Pathophysiologic Basis of Autoimmune Disorders Linda Felver, Ph.D., R.N. Associate Professor School of Nursing Oregon Health & Science University The immune system has two arms: Adaptive (Acquired) Immune Cells Cytokines Chemical messengers Cell-to-cell communication Adaptive Immune Cells Immunological synapses 1
Immunity Immunity Cells Cells of Immunity Adaptive Cells Other Components Neutrophils (PMNs) Macrophages Immunity Cells Cells of Immunity immunity is nonspecific. Neutrophils (PMNs) Watch out if I get activated! NK Cell I can drill holes in you! Each innate immune cell or other component can respond to many different antigens. I eat any antigen! Macrophages Immunity Cells Some Functions of Immunity Cells of Immunity First line of defense against microorganisms Inflammation (the first phase of tissue healing) Initiate second phase of tissue healing Present antigens to adaptive immune cells Note: The innate and adaptive arms of the immune system communicate with each other! Neutrophils (PMNs) Macrophages Watch out if I get activated! NK Cell I can drill holes in you! I am a professional APC! Dendritic cells 2
Antigen-Presenting Cells Why do we need antigen-presenting cells (APCs)? Naive adaptive immune cells must meet an antigen and become committed to it before they can recognize and act against it. Naïve lymphocyte wants to meet antigen for lifelong commitment. Adaptive immunity is specific. Each adaptive immune cell or other component responds to only one antigen. I recognize only one antigen. I am committed to it! I am picky! I bind only one specific antigen. Some Functions of Adaptive Immunity Immunological memory Vigorous defense against specific antigens Orchestrate the immune response Note: The innate and adaptive arms of the immune system communicate with each other! Remember: Each committed adaptive immune cell responds to only one antigen. Adaptive Immunity Cells Cells of Adaptive Immunity T lymphocytes () B lymphocytes (B cells) Remember: Each adaptive immune cell or component responds to only one antigen. 3
Adaptive Immunity Cells Cells of Adaptive Immunity T lymphocytes () B lymphocytes (B cells) Humoral immunity: Secrete antibodies Remember: Each adaptive immune cell or component responds to only one antigen. Adaptive Immunity Cells Cells of Adaptive Immunity T lymphocytes () Cellular Immunity: Function depends on subtype B lymphocytes (B cells) Humoral immunity: Secrete antibodies Remember: Each adaptive immune cell or component responds to only one antigen. Adaptive Immunity Cells Cells of Adaptive Immunity T lymphocytes () Helper secrete cytokines that orchestrate the immune response. Cytotoxic directly kill their target cells. Remember: Each committed T lymphocyte responds to only one antigen. Adaptive Immunity: Helper Subtypes of Helper T Cells Secrete Different Cytokines T H 1 secrete cytokines that promote cytotoxicity. This response fights intracellular pathogens. T H 2 secrete cytokines that promote antibody production. This response defends against parasites and chronic infections. T H 17 secrete cytokines with pro-inflammatory actions. This response defends against extracellular pathogens at the borders of the body. T H 3 Treg secrete cytokines that have anti-inflammatory effect. This response protects self-tissues and our normal microbiota. These often damage tissue in an autoimmune disorder, driven by the helper. Immunity Adaptive Cells Other Components Autoreactive (and often B cells as well) are involved in an autoimmune disorder. Humoral B cells and antibodies Helper Cellular Other Cytotoxic 4
Genetic Predisposition plus Environmental Factors Two events occur (in this order): 1) meet the self-antigen and become autoreactive 2) Regulatory fail to manage the autoreactive meet selfantigen Immunological Tolerance Normal Autoimmune Disorder Immune Response Regulatory T Cells Regulatory (Treg): Are of numerous types o Some are cytotoxic and kill autoreactive or overactive T cells o Some secrete IL-10 and other anti-inflammatory cytokines Immunological Tolerance Normally, regulatory (Treg) act on autoreactive lymphocytes by either destroying them (by causing apoptosis), or controlling them (by suppressing their activity). Tolerance to self-antigens is a very important attribute of the immune system. 5
Two events occur (in this order): 1) meet the self-antigen and become autoreactive 2) Regulatory fail to manage the autoreactive Examples of events that facilitate lymphocytes meeting self-antigens: Tissue damage (trauma or infection) that exposes previously-sequestered self-antigens Molecular mimicry (immune response to infectious agent cross-reacts with self-antigen) Delayed clearance of apoptotic bodies Treg and T H 17 Cells For normal immune function, we need a balance between Treg and T H 17 cells. Normal Immune System Development Infants normally have T H 17 dominance. Normal Immune System Development With appropriate environmental stimuli, Treg function develops and balances T H 17. I am TH 17. These stimulate Treg development: Infection with some parasitic worms Intestinal microbiota that produce the short chain fatty acid butyrate Tissue environment without IL-6 (a pro-inflammatory cytokine) Other stimuli under investigation Tregs 6
