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M228: Biology of HIV

M228: Biology of HIV. Dr. Beth D. Jamieson 310-206-8217 jamieson@mednet.ucla.edu. Reading material: Course Reader Material 1080 Broxton Ave. 1081 Westwood Blvd. (310) 443-3303. Website: http://cyto.mednet.ucla.edu/biohiv. Lectures available at www.bruincast.ucla.edu

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M228: Biology of HIV

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  1. M228: Biology of HIV • Dr. Beth D. Jamieson • 310-206-8217 • jamieson@mednet.ucla.edu • Reading material: Course Reader Material • 1080 Broxton Ave. • 1081 Westwood Blvd. • (310) 443-3303 • Website: http://cyto.mednet.ucla.edu/biohiv • Lectures available at www.bruincast.ucla.edu • UCLA logon and ID required to access lectures • For problems, call (310) 794-9164 or (310) 794-9232 • Office Hours: TBA

  2. You can’t understand HIV pathogenesis without understanding basic immunology

  3. You can’t understand HIV pathogenesis without understanding basic immunology WHY?

  4. RAISON D’ETRE OF THE IMMUNE SYSTEM: To Distinguish Self from Non-Self Thereby Protecting Us From OurHostile Environment. Adaptive Immunity Innate Immunity

  5. (Antigen nonspecific) defense mechanisms that are used by the host immediately or within several hours of encountering antigen. Innate immunity: -

  6. Cells of the Innate Immune System • Mast Cells – release of histamines, hormones, chemokines. Important in inflammation and allergies. • Neutrophils – phagocytosis • Basophils – histamines • Eosinophils - toxic proteins and free radicals • Macrophages – phagocytosis & antigen presenting cells (APC) • Dendritic Cells - phagocytosis & APC • Natural Killer Cells – lysis of altered cells • gd T-cells and iNKT- border between innate and adaptive immunity

  7. Cells Use Surface Proteins to Communicate • CD: Cluster Designation (CD4, CD8, CD3) • MHC: Major Histocompatibility Complex encoded by chromosome 6 in humans. Approx. 140 genes, ~70 of these are involved in immune responses. • HLA: Human Leukocyte Antigens. Is the name of the MHC in humans = interchangeable.

  8. Cells Use Surface Proteins to Communicate • Antigen Receptors: Allows cells to bind antigens with some specificity.

  9. Antigen Presenting Cells • These specialized cells internalize antigen by • phagocytosis or endocytosis and then express • parts of the antigen on the cell surface. These • cells are distinguished by two properties: • Express class II MHC molecules (Helps in • in presentation of antigen) • Provide co-stimulatory signals necessary for • activation of T-cells.

  10. Acquired Immunity Is adaptive and displays four characteristic attributes: • Antigen specific • Diversity • Immunologic Memory • Self/nonself recognition

  11. Adaptive Immunity • Involves two major types of cells: • Lymphocytes: • Tcells • B cells • Antigen presenting cells: (APC) • Macrophages • B cells • Dendritic cells

  12. Lymphocytes • B-cells: • Produce antibodies and can present antigens. • Are identified by the markers CD19 and CD20. • T-cells: • Cytotoxic T cells kill infected cells. • Are identified by the surface marker CD8. • Helper T cells (Th) provide “help” for • Cytotoxic T cells and B cells. • Are identified by the surface marker CD4.

  13. Effector functions Are induced following physical contact with non-self: • B cells secrete their antigen receptors: • antibodies. • CD4+ T-cells secrete cytokines and • chemokines. • CD8+ T-cells seek and kill cells that express • nonself and also secrete cytokines • and chemokines.

  14. “cyto” = cell, “kine” = indicating movement-intercellular messengers of the immune system; regulate intensity and duration of immune responses by: stimulating or inhibiting the activation, proliferation, and/or differentiation of various cells regulating the secretion of antibodies or other cytokines -a.k.a. lymphokines (secreted by l’cytes),monokines (secreted by mo), interleukins (“between white blood cells”; now up to IL-22). Cytokine:

  15. Chemokine: Small cyotokines that contain four cysteine residues. They are chemotactic, they induce movement of cells.

  16. APC Antigen: ag CD4+ T-cell Y Y CD8+ T-cell B-cell Cytokines And Interferon Y Y Y Y Death signals: Perforin Granzyme etc. Y Y Lysis Clearance, Neutralization

  17. Cell mediated immune responses Humoral responses

  18. T and B cells use specialized receptors to make physical contact with non-self. Although the structure of these receptors are similar, they embrace non-self in very different ways. Binding specificity Cell Antigen receptor B cell Immunoglobulin ( Ig) Soluble antigen T cell T cell receptor (TCR) Processed antigen Lymphocytes cont. * * CD4+ T cells bind antigen with MHC class II CD8+ T cells bind antigen with MHC class I

  19. Immune responses are most efficient in tissue parenchyma. Lymph nodes and the spleen provide architectural support for cell-to-cell interactions, and serve as “filters” for fluids draining other tissues.

  20. Thymus Spleen Bone Marrow

  21. Antigen Specificity: Is determined by interactions between cellular receptors (T-cell receptor and B-cell receptor complex), antigen and human leukocyte antigens (HLA).

  22. Human Leukocyte Antigens: Are encoded by the major histocompatibility complex (MHC) on chromosome 6 in humans. Class I antigens are found on all nucleated cells. = A,B,C CD8+ T cells recognize Class I antigens Class II antigens are primarily on antigen presenting cells (macrophages, dendritic cells and B cells). = DR, DP, DQ CD4+ T cells recognize Class II antigens.

  23. Processing and presentation of antigens

  24. Diversity of the adaptive immune response is due to the diversity of the T-cell and B-cell receptor complexes.

  25. sjPCR cjPCR Signal joint (sj) and coding joint (cj) TREC production from the a/d locus Va Vd dRec Dd Jd Cd yJa Ja Ca Douek et al. Nature 1998

  26. MHC – peptide binding T-cell recognition sequences Anchor Anchor Anchor sequences bind to the MHC.

  27. Peptide sequences effect MHC binding and TCR recognition: Binds MHC AndTCR Loss or decrease In MHC binding Loss or decrease in TCR binding

  28. Antibody – antigen recognition Y Antibodies recognize either linear epitopes or epitopes in secondary structures. A change is the amino acid sequence or secondary structure can eliminate or diminish the antibody binding. Y No binding

  29. APC Class II APC Class II T-cell anergy T-cell activation Activation of T-cells requires signaling through the TCR and co-stimulatory molecules CD80:86 CD4 CD4 CD28

  30. B-cell T-cell TCR complex MHC class II Ag processed For MHC presentation TCR and CD4 Engagement of MHC and ag CD28 Engagement of CD80/86 Upregulation Of CD80/86 CD40 engagement of CD40 Upregulation of CD40 MHC class II TCR complex

  31. Memory Is established through the clonal expansion of activated T or B cells:

  32. Self/nonself recognition: Is achieved through the interaction of antigen receptors, HLA, and antigen. Responses to this complex are controlled through A process of “education”.

  33. Tolerance: The inability to react with self. Autoimmunity: The state in which tolerance to self is lost.

  34. Take Home Points • There are two arms of the immune system • The immune system is designed to protect us from pathogens like HIV • HIV primarily infects cells of the immune system • Know the major functions of each major lymphocyte type • Understand how the body responds to an antigen

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