Autoimmunity PDF 2014

Autoimmunity – Chapter 19  Outline for Today  What is Autoimmune Disease  Mechanisms of Disease  Examples of Autoimmune Diseases  Determinants of Autoimmune Disease  Therapy  What is Autoimmune Disease?  Note that all individuals have some underlying autoim...

Autoimmunity – Chapter 19  Outline for Today  What is Autoimmune Disease  Mechanisms of Disease  Examples of Autoimmune Diseases  Determinants of Autoimmune Disease  Therapy  What is Autoimmune Disease?  Note that all individuals have some underlying autoimmunity, in the form of self-reactive T cells and Antibody  Autoimmune Disease occurs when clinical pathology develops.  It is unclear as to whether this develops due to the immune system beginning to cause damage, OR damage leading to inappropriate regulation of the immune system.  Mechanisms of Autoimmune Disease  Some of these mechanisms are well understood, others are theoretical  Is this a failure in central tolerance? Peripheral Tolerance? Role of Regulatory T cells?  At the most basic level, autoimmune disease occurs because the immune system is doing what it is supposed to, but against the wrong target!  Prerequisites  1. Autoreactive T/B cells escape central tolerance during development.  2. The escaped autoreactive cells encounter antigen in the periphery.  3. Peripheral tolerance mechanisms must fail.  4. The response must cause damage or clinical signs in some way.  Mechanisms underlying disease reflect these four, distinct conditions.  Mechanism 1. Infection Induced  In this situation, infection results in initiation of autoimmune disorders.  You may have experienced this yourself, transiently, when you hurt your joints and experience reactive arthritis.  Normally, this clear. In sever situations, it does not clear, and becomes chronic with progressive destruction of joint tissue.  How Can Infection Lead to Autoimmunity?  Cross-Presentation/Activation by DCs  Liberation of Protected Antigen.  Failure to resolve Inflammation  Molecular Mimicry. Fig. 19.1 9 Copyright © 2014 Elsevier Inc. All rights reserved. Fig. 19.2 Copyright © 2014 Elsevier Inc. All rights reserved. 10  Defects in Immune Components  This includes genetic and or predisposing defects in cells of the immune response.  This can include mutations/defects in regulatory genes of T-helper cells, cytokine responses, or generation of antigen-specific peptides.  All cells – B cells, APCs, T cells, Cytokines,Complement – may have abnormalities resulting in inappropriate activation.  Epitope Spreading  Refers to the evolution of the immune response to include further epitopes  Some of these may be autoantigens, activated as a result to an extended or hyper immune response.  Examples of Autoimmune Diseases  Your book gives a LARGE list of Autoimmune diseases. We will select SOME of these to focus on, particularly as they illustrate importance clinically, or alternatively from a mechanistic point of view.  Focus on the mechanisms of pathogenesis and function with the diseases we discuss. Read all of them through, but for the exam we’ll only focus on a few. Fig. 19.3A Copyright © 2014 Elsevier Inc. All rights reserved. 14 Fig. 19.3B Copyright © 2014 Elsevier Inc. All rights reserved. 15  Autoimmune Diseases  Characterized by an aberrant T, B, or combined immunological response against self organs or proteins.  Symptoms may be caused by destruction due to the host response, or due to substitution of the antibody for a normal host protein  Widespread examples include Systemic Lupus Erythmatosis, Rheumatoid Arthritis, Insulin- Dependent Diabetes Mellitus, Myasthenia Gravis, Multiple Sclerosis  Systemic Lupus Erythematosis  The prototypic systemic autoimmune disease.  Females 10-times more susceptible than males  Characterized by a systemic production of anti- self antibodies (most commonly associated with anti-DNA antibodies) including DNA, RBCs, histones, etc. (normally, internal antigens).  Damage is caused by Type II and Type III hypersensitivity responses, vasculitis Unn Fig. 19.1 Copyright © 2014 Elsevier Inc. All rights reserved. 18  Rheumatoid Arthritis  Characterized by the production of autoantibodies against joint proteins, as well as Rheumatoid Factor (an IgM antibody against self-IgG Fc regions).  Results in inflammation, Type III hypersensitivity within the joints. Unn Fig. 19.2 Copyright © 2014 Elsevier Inc. All rights reserved. 20  Multiple Sclerosis  Symptoms my range from numbness in extremeties, through blindness, paralysis, death.  Results due to autoreactive T cells destroying the myelin sheath surrounding nerve cells.  There are both environmental and genetic components to the disease  Animal models of this disease exist. Unn Fig. 19.3 Copyright © 2014 Elsevier Inc. All rights reserved. 22 Antibody-mediated Autoimmune Diseases  Antibody may mimic a normal host component, either over-stimulating or blocking a normal host receptor.  E.g. In Graves’ disease, autoantibody to the receptor for Thyroid Stimulating Hormone stimulates an unregulated overproduction of thyroid hormones.  E.g. In Myasthenia Gravis, autoantibody blocks acetylcholine receptors on muscles, resulting in loss of signaling and muscle function. Fig. 19.4 Copyright © 2014 Elsevier Inc. All rights reserved. 24  Genetic Factors  While anyone may be susceptible to a spontaneous autoimmune disease, there are clearly genetic factors predisposing some individuals to disease.  In some cases, these are broadly-susceptible (ie HLA-B27). In others, this may be due to individual defects, as described. Fig. 19.5 Copyright © 2014 Elsevier Inc. All rights reserved. 26  Treatment  While there are elegant treatments in development, most treatments (like Transplantation) are somewhat untargeted schemes to downregulate the immune system.  This may include removal of the specific antibody (plasmapheresis), T cells (anti-T cell therapies, including cyclosporines and similar agents), NSAIDs to limit inflammation, etc.  Table 19-3 lists some of these, and you can should be able to understand the mechanism of action of these agents as related to the immune response.