Revised hygiene hypothesis: Inappropriate environmental stimuli during infancy and childhood lead to underdeveloped Treg function and thus increased incidence of allergic and autoimmune diseases that involve T H 17 and T H 2 or T H 1 dominance. T H 1 and T H 2 Cells For normal immune function, we also need a balance between T H 1 and T H 2 cells. I am T H 1. I am T H 2. T H 1 and T H 2 Cells Disrupted T H 1-T H 2 balance is important in autoimmune disorders. Many autoimmune disorders are driven more by cytokines from a predominance of autoreactive T H 1 cells; a very few may be driven by cytokines from a predominance of autoreactive T H 2 cells. T H 2 cytokines activate B cells, increasing antibody formation. What do T H 1 cytokines activate? I am Helper T! Obey my cytokines! T H 1 cytokines activate cytotoxic cells. Watch out if I get activated! NK Cell I can drill holes in you! T H 1 Cells I am Killer T! If I choose you, you are dead! Two events occur (in this order): 1) meet the self-antigen and become autoreactive 2) Regulatory fail to manage the autoreactive These often damage tissue in an autoimmune disorder, driven by the helper. Immunity Cells Other Components Autoreactive (and often B cells as well) are involved in an autoimmune disorder. Adaptive Humoral B cells and antibodies Helper Cellular Other Cytotoxic 7
Influencing Factors What are some factors that influence the manifestations of autoimmune disorders? Influencing Factors What are some factors that influence the manifestations of autoimmune disorders? Obesity Intestinal Microbiota Obesity Influencing Factors Adipose tissue normally secretes adipokines that influence metabolic processes and other functions, including some immune actions. Obesity alters adipokine secretion, causing pro-inflammatory effects as well as decreased numbers of circulating Tregs. Obesity is associated with increased risk, more severe clinical course, and even treatment resistance of some autoimmune disorders. Intestinal Microbiota Influencing Factors Intestinal microbiota influence the immune system by interacting with it and through bacterial metabolic products. Butyrate, a short-chain fatty acid produced by some species of gut bacteria acting on dietary fiber, stimulates development of Treg. Intestinal microbiota composition is greatly influenced by diet. Gut bacteria in people who eat plant-based diets make much more butyrate than the bacteria in people who eat animal-based diets. for Autoimmune Disorders Diet, Lifestyle, and Stress Management Individualized Management Diet Plant-based diet may be more beneficial than animal-based diet for some autoimmune disorders?? (More research needed) There is a lot of hype about diet on the Internet! For some autoimmune disorders, avoid dietary triggers. Is weight loss indicated? 8
Lifestyle Exercise is known to influence immune function, with regular moderate or vigorous exercise often considered to have anti-inflammatory effect. Regular moderate or vigorous exercise increases microbial diversity in the gut, which is considered a positive effect. Exhaustive prolonged exercise may have deleterious effects on both immunity and gut microbiota-immune interaction. Consider writing an exercise prescription. Stress Management Firing of the vagus nerve initiates the cholinergic anti-inflammatory pathway that suppresses various innate immune cells. Increased firing of the vagus nerve has a measurable greater anti-inflammatory effect. Stimulation of the cholinergic anti-inflammatory pathway is under study for management of various autoimmune disorders. Individualized Management For specific autoimmune disorder For specific patient and family Suggestions for Further Exploration Microbiota and Autoimmunity Kuhn, K., Pedrazza, I., & Demoruelle, M. (2014). Mucosal immune responses to microbiota in the development of autoimmune disease. Rheumatic Disease Clinics of North America, 40, 711-725. McLean, M., et al. (2015). Does the microbiota play a role in the pathogenesis of autoimmune diseases? Gut, 64, 332-341. Suggestions for Further Exploration Microbiota and Exercise Berman, S., et al. (2015). The microbiota: an exercise immunology perspective. Exercise Immunology Review, 21, 70-79. Microbiota and Diet David, L., et al. (2014). Diet rapidly and reproducibly alters the human gut microbiome. Nature, 505, 559-563. Suggestions for Further Exploration The Cholinergic Anti-Inflammatory Pathway Forsythe, P., Bienenstock, J., & Kunze W. (2014). Vagal pathways for microbiome-brain-gut axis communication. Advances in Experimental Medicine and Biology, 817,115-133. Tracey, K.J. (2009). Reflex control of immunity. Nature Reviews. Immunology, 9, 418-428. van Maanen, M., Vervoordeldonk, M., & Tak, P. (2009). The cholinergic anti-inflammatory pathway: toward innovative treatment of rheumatoid arthritis. Nature Reviews. Rheumatology, 5, 119-232. 9