IMMUN441 Week 9 AC Quiz Section Autoimmunity Transplantation

Announcements Final Exam Wednesday Dec. 14th 8:30-10:20 in room T-435 Covers lectures 17-26 Final Exam Review Tuesday Dec. 13th 10:30-12:20 in room T-733 Complete your course evaluations Extra 0.1 added to your GPA

Zero or little amount of Ag Zero or little amount of Ag mTEC MHC II CENTRAL TOLERANCE Thymus Naïve T cell TCR High amount of Ag Deletion High avidity mTEC High affinity TCR Zero or little amount of Ag Escape Low avidity mTEC MHC II High amount of Ag Escape Naïve T cell TCR Low avidity mTEC Low avidity Low affinity TCR Zero or little amount of Ag Deletion

AIRE induces tissue-restricted antigen expression to aid central tolerance Answers question of how developing T cells see localized self antigen?

Recessive Peripheral Tolerance Dominant Peripheral Tolerance Vs. Dominant Peripheral Tolerance Non-inflammatory Environment mTEC MHC II T cell TCR APC No costimulatory signals Cell Type: regulatory T Cell High amount of Ag No Ag TCR specific for what type of Antigen? Self-Antigen Intermediate Ag Effector Function? Inhibition of other self-reactive T cells via cytokine secretion (IL-10, TGFβ) Ignorance Deletion Anergy TCR downregulation TCR 2 Types of Regulatory T Cells Inflammatory Environment T cell TCR APC expressing enhanced costimulatory signals Type : Natural Tregs Type: Inducible Tregs Location of Development: Location of Development: Thymus Periphery (post-Ag encounter) Autoimmunity

Mechanisms of dominant tolerance by regulatory T cells

Escape of self-reactive lymphocytes from central and peripheral tolerance mechanisms can lead to autoimmunity mTEC MHC II TCR Treg Naïve T cell TCR T cell TCR APC THYMUS PERIPHERY Autoreactive effector T cells Tissue-specific (T1D) or systemic (SLE) Any tissue could be a potential target Involves loss of B cell and/or T cell tolerance Autoantibodies Self-reactive T cells

Autoantibodies can induce diverse pathology Activation of cell surface receptors (Graves’ disease) Cell depletion (autoimmune hemoytic anemia) Inhibition of cell surface receptors (myasthenia gravis) Formation of immune complexes (Systemic lupus erythematosus)

Intermediate interaction Environmental triggers of autoimmune disease Infection can potentially trigger autoimmunity through multiple mechanisms: Activation of the innate immune system leads to presentation of self-antigens in more immunogenic context Non-inflammatory Low levels of MHC, CD40, CD80, CD86 Weak interaction What’s a physical way to trigger autoimmune disease? Intermediate interaction Strong signal Deletion or iTreg generation Ignorance Anergy ↓ TCR/Co-receptor

Environmental triggers of autoimmune disease Infection can potentially trigger autoimmunity through multiple mechanisms: Activation of the innate immune system leads to presentation of self-antigens in more immunogenic context Infection Co-stimulatory molecules, inflammatory cytokines Autoimmunity Genes involved in regulation/activation of innate immune system are associated with some autoimmune diseases – e.g. NOD2/Crohn’s disease

Breaking tolerance via viral infection – changing the context of antigen presentation can result autoimmunity Tolerance broken by physical damage

Rheumatoid Arthritis: T-cell mediated autoimmune disease affecting joints Clinical Intervention: TNFα blockade using a monoclonal antibody

Myasthenia Gravis Clinical Intervention: Autoantibodies cause degradation of acetylcholine receptors, preventing Na+ influx and muscle contraction Weakness of the eyelid muscles, often the first symptom of the disease Autoantibodies can be transferred across the placenta to the fetus and newborn infant Clinical Intervention: drugs to inhibit acetylcholinesterases, the enzyme that degrades acetylcholine thymectomy

CD8 T-cells destroy insulin-producing β cells of the pancreatic islets Type-1 Diabetes: CD8 T-cells destroy insulin-producing β cells of the pancreatic islets Clinical Intervention: Monoclonal antibody for CD3 to deplete effector T cells while preserving regulatory T cells. Commonly known as “juvenile diabetes”

Systemic Lupus Erythematosus (SLE): Production of autoantibodies; propagated by epitope spreading Clinical Intervention: CD20 monoclonal antibody (depletes B cells)

And IL-17-producing TH17 cells. Multiple Sclerosis: T-cell mediated inflammatory demyelinating autoimmune disease of the CNS Clinical Intervention: Monoclonal antibody for α4 integrin to block cellular migration to inflamed CNS And IL-17-producing TH17 cells.

Graves’ Disease Clinical Intervention: Autoimmune B cells make antibodies that activate thyroid-stimulating hormone (TSH) receptor, causing hyperthyroidism Proptosis, a bulging of the eye, is a symptom of Graves’ disease Clinical Intervention: antithyroid drugs that reduce the production of thyroid hormone destruction of the thyroid with radioactive iodine surgical removal of the thyroid

Thyroid autoimmunity: same target cell, different outcome

Transplantation

Host immune response against foreign grafted tissue Durability of transplanted tissues remains significant challenge within the field Host immune response against foreign grafted tissue

Subsets of host tolerant immune cells can react with non-self (donor) components

What is the evidence that immune system is responsible for graft rejection? Graft rejection follows principles of self/non-self recognition, and like anti-pathogen responses displays memory.

