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Primary and Acquired Immunodeficiencies

Primary and Acquired Immunodeficiencies. Lecture 50 Tuesday, May 1, 2007 Refs. Kuby Immunology Chapter 20 Brock Biology of Microorganisms Basic Pathology p. 147-158. Primary immunodeficiencies. Lymphoid progenitor line- (continued) Bare-lymphocyte syndrome-lack of class II MHC

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Primary and Acquired Immunodeficiencies

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  1. Primary and Acquired Immunodeficiencies Lecture 50 Tuesday, May 1, 2007 Refs. Kuby Immunology Chapter 20 Brock Biology of Microorganisms Basic Pathology p. 147-158

  2. Primary immunodeficiencies • Lymphoid progenitor line- (continued) • Bare-lymphocyte syndrome-lack of class II MHC • Similar to SCID • B cell disorders vary in severity • IgA deficiency can be asymptomatic • Myeloid progenitor line- affects innate immunity • Agranulocytosis or neutropenia • Chronic granulomatous disease • Defect in microbial killing • Caused by defective cytochrome or one of the phagocyte oxidase genes • Leukocyte adhesion deficiency • Chédiak-Higashi syndrome

  3. Causes of SCID Deficiency of the IL-R g chain (x-linked) • Adenosine deaminase (ADA) deficiency • Deficiency in CD45 • Deficiency in JAK-3 • Deficiency of the IL-7Ra chain • Tyrosine kinase ZAP-70 deficiency • depleted CD8+ and nonfunctional CD4+ T cells • Purine nucleoside phosphorylase (PNP) defect • Deficiency in RAG-1 or RAG-2 • Undetermined

  4. Distribution of genetic defects in SCID based on 170 casesKI 20-3a

  5. Lymphocyte phenotypes in different genetic defects of SCID KI 20-3b

  6. Summary of X-linked immuno-deficiencies.Loci on the X chromosome.KI 20-2

  7. Defects in signaling cause immunodeficiency 20-4

  8. Defects in cell signaling lead to immunodeficiency • Lack of IL R g chain • Lack of receptors for IL-2, IL-4, IL-7, IL-9, IL-15 • Results in SCID • X-linked hyper-IgM syndrome • Elevated levels of IgM and deficiency of other isotypes • Defect is lack of CD40 ligand on T cell • Lack of T cell help for isotype switching • X-linked agammaglobulinemia • Study of patient with this disorder lead to discovery Bruton’s tyrosine kinase in signal transduction pathway

  9. Animal models of immunodeficiency • Nude mice • Lack thymus and T cells • Autosomal recessive- spontaneous mutation • Hairlessness may be due to same or closely linked gene • SCID mice • Discovered 1983 • Autosomal recessive- spontaneous mutation • “Leaky” some mice produce some antibodies and CTLs • RAG knock-out mice • Deletion of either recombinase activating gene • Cannot rearrange T or B cell receptors

  10. Treatment of primary immunodeficiencies • Administration of protein • Human immunoglobulin for impaired of antibody production • Recombinant IFN g helps CGD • Replacement of cell or lineage • Bone marrow transplant • Replacement of missing or defective gene • Replace defective ADA gene for SCID • Replace defective phagocyte oxidase in CGD

  11. Acquired immunodeficiency • Most common cause is infection with the retrovirus HIV-1or HIV-2 • Other causes are: • Chemical exposure • Irradiation • Immunosuppressive therapy • Cancer chemotherapy • Idiopathic • Acquired hypogammaglobulinemia

  12. Characteristics of retroviruses • Enveloped virus • Genome is ssRNA + strand • Nucleocapsid contains 2 copies of RNA. • 5’ end is capped; 3’end is polyadenylated, but it is not used as mRNA • Nucleocapsid also contains 3 enzymes • Replicate through a DNA intermediate • Terminal repeats are essential in replication • First viruses shown to cause cancer • e.g. Rous sarcoma virus • DNA becomes integrated into host genome. • Use as vector for gene therapy

  13. Human Immunodeficiency Virus-1 • Recognized AIDS in 1981 in U.S. • Isolated HIV-1 in 1983 (by 2 groups Montagnier and Gallo) • HTLV-1 isolated in 1980 (at first thought to be the cause of AIDS) • HTLV-II isolated in 1982 causes hairy cell leukemia • Cells that can be infected by HIV express CD4 • Lymphocyte • Monocyte/Macrophage

  14. Transmission of HIV-1 • Via body fluids and infected cells- lymphocytes, macrophages, and dendritic cells • Virus can be transferred in: • Blood • Contact of abraded skin or mucosal surfaces • Transfusion, needle sharing, accidental needle stick • Semen or vaginal fluid • concurrent STD increases transmission • Milk of infected mother • Babies of infected mothers may be exposed by placental transfer, maternal blood during parturition, or milk. • 90% of infected children acquired infection at birth • Decreasing maternal viral load with antiretroviral therapy decreases number of infected children • There is no evidence for airborne transmission or spread by casual contact.

  15. US death rates in 25-44 year-olds Imm. KI 20-7

  16. Schematic structure of HIV-1 KI 20-9

  17. EM of HIV-1 at 200,000 x KI 20-9b

  18. Organization of HIV-1 genome. 3 major genes, gag, pol, and env encode proteins that are then cleaved to form nucleocapsid proteins, enzymes, and envelope proteins. KI 20-11a

  19. Functions of proteins encoded by the HIV-1 genome KI 20-11b

  20. HIV-1 infection of target cell KI 20-12a

  21. Reverse transcription • Only one copy of ssRNA is reverse transcribed. • The primer for the reverse transcriptase is a tRNA from the previous host cell packaged in the core. • Formation of dsDNA takes place in the cytoplasm of host cell within the nucleocapsid of the virus. • The formation of dsDNA is complicated and involves 3 activities of the polymerase. • Reverse transcriptase (RNA-dependent DNA polymerase, RNase H activity, and DNA polymerase. • During formation of dsDNA, the repeats become long terminal repeats. • The dsDNA with the viral integrase enter the nucleus of the host cell.

  22. Steps in formation of dsDNA from retroviral ssRNA Brock 16.23

  23. Production of viral particles KI 20-12b

  24. Coreceptors for HIV-1 infection KI 20-12c

  25. Changes in viral load and CD4+ T cells after HIV-1 infection KI 20-13

  26. Current therapy inhibits reverse transcription and protease Imm 20-16

  27. HAART (highly active anti-retroviral therapy) • Multiple drug regimen • Usually 2 nucleoside analogs and a protease inhibitor • Decreases viral load and allows increase in CD4+ T cells • Improves health and allows patients to function at a normal level • Problems are side effects, difficult dosing regimen, expense ($15,000/yr), and inability to eradicate infection due to latent proviral state

  28. Problems in development of AIDS vaccine • Natural immune response does not produce cure. • Vaccine must prevent infection. • HIV-1 mutates at a very rapid rate. • Killed HIV-1 does not retain antigenicity. • Live attenuated virus is too risky. • Repeated exposure/high level exposure. • Route of infection primarily through genital tract. • Lack of suitable animal model.

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