Immunodeficiency

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Immunodeficiency

• Mitzi Nagarkatti
• Professor and Chair, Dept. Pathology,
  Microbiology and Immunology
• Deputy Director, USC Cancer Center
• USC School of Medicine
• Tel. [phone]
• E-mail mnagark_at_med.sc.edu

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Outline

• Common Primary Immunodeficiencies
• Acquired Immunodeficiency (HIV)
• Therapy and prevention of AIDS

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Immunodeficiency

• Defect in 1 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)

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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
WASWiskott- Aldrich Syndrome x
Bare Lymphocyte Syndrome
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DiGeorge syndrome
3rd and 4th pharyngeal pouch
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Defects in T cell-B cell interactions
BtkBruton 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
RAG 1/2
Ag
RAG1/2
MHC II
TCR
Ig
Bare Lymphocyte Syndrome (MHC II- ve)
CD4
T cell
B cell
RAGRecombinase activating gene defect (SCID)
JAKJanus kinase
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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

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Nude Athymic mouse
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Immunodeficiencies

• IL-2Rg Common Chain deficiency (IL-2, 4, 7, 9 and
  15 signaling)
• Adenosine Deaminase (ADA deficiency)
• ADA
• Adenosine--------?Inosine
• (T, B and NK cell deficiency)
• Recombinase activating gene (RAG-1 and 2)
• (T and B cell deficiency)

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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)

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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

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Kaposi Sarcoma
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Acquired Immunodeficiency Syndrome (AIDS)
Structure of HIV-1
gp120
env
gp41
Protease
Envelope
Reverse Trascriptase
pol
Integrase
Matrix (p17)
gag
Capsid (p24)
Genome
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HIV Infection
Coreceptors Chemokine receptors T cell-tropic
(Syncitium-inducing)
CXCR4 SDF1 (Stromal cell derived factor)
gp120
CD4
Provirus
ssRNA
Macrophage-tropic (Nonsyncitium inducing)
Reverse transcriptase
CCR5 RANTES (regulated on activation, normal T
cell expressed and Secreted), MIP1a, MIP1b
(Macrophage Inflammatory Protein)
dsDNA
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Serological Profile
Kuby, 2007
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Immunological Abnormalities

• Infection and destruction of dendritic cells,
  macrophages and Th cells
• Late decrease in Th cell numbers (200/mm3 blood)

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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

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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)

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Animal Models

• Primate Model
• HIV grows in chimpanzees but do not develop AIDS
• Simian immunodeficiency virus (SIVagm in African
  green monkey no disease SIVmac in Macaques
  AIDS like) Feline immunodeficiency virus (FIV),
  etc.
• Mouse Model
• Grows in Severe Combined Immunodeficiency (SCID)
  mice reconstituted with human lymphocytes

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Therapeutic targets
























Kuby, 2007
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Therapy

• Reverse Transcription Inhibitors
• Nucleoside RT inhibitors e.g. Zidovudine or AZT
  (azidothymidine)
• Non-nucleoside RT inhibitors e.g. nevirapine
  (Inhibit RT)
• Protease inhibitors (proteases cleave precursor
  proteins into proteins that are needed for virion
  assembly)
• Integrase inhibitors (integration of provirus in
  the cell DNA e.g. ritonavir)
• Entry/Fusion inhibitors e.g. enfuvirtide
• HAART (Highly active anti-retroviral therapy)
  combination
• Problems
• Anemia
• Virus in brain
• Antigenic variation
• BBB not penetrated by drugs
• High costs (15K/yr)

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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. -gt 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

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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.

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Reading

• Immunology
• By Male, Brostoff, Roth and Roitt
• 7th Edition
• Pages299-324