Mucosal Immune System

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1 Exam Format 100 points - 60 pts mandatory; 40 points where 4, 10 point questions will be chosen Some open-ended questions, some short answer. Kuby question

2 Cytokines Terminology How do cytokines achieve their effect? Radius of action Specific cytokines - also Th1 vs Th2 cytokines Receptor families Regulation of cytokine action

3 granuloma formation

4 Mucosal Immune System Components of the intestinal immune system Barrier system Innate immune system Adaptive immune system Antigen transport in the intestine IgA Commensal bacteria

5 Primary Immunodeficiency Diseases Matching

6 lymphocytes monocytes DCs microglia CCR5, CXCR4

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8 Activated CD4+ T cells

9 Study Points for Ponzio Lectures Cell-mediated immunity キ Interactions between Antigen Presenting Cells (APC) and T cells, and the sites where these interactions occur キ Compare and contrast TH subsets and the types of immune responses in which they are involved, and the mechanisms by which they mediate these immune responses キ Interactions between TH1 cells and effector Cytotoxic T Lymphocytes (CTL) キ Interactions between TH1 cells and effector macrophages キ Mechanisms by which CTL and other cytotoxic effector cells kill target cells

10 Ponzio, cont. Cancer immunology キ Various types of tumor-associated antigens, and different ways they can be detected to identify malignant cells in the body キ How T cells recognize tumor-associated antigens and are stimulated to become activated, clonally expand, and differentiate into effector cells キ Ways in which tumor cells avoid detection and/or rejection by the immune system キ Strategies for cancer immunotherapy that are based on our knowledge of how APC process and present antigens, and how T cells recognize and respond to antigens

11 Transplantation Transplantation is the process of transferring cells, tissues or organs, called a graft from one site to another or from one individual to a different individual. Graft rejection is an immunological response displaying specificity, memory and self-nonself recognition. Three major types of rejection: Hyperacute rejection, mediated by preexisting recipient (host) antibodies to graft antigens. Acute graft rejection, in which TH cells and/or cytotoxic T cells mediate tissue damage. Chronic rejection, which involves both cellular and humoral immune components. The immune response to antigens encoded within the major histocompatibility complex is the major factor in rejection. Matching between a recipient and potential graft donors is determined by typing blood-group antigens and MHC class I and class II tissue antigens (tissue typing). Host T cells recognize allogeneic MHC molecules in two different ways termed direct and indirect presentation. Direct presentation occurs when host T cells bind directly to intact allogeneic MHC molecules on graft antigen presenting cells. Indirect presentation occurs when allogeneic MHC molecules from the graft cells are taken up, processed by host antigen presenting cells and presented as peptide fragments by self-mhc. Graft rejection is suppressed by nonspecific immunosuppressive agents such as cyclosporin A, FK506 and rapamycin. Specific immunosuppression using monoclonal antibodies are experimental approaches which act by deleting populations of reactive cells or by inhibiting costimulatory signals leading to anergy. A major complication in bone marrow transplantation is graft-versus-host disease, mediated by the immunocompetent lymphocytes within the donor bone marrow. The shortage of organs available for transplantation has focused attention on xenotransplantation.

