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Autoimmunity
The document discusses the mechanisms of autoimmunity, detailing how the immune system can mistakenly attack healthy cells due to failures in immunological tolerance. It outlines various autoimmune diseases, potential triggers, and phases of autoimmunity, as well as factors contributing to disease development. Additionally, it highlights the environmental and genetic influences on autoimmunity and emphasizes that while treatments exist, no definitive cures have been found.
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Autoimmunity
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- 2. Autoimmune The organism possessespowerful mechanism to avoid immune auto aggression The acquired ability of the immune system to avoid responsiveness to self antigens is defined as ‘ tolerance’ It is obtained by the cooperative efforts of central and peripheral mechanisms, which allow a rapid and efficient removal of pathogens ( Virus and Bacteria ) in the absence of self- recognition It is a dysfunction of the immune system The immune system protects you from disease and infection. Sometimes, though, the immune system can produce autoantibodies that attack healthy cells, tissues, and organs. This can lead to autoimmune disease Autoimmune diseases can affect any part of the body 12/19/2014 [email protected]
- 3. More than 80autoimmune diseases have been identified. Some of the more common ones include: Diabetes (Type 1) Lupus Multiple sclerosis Rheumatoid arthritis Celiac disease Myositis They are more common among women Some autoimmune diseases are life-threatening, and most are debilitating and require a lifetime of treatment. Autoimmunity is not set off by a single cause and is triggered by a variety of agents and molecular and cellular pathways and events. 12/19/2014 [email protected]
- 4. Hormones estrogenand progesterone might be affecting the immune system There are treatments available to reduce the symptoms and effects from many autoimmune diseases, but cures have yet to be discovered Low birth weight and low socioeconomic factors in childhood were associated with the later development of rheumatoid arthritis as an adult Certain enzyme creates mutations in DNA and is a major player in the development of autoantibodies Exposure to solvents, which are used in thousands of products, including paint thinners, cleaning supplies, and nail polish, contributes to the development of systemic sclerosis Smoking contributes to the development of two types of rheumatoid arthritis The susceptibility to ADs can be either inherited or acquired (and in many diseases, both) ADs traditionally have been categorized as organ specific or systemic or both 12/19/2014 [email protected]
- 5. Eating gluten, presentin wheat and some other grains, contributes to the development of celiac disease, a disorder that affects the small intestine and commonly causes chronic diarrhea and fatigue. Taking certain supplements containing L-tryptophan, an essential amino acid used as a dietary supplement, contributes to development of eosinophilia myalgia syndrome, an incurable and sometimes fatal condition involving severe muscle pain. The organ-specific ADs may represent examples of normal immune responses that produce disease because they are “misdirected” against a self-antigen or organ example- Pancreatic islets organ developed a disease called Type 1 Diabetes in which the Beta cell antigens (Glutamic acid decarboxylase, insulin) self antigens is destroyed by T cells (Autoantibodies present) In systemic ADs, multiple organs are targets for immune attack, and chronic activation of innate and adaptive immune cells is usually present. SLE is considered to be the prototypic systemic AD. It should be noted that the categorization of an AD as organ-specific or systemic is based primarily on clinical observations rather than the expression pattern of the self antigen that appears to be targeted in the attack. 12/19/2014 [email protected]
- 6. The development ofADs can be divided in four phases- Susceptibility phase- ADs result from a complex interplay of pathways and events which initially allow auto reactivity to manifest. Initiation phase- An initiating event, allow development of self-sustaining tissue damage. Factors that trigger the initiation include abnormalities in tolerance induction, regulatory T-cell (Treg) development, or immune signalling thresholds Propagation phase- The propagation phase is marked by a feed-forward cycle of autoimmunity and tissue damage, in which immune effectors pathways cause damage and provide antigen to drive the ongoing immune response. In many cases during disease propagation, immunoregulatory pathways are also activated, which may result in natural inhibition of clinical disease over time. Such immunoregulation is likely absent or fails in a susceptible host. Regulation phase 12/19/2014 [email protected]
- 7. Immunological Tolerance As lymphocytesundergo development within each individual , the antigen specific receptors on T lymphocytes and the immunoglobulin in B lymphocytes are generated afresh, with specificities for all kinds of antigens. Initially this is a random process with T cell receptors in (T cells) and immunoglobulin (in B cell) being generated with a large and diverse variety of antigen specificities; these spec ificites will of course include those against nonself and those that are potentially reactive for self antigens. The immune system has a selective method by which T and B Cells that are specific foe nonself are allowed to persist while those that are self –reactive are eliminated. This method is referred to as immunological tolerance and the immune system is in a state of tolerance. The normal state in which immunity is maintained for use against infections and foreign antigens, i.e. non-self, and not for reactions against self. 12/19/2014 [email protected]
