1. Immunodeficiency

2. Objectives Definition Primary Immunodeficiencies Characteristics
Types of primary immunodeficiency disorders
Mode of inheritance
Secondary Immunodeficiency
Human Immunodeficiency Virus
Immune response to HIV

3. Immunodeficiency Defect in 1 or more components of immune system
Types:
Primary or Congenital:
Born with the immunodeficiency
Inherited (Mutation in gene controlling immune cells)
Susceptible to recurrent and severe infections
Start in childhood
Cannot recover without treatment
Secondary or Acquired: As a consequence of other diseases, drug therapy or environmental factors
(e.g. infection, malignancy, aging, malnutrition, drugs, trauma, radiation, surgery). Prototype - Human Immunodeficiency Virus s

4. Inheritance of Primary Immunodeficiency disorders
22 pairs of autosomes and 1 pair of sex chromosomes (X and Y)
Follow the Mendelian laws of inheritance

5. Examples of Inheritance Patterns of Primary Immunodeficiency
Carrier x Carrier
Mother Father
Aa Aa
Normal x Affected
Mother Father
aa Aa
Carrier x Normal
Mother Father
XX XY M F X Y XX
Normal XY
Carrier
Affected
Autosomal Recessive Autosomal Dominant X-linked
Heterozygous are not affected Heterozygous are affected % of males are affected

6. Hematopoiesis
Progenitor
Progenitor

7. Hematopoietic Stem Cell (HSC) deficiency
HSC are multipotent (differentiate into all blood cell types)
Self renewing cells
Defect in HSC results in immunodeficiency known as Reticular Dysgenesis
Affects development of all leukocytes
Patients are susceptible to all infections (bacterial, viral, and fungal)
Fatal without treatment
Treated with bone marrow or HSC transplantation

8. Defects in Lymphoid Lineage
Progenitor
Progenitor

9. Defect in Lymphoid Progenitor
Results in Severe Combined Immunodeficiency (SCID)
Lack T, B and/or NK cells
Thymus does not develop
Myeloid and erythroid cells are normal.
Generally lethal
Susceptible to bacterial, viral and fungal infections.
In infants, passively transferred maternal Abs are present.
Live attenuated vaccines (e.g. Sabin polio) can cause disease.

10. Bubble Boy David Vetter (1971-84; SCID patient died of
EBV-induced lymphoma and not due to
GVHD following BM transplantion from sister)
Ted DeVita ( ) – Aplastic anemia
Died of iron overload due to repeated
transfusions

11. Types of SCID TCR Ig B cells T cells T cells/ NK cells IL-2
RAG-1/2 (Recombinase activating gene) deficiency: Required for TCR and Ig gene rearrangement. lack T and B cells but have NK cells
IL-2R γ gene defect (X-linked)
Adenosine deaminase (ADA) deficiency
Adenosine Inosine Uric acid
T, B and NK cell deficiency due to toxicity of accumulated metabolites
First successful gene therapy done in patient (Ashanti DeSilva treated at NIH in 1990)
TCR Ig
B cells
T cells
T cells/
NK cells
IL-2 receptor (α,β and γ common chain).
γc chain common for IL-2, 4, 7, 9, 15
IL-2
ADA

12. Defect in T cell development
Progenitor
Progenitor

13. DiGeorge syndrome

14. Precursor T cell differentiation defect
Athymic - DiGeorge Syndrome
Lack of T helper (Th) cells , Cytotoxic T cells (CTL) and T regulatory (Treg) cells
B cells are present but T-dependent B cell responses are defective
Anti-viral and anti-fungal immunity impaired
Developmental defect in the 3rd and 4th pharyngeal pouch
Results in facial defect, congenital heart disease, parathyroid defect
Treated with MHC-matched thymic epithelial cell transplant
Autosomal dominant trait