12 Neuroimmunology Neuroimmunology is the biomedical discipline that centers on the bidirectional communication between the central nervous system (CNS) and the immune system. CNS can affect the immune system via the autonomic outflow or the neuroendocrine outflow. Autonomic nervous system controls independent activities such as blood circulation, eyelid blinking and one component is the sympathetic (noradrenergic) system. Sympathetic nerve fibers innervate primary (thymus & bone marrow) and secondary (lymph node & spleen) lymphoid organs. Norepinephrine is the neurotransmitter released by the sympathetic nerve fibers and receptors for norephinephrine are found on various cells of the immune system. Norepinephrine has numerous effects on the immune system. Hypothalamic-pituitary-adrenal (HPA) axis- brain stimulation results in increased IL-1 that triigers releae of corticotrophin releasing hormone that acts on the anterior lobe of the pituitary gland. Adrenocorticotropin (ACTH) is released by the pituitary and induces the release from the adrenal gland of corticosteroids which suppress the immune system. Cytokines such as IL-1, IL-2, TGF- and IFNs exert various affects on the central nervous system such as induce fever, stimulate proliferation of astrocytes, and foster neural differentiation. Brain is an immunologically privileged site. Immune privilege is an active process associated with antigenspecific suppression of cell-mediated and humoral immunity. An important aspect of the neuroimmune axis is its relationship to diseases. Immune system is involved in the pathogenesis of numerous diseases of the central and peripheral nervous system, such as multiple sclerosis, Guilllain-Barre syndrome, myasthenia gravis. Multiple sclerosis (MS) is an inflammatory, demyelinating disease affecting the myelin sheaths surrounding nerve fibers and nerve axons. Genetic, environmental and autoimmune factors play a role in the pathogenesis of this disease. Studies from the animal model experimental autoimmune encephalomyelitis (EAE) suggest that Th1 and Th17 cytokines are critical mediators of the inflammation and that antibodies also play a role. The class II HLA alleles, DR15, DQ1 are the most consistently identified genes. Interferon- is one FDA approved therapy for MS. Myastenia gravis is a disease that affects the neuromuscular junction causing weakness of voluntary muscles eye closure, face, chewing, swallowing. The target autoantigen is the nicotinic acetylcholine receptor (AChR) and antibodies to this receptor are found in about 90% of patients. Guillian-Barre syndrome is an acute demyelinating disease of the peripheral nervous system. Numerous viruses and bacteria are implicated with the onset of disease. This disease is believed to be primarily antibody mediated.

13 Fitzgerald-Bocarsly - Immunity to Infectious Diseases Mechanisms of host defense to different pathogens Bacteria, viruses, parasites: be fluent with the mechanisms if I stressed them Pathways to get CD4 activation vs. CD8 Cytosolic vs. endosome-expressed antigens The presence of an immune response does not always = protection Th1 vs. Th2 responses: What are Th1 vs. Th2 cells? What do they do and what do they make? In what systems is one more important than the others? Host evasion strategies: Infectious organisms put a lot of their energy into evading the immune response Antigenic variation - examples Immunosuppressive cytokines Inhibition of antigen presentation to CD8s (many viruses) Decoy receptors Immunopathology: what is it and when does it occur?

14 Vaccines and Immunotherapy Distinguish passive and active therapy Passive immunotherapy (mostly Ab, but could be cells) is given for immediate protection Quick acting Short-lived May be used acutely for known exposure or a prophylaxis (e.g. to patients with a known Ig immunodeficiency) Active immunization Immunize to get to a primary, then secondary response and memory Type of vaccine can determine type of immune response Immunotherapy Cytokines Antibodies to block function of cytokines, receptors

15 Types of Vaccines Do we want CTL? Then we have to get the antigen into the endogenous processing pathway (cytoplasm to proteasome to TAP to ER to MHC I to surface) Live vaccine that can infect cells - attentuation Viral vectors DNA vaccine that gets genes products expressed in the cytoplasm Other strategies such as liposomes, ISCOMs Do we want CD4 help and antibody? Then we need to get antigen into the endosomal pathway and processed and presented with MHC Class II Subunit vaccines Recombinant protein vaccines Killed vaccines Toxoids Conjugate vaccines

16 Other vaccine issues What diseases is it reasonable to hope to eradicate? Role of non-human hosts, whether the virus integrates,relative infectivity (higher infectivity means more of the herd needs to be immunized) Adjuvants Compliance Can we make therapeutic vaccines? KUBY QUESTION from chapters assigned to my lectures (Chapters 18,19)

17 Mechanisms Leading to Autoimmunity No Central Tolerance Self reactive TH Infectious Agent Decreased Tregs