease.
IgA Deficiency and genetic factors: association with HLA-A2, B8 and DW3 or A1 and B8.
IgA Deficiency and drug.
Serum IgA<5mg/dl but normal IgM and IgG
Immunopathogenesis :arrest in the B cell differentiation.

26. Selective IgG subclass deficiency
Total serum IgG levels are normal
One or more subclasses are below normal.
IgG3 deficiency is the most common subclass in adults.
IgG2 deficiency associated with IgA deficiency in children.
Pathogenesis: abnormal B cell differentiation.
Some individual have recurrent bacterial infection.

29. Nude Athymic mouse

30. Secondary or Acquired Immunodeficiencies
Agent-induced immunodeficiency: e.g. infections, metaboic disturbance, trauma, corticosteroids, cyclosporin A, radiation, chemotherapy
Acquired Hypogammaglobulinemia (Low levels of Ig; recurrent infections; treat with Ig)

31. Secondary Immunodeficiency
- Infection
- Renal failure, or protein losing enteropathy
Leukaemia or Lymphoma
Myeloma
Extremes of age
- Certain Drug Therapies

33. MALNUTRITION Most common cause of secondary immune deficiency.
Protein-calori malnutrition can lead to abnormalities of T cells, B cells and phagocytes
Atrophic and fibrotic thymus
Reduced lymphocyte proliferation in response to antigens.

35. INITIAL SCREENING for ID’s
Blood Count
Quantitative Immunoglobulins
Antibody responses to previous vaccines
Isoagglutinin (Anti-A and Anti-B) titers
Total hemolytic complement
Infection Evaluation (ESR, appropriate cultures, X-rays)

36. Human Immunodeficiency Virus
Discovered in 1983
Luc Montagnier and Robert Gallo
Retrovirus
HIV-1 and HIV-2
Patients with low CD4+ T cells
Homosexual; promiscuous heterosexual, i.v. drug users; transfusion; infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii, Candida albicans, Mycobacterium avium, etc.
Kaposi sarcoma

37. Kaposi Sarcoma

38. Acquired Immunodeficiency Syndrome (AIDS)
Structure of HIV-1
gp120
env
gp41
Protease
Envelope
Reverse
Trascriptase
pol
Integrase
Matrix (p17)
gag
Capsid (p24)
Genome

39. HIV Infection Coreceptors: Chemokine receptors
T cell-tropic (Syncitium-inducing)
gp120
CXCR4:
SDF1 (Stromal cell
derived factor)
CD4
ssRNA
Macrophage-tropic (Nonsyncitium
inducing)
Provirus
CCR5:
RANTES (regulated
on activation, normal
T cell expressed and
Secreted),
MIP1a, MIP1b
(Macrophage
Inflammatory
Protein)
Reverse
transcriptase
dsDNA

40. Serological Profile
Kuby, 2007

41. Host Factors influencing course
Transmission of HIV
Sexual contact
Breast feeding
Transfusion
During birth
Sharing needles
Resistance to HIV in individuals
CCR5D32
Some HLA types (HLA-A2 are resistant; HLA-B35 are susceptible)

42. Virus-induced effects on immune cells
Th Cells
Initially control viral load
Destruction of infected Th cells by CTL
Cytopathic virus
Anergy of surviving Th cells
CTL
gp120 specific CTL
Virus mutation induces resistance to CTL
Lack of Th affects CTL activation
Resistance to CTL by downregulation of class I MHC on target cells Ab
Develops after 3 weeks
Virus Agic variability
Non-neutralizing. Thus, ineffective

44. Immunomodulation HAART + IL-2 (To reconstitute the immune system)
Chemokine receptor inhibitors
Vaccines: Proteins, DNA, subunit and recombinant virus (SIV-HIV chimeric virus )
Problems
HIV-1 inf. -> AIDS in the presence of Abs
Low immunogenicity
Destruction of CD4+ T cells by vaccine
Integration of virus in host genome
Instability of HIV-1 genome
High rate of virus replication (109 viruses/day)
Live attenuated or heat killed organism (vaccinia virus carrier for HIV proteins)
Route of exposure (Rectal or vaginal challenge)
Lack of animal models and in vitro testing system

45. Summary Primary immunodeficiencies are inherited
They can affect hematopoietic stem cells, lymphoid or myeloid cells.
Secondary immunodeficiencies are due to infections, aging, cancer or chemical exposure
HIV affects immune system by eliminating CD4+ T cells
Vaccine development has been hindered by lack of an experimental model, antigenic variation, etc.