Hyperacute rejection relies on pre-formed antibodies Hyperacute rejection: have premade Abs against ABO blood groups or type I HLA, when solid organ transplanted, needs to get hooked into the blood supply of host, thus once the transplant is complete the Abs could bind to their antigen on the vascular endothelium and induce inflammation and immune cell recruitment that would completely block blood from getting through the vessel, thus the transplant would rapidly be starved of oxygen and die Acute: takes bit longer, t cell mediated (type IV hypersens), donor APCs migrate to secondary lymphoid organs where they can activate host t cells, because there is likely hla incompatibility some of the host t cells could react very strongly to the foreign hla:self complexes and become activated, this allows them to traffic out to site of transplantation and attack the donor cells (direct recog) Chronic: takes months to years, caused by activation of Abs specific for donor HLA type I, first cd4s activated via indirect pathway (host apcs present part of donor hla)

Acute rejection is T cell-mediated Hyperacute rejection: have premade Abs against ABO blood groups or type I HLA, when solid organ transplanted, needs to get hooked into the blood supply of host, thus once the transplant is complete the Abs could bind to their antigen on the vascular endothelium and induce inflammation and immune cell recruitment that would completely block blood from getting through the vessel, thus the transplant would rapidly be starved of oxygen and die Acute: takes bit longer, t cell mediated (type IV hypersens), donor APCs migrate to secondary lymphoid organs where they can activate host t cells, because there is likely hla incompatibility some of the host t cells could react very strongly to the foreign hla:self complexes and become activated, this allows them to traffic out to site of transplantation and attack the donor cells (direct recog) Chronic: takes months to years, caused by activation of Abs specific for donor HLA type I, first cd4s activated via indirect pathway (host apcs present part of donor hla)

Chronic rejection can develop over months/years Acute: takes bit longer, t cell mediated (type IV hypersens), donor APCs migrate to secondary lymphoid organs where they can activate host t cells, because there is likely hla incompatibility some of the host t cells could react very strongly to the foreign hla:self complexes and become activated, this allows them to traffic out to site of transplantation and attack the donor cells (direct recog) Chronic: takes months to years, caused by activation of Abs specific for donor HLA type I, first cd4s activated via indirect pathway (host apcs present part of donor hla)

Are MHC molecules the only target antigens. No Are MHC molecules the only target antigens? No! Many other ‘minor’ histocompatibility antigens exist.

Targets both Major Histocompatibility (MHC) & Minor Histocompatibility (minor-H) antigens from Donor APCs

APCs during graft rejection Targets mainly minor-H antigens or processed MHC antigens presented by Host APCs *Rejection delayed/slowed

Indirect allorecognition leads to chronic rejection

Transplant rejection vs GVHD

Mechanism of GVHD

Remember this is a balancing act!! Autoimmunity Tolerance Many factors play a role in the development of autoimmunity MHC, FoxP3, AIRE, CTLA4 Genetic Susceptibility Autoimmunity Immune Regulation (loss of) Environmental Triggers Stress Inflammatory setting (increased activation and Ag presentation) Hormones Infection Autoimmunity can be organ specific or systemic, B-cell and/or T-cell mediated

Clinical interventions Immunosuppression: Cyclosporine or equivalent + steroids Some biologics: OKT3 (anti-CD3) Campath-1h (anti-CD52) Major problems: Lifelong, expensive, no selectivity (susceptibility to infectious disease!), off-target effects.

Clinical interventions Holy grail – Donor-specific tolerance (DST) Readily achieved in several animal systems with immune modulating antibodies Modify immune environment to promote activation/development of alloantigen-specific regulatory T cells. Still being developed for clinical use.

Supplemental slides

Autoimmune Disease Immune Effector Reactivity/Target Mechanism Tolerance Affected Pathological Outcome Systemic Lupus Erythematosus (SLE) Autoantibodies (Form immune complexes with target) Chromatin (Histones and DNA) Lodging of immune complexes in kidney glomeruli B cell Kidney inflammation (nephritis); proteinuria Kidney dysfunction Deposition of immune complexes in blood vessels; complement activation Skin inflammation (rash) Hemolytic Anemia (Induce complement activation, phagocytosis of target) Erythrocytes (RBCs) Lysis of erythrocytes Anemia Graves’ Disease (Activation of target) Thyroid stimulating hormone receptor (TSHR) Consitutive activation of TSHR Hyperthyroidism; dysregulated metabolism Myasthenia gravis Autoantibodies (Inhibition of target) Acetylcholine receptor Inhibition of acetylcholine signaling Peripheral muscle weakness Type-1 diabetes Autoreactive CD8+ T cells Beta islet cells (produce insulin) Lysis of beta cells in pancreas T cell Loss of insulin production; dysregulated blood glucose metabolism Rheumatoid arthritis Autoreactive CD4+ T cells Synovial joint antigens Production of MMP/RANKL by synovial fibroblasts; recruitment and activation of osteoclasts Degradation of bone and cartilage in joints Multiple sclerosis (MS) Autoreactive Th1, Th17 CD4+ T cells Myelin sheath protein Demyelination of neurons Neurodegeneration; paralysis