15. Defects in B cell development
Progenitor
Progenitor

16. Hyper IgM Syndrome (HIgM)
X-linked Agammaglobulinemia (x-LA)
Absence of Igs and B cells
Arrest at Pre-B cell stage (H-chain rearranged but not L chain)
Block in Th cell interaction with B cells
B cells express IgD and IgM on membrane
Increased IgM in serum
Deficiency in IgG, IgA and IgE
X-linked
Recurrent infections
e.g. IgA deficiency
Due to defect in isotype switching
Recurrent respiratory, gastrointestinal and/or
genitourinary infection
Hyper IgM Syndrome (HIgM)
Pre B
cells
Mature B
x-LA
Proliferation
Differentiation
Isotype
switching
CVD
IgA def.
Plasma
IgM
HIgM
Selective Ig class deficiency

17. Defects in Myeloid Lineage
Progenitor
Progenitor

18. Myeloid Progenitor Cell Differentiation Defect
Myeloid Progenitor Cells develop into neutrophils and monocytes
Defect in differentiation from myeloid progenitor cells into neutrophils results in
Congenital Agranulocytosis
Recurrent bacterial infections seen in patients
Treated with granulocyte-macrophage colony stimulating factor (GM-CSF) or granulocyte
colony stimulating factor (G-CSF)

19. Defective Neutrophils
Patients have neutrophils that are defective in NADP oxidase and production of reactive oxygen species (ROS) that is responsible for killing of phagocytosed microbes.
This results in accumulation of granulocytes, Mf and T cells forming granulomas. These patients suffer from
Chronic Granulomatous Disease.
Have recurrent bacterial and fungal infections
Commensals can become pathogenic
X-linked or autosomal recessive
Treated with antibiotics/IFN-g against infections

20. Overview of Primary Immunodeficiencies
DiGeorge Syndrome (Autosomal dominant)
SCID
Common Variable
Hypogglobulinemia/
X-linked hyperIgM
Syndrome/Selective
Ig deficiency
Progenitor
xLA
Reticular
Dysgenesis
Progenitor
Congenital
Agranulocytosis
Chronic Granulomatous Disease
Auto rec./X-linked)

21. Secondary or Acquired Immunodeficiencies
Agent-induced immunodeficiency: e.g. infections including HIV
Metabolic disorders and trauma
Splenectomy
Drugs such as corticosteroids, cyclosporin A, radiation and chemotherapy
Aging

22. Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Is a member of genus retrovirus (RNA virus) belonging to Lentiviridae
Characterized by long incubation period and slow course of disease
HIV-1 (Common in US) and HIV-2 (in Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual, promiscuous heterosexual, i.v. drug users, transfusion, infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii, Candida albicans, Mycobacterium avium, etc.
Patients with HIV have high incidence of cancers such as Kaposi sarcoma

23. Course of AIDS Anti-HIV Ab/CTL ACUTE CHRONIC AIDS
Dissemination of virus;
Seeding of lymphoid organs
Anti-HIV Ab/CTL
ACUTE CHRONIC AIDS
PHASE PHASE (<200cells/mm3)

24. Structure of HIV env (Envelope) (p24) (p17) Protease Matrix Capsid
Integrase
gag
pol

25. Abs are ineffective to control HIV
Virus grows intracellularly
Abs develop after ~3 weeks. Thus cannot be used as a diagnostic test initially
Reverse transcriptase is a sensitive test for diagnosis.
Abs are not neutralizing

26. Role of T cells in development of AIDS
Initially Th cells control viral load
Cytopathic virus
Syncitium formation with infected/uninfected cells
Surviving Th cells are anergic
Destruction of infected Th cells by CTL
CTL that develop are ineffective because of high viral mutations
Lack of Th cells affects CTL activation
Resistance to CTL by downregulation of class I MHC on target cells

27. Coreceptors of HIV: In addition to gp120 binding to CD4, HIV has to bind coreceptors to gain entry into the cells. These coreceptors also serve as receptors for chemokines.
Chemokine receptors
T cell-tropic (Syncitium-inducing; X4 virus strain)
Macrophage-tropic (Nonsyncitium-inducing; R5 virus strain)
CD4
CXCR4:
Ligand is SDF1 (Stromal cell
derived factor)
CD4
CCR5:
Ligands are RANTES (Regulated on activation, normal T cell expressed and secreted),
MIP1a, MIP1b (Macrophage Inflammatory Protein)