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M228: Biology of HIV • Dr. Beth D. Jamieson – 310-206-8217 – [email protected] • 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 You can’t understand HIV pathogenesis without understanding basic immunology You can’t understand HIV pathogenesis without understanding basic immunology WHY? RAISON D’ETRE OF THE IMMUNE SYSTEM: To Distinguish Self from Non-Self Thereby Protecting Us From Our Hostile Environment. Innate Immunity Adaptive Immunity Innate immunity: (Antigen - nonspecific) defense mechanisms that are used by the host immediately or within several hours of encountering antigen. 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 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. Cells Use Surface Proteins to Communicate • Antigen Receptors: Allows cells to bind antigens with some specificity. 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: 1. Express class II MHC molecules (Helps in in presentation of antigen) 1. Provide co-stimulatory signals necessary for activation of T-cells. Acquired Immunity Is adaptive and displays four characteristic attributes: •Antigen specific •Diversity •Immunologic Memory •Self/nonself recognition Adaptive Immunity Involves two major types of cells: Lymphocytes: a. Tcells b. B cells Antigen presenting cells: (APC) a. Macrophages b. B cells c. Dendritic cells 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. 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. Cytokine: “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). Chemokine: Small cyotokines that contain four cysteine residues. They are chemotactic, they induce movement of cells. APC Antigen: ag CD4+ T-cell Lysis Y B-cell Y Death signals: Perforin Granzyme etc. Cytokines And Interferon Y Y YY CD8+ T-cell YY Clearance, Neutralization Cell mediated immune responses Humoral responses Lymphocytes cont. 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. Cell Antigen receptor Binding specificity B cell Immunoglobulin (Ig) Soluble antigen T cell T cell receptor (TCR)* Processed antigen *CD4+ T cells bind antigen with MHC class II CD8+ T cells bind antigen with MHC class I 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. Thymus Spleen Bone Marrow Antigen Specificity: Is determined by interactions between cellular receptors (T-cell receptor and B-cell receptor complex), antigen and human leukocyte antigens (HLA). 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. Processing and presentation of antigens Diversity of the adaptive immune response is due to the diversity of the T-cell and B-cell receptor complexes. Signal joint (sj) and coding joint (cj) TREC production from the a/d locus Va Vd dRec Dd Jd Cd yJa Ja Ca sjPCR Douek et al. Nature 1998 cjPCR MHC – peptide binding T-cell recognition sequences Anchor Anchor Anchor sequences bind to the MHC. Peptide sequences effect MHC binding and TCR recognition: Binds MHC AndTCR Loss or decrease In MHC binding Loss or decrease in TCR binding Antibody – antigen recognition 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. No binding Activation of T-cells requires signaling through the TCR and co-stimulatory molecules APC Class II APC Class II CD80:86 CD4 CD4 CD28 T-cell anergy T-cell activation T-cell TCR complex B-cell MHC class II TCR and CD4 Engagement of MHC and ag Ag processed For MHC presentation CD28 Engagement of CD80/86 Upregulation Of CD80/86 Upregulation of CD40 CD40 engagement of CD40 TCR complex MHC class II Memory Is established through the clonal expansion of activated T or B cells: 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”. Tolerance: The inability to react with self. Autoimmunity: The state in which tolerance to self is lost. 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