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1 AUTOIMMUNITY

2 DISCLOSURE Relevant relationships with commercial entities none Potential for conflicts of interest within this presentation none Steps taken to review and mitigate potential bias N/A

3 MODULE OBJECTIVES By the end of this module, you should be able to: 1. List the requirements for the development of autoimmunity 2. Distinguish between autoimmunity and autoimmune disease 3. Describe the mechanisms by which immune tolerance is broken 4. List the ways in which genetic factors can influence the development of autoimmune disease

4 INTRODUCTION To review: 1. A critical function of the immune system is to discriminate self from non-self 2. Multiple tolerance mechanisms normally prevent autoimmunity

5 AUTOIMMUNITY VS AUTOIMMUNE DISEASE Autoimmunity describes the phenomenon of the immune system recognizing the self To some extent this exists in everyone, but not everyone develops autoimmune disease Autoimmune disease occurs when autoimmunity leads to tissue damage

6 HOW TOLERANCE IS BROKEN Enabling environments, i.e., infection Molecular Mimicry Access to hidden sites

7 HOW TOLERANCE IS BROKEN: ENABLING ENVIRONMENTS Remember that self-reactive lymphocytes in the absence of costimulation may become anergic. Certain situations, such as infection, can wake up these anergic lymphocytes.

8 HOW TOLERANCE IS BROKEN: ENABLING ENVIRONMENTS E.g., Systemic lupus erythematosus (SLE) SLE is a systemic auto-inflammatory disease that causes widespread organ damage Patients with SLE have autoantibodies that recognize self nuclear antigens. The B cells that make the autoantibodies likely existed prior to the onset of disease, but were probably anergic.

9 HOW TOLERANCE IS BROKEN: ENABLING ENVIRONMENTS Then, as an example, if there is an infection, the associated inflammation may give rise to the costimulatory signals that wake up the previously anergic self reactive B cells leading to autoantibody production.

10 HOW TOLERANCE IS BROKEN: MOLECULAR MIMICRY Some pathogens express protein or carbohydrate antigens that resemble host molecules, a phenomenon known as molecular mimicry In such cases, antibodies produced against a pathogen epitope may cross-react with a self protein.

11 HOW TOLERANCE IS BROKEN: MOLECULAR MIMICRY An example of an autoimmune condition associated with molecular mimicry: Reactive arthritis occurring after gastrointestinal infections

12 HOW TOLERANCE IS BROKEN: ACCESS TO HIDDEN SITES Immunologically privileged sites: brain, eye, testis, uterus. Evade attack by the following mechanisms: Antigens do not circulate in lymphatics Anti-inflammatory cytokines and receptors prevent tissue damage and induce lymphocyte apoptosis

13 HOW TOLERANCE IS BROKEN: ACCESS TO HIDDEN SITES

14 QUIZ List 3 ways that tolerance can be broken.

15 QUIZ If a patient is found to have self-reactive antibodies, for example, antibodies that bind to self-protein, does that patient have an autoimmune disease?

16 TISSUE DAMAGE IN AUTOIMMUNE DISEASE CAN BE CAUSED BY DIFFERENT MECHANISMS

17 Components of the adaptive immune system cause disease pathology

18 THE GENETIC BASIS OF AUTOIMMUNE DISEASE Many genes that predispose to autoimmunity fall into categories that affect one or more of the mechanisms of tolerance A defect in a single gene can cause autoimmune disease MHC genes have an important role in controlling susceptibility to autoimmune disease

19 SINGLE-GENE TRAITS ASSOCIATED WITH AUTOIMMUNITY

20 * You do NOT have to memorize this chart, it is simply an example of how certain HLA serotypes are associated with autoimmune disease; an example of genetic susceptibility.

21 KEY MESSAGES 1. Autoimmune diseases develop when central and peripheral tolerance mechanisms are breached. 2. Both B cells and T cells can play a role in autoimmune disease. 3. Some autoimmune diseases have known genetic associations.

22 MODULE OBJECTIVES By now you should be able to: 1. List the requirements for the development of autoimmunity 2. Distinguish between autoimmunity and autoimmune disease 3. Describe the mechanisms by which immune tolerance is broken 4. List the ways in which genetic factors can influence the development of autoimmune disease

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