- 8. Mechanism of immunologicalself- tolerance normally protect us from self- reactive immune responses. Failures of immunological tolerance do occur and thus inappropriate self reactive or autoimmune responses and disease do occur. The immune system is equipped with the ability to distinguish between self and non self ;it has specialized molecules and cells that detect and distinguish self and non self as well as molecules and cells that attack and eliminate non-self Interestingly, while one might think that lymphocytes in the immune system recognize only ‘foreign’ or non-self antigens, this is not entirely true. Most T cells and B cells recognize foreign antigens but some T and B cells receptors do indeed recognize self antigens. Thus self-reactive lymphocytes are produced and do exist. What if self- reactive lymphocytes get activated? Would these cells not attack the body’s own cells, tissues and organs, and cause deleterious autoimmune responses? 12/19/2014 [email protected]
- 9. Immunological tolerance isestablished by a process called Thymic education; a process that teaches immune cells what is self and thus, what is non-self As early developing T cells circulate around the body , they undergo a ‘negative selection’ in which T cells which have receptors specific for ‘self’ antigenic peptides are given a death signal and undergo apoptotic death. Generally about 99% of early T cells that begins the developmental process are actually eliminated due to self reactivity. B cells also undergo a form of negative selection in the bone marrow ; B cells expressing immunoglobulin specific for self antigens are eliminated. These methods of eliminating self reactive T and B cells are referred to as central tolerance Clearly this process is not foolproof ;surely not all the millions of self antigens can be expressed in the thymus and bone marrow, thus T and B cells with specificity for self antigens can and do survive negative selection Many such lymphocytes with the ability to recognize and bind self antigens still enter the blood circulation. 12/19/2014 [email protected]
- 10. To handle thispotential and real problem, peripheral Tolerance mechanisms operate to control or eliminate these cells at the level of secondary lymphoid organ, i.e. in the periphery These mechanisms include those such as anergy , a state of induced non responsiveness to self antigens’ If such mechanisms did not exist, for example, for self –reactive cytotoxic T (Tc) cells, presumably these cells could kill cells that express the self antigens. Clonal anergy refers to the maintenance of self reactive T cells in a non-responsive state. Besides anergy, peripheral tolerance is also maintained by the presence of suppressor or regulatory cells that inhibit autoreactive lymphocytes Thus, the immune system is equipped with both central (in the primary lymphoid organs) and peripheral (in secondary lymphoid organs and in circulation) tolerance mechanisms to prevent and control autoimmunity. Given these mechanisms, one might imagine that autoimmunity would not occur; how then do we develop autoimmune reactions? 12/19/2014 [email protected]
- 11. Clearly, while mechanismsof self-tolerance normally protect an individual from potentially self – reactive lymphocytes there are failures ;these failures results in appropriate responses of the immune system against self antigens, a process termed autoimmunity . The existence of autoimmune disease is proof that neither central nor peripheral mechanisms of tolerance are entirely successful How then is self tolerance bypassed or broken? Several situation s can lead to the bypass or breakage of self –tolerance . These include: 12/19/2014 [email protected]
- 12. A number ofviruses and bacteria have been shown to possess antigenic determinants that are identical or similar to normal host cell components ;such ‘Molecular mimicry’ has been shown between Peptides from the myelin basic protein, a molecule expressed on myelin sheaths enclosing nerve fibres, are mimicked by peptides from several viruses including: 1. Molecular Mimicry 12/19/2014 [email protected]
- 13. Infection with someof these viruses expressing peptides that mimic self components such as myelin basic protein, may induce autoimmunity to those self components. An example of molecular mimicry leading to autoimmunity is heart damage that sometimes follows Rheumatic fever, Antibody responses generated against antigens of S. pyogenes cross react with antigens of the heart value and cross reactive antibodies generated against the bacterial antigens can cause damage that can impair cardiac function. Rheumatic Fever An inflammatory disease that develops from pharyngeal infection with Streptococcus pyogenes. 12/19/2014 [email protected]
- 14. Another example ofmolecular mimicry in autoimmunity diseases is Type 1 Diabetes Mellitus 12/19/2014 [email protected]
- 15. Cross-reactive stress proteinsare also believed to be involved in the pathogenesis of some autoimmune disease. These are a series of evolutionarily preserved proteins expressed in increased amounts by cells when subjected to a range of different stresses such as heat, hypoxia and physical trauma. Stress proteins induced by heat are called heat shock proteins (HSPs) and are found in cell types from bacteria to humans. Thus, in the case of bacterial infections, the host immune system may mount an immune response to bacterial HSPs . These antibacterial HSPs antibodies may cross- react with human HSPs in an apparent autoimmune response. For example- In rheumatoid arthritis, T cells responses have been demonstrated against one such heat shock protein, HS P70 which cross –reacts with proteins in the Epstein Barr virus and E.coli. 12/19/2014 [email protected]
- 16. 2. Exposure ofHidden Antigens The second situation that leads to breakage of self-tolerance is when an immune response occurs to antigens that are usually ‘Hidden’ from the immune system. During thymic education, induction of tolerance to self antigens involves only those antigens that are ‘seen’ by developing T cells in the thymus. When previously hidden antigens are revealed, they could well become targets for T cells responses. The immune system does not normally ‘see’ these so called sequestered (or hidden) antigens . 12/19/2014 [email protected]
- 17. The testis isthus an example of an immunologically privileged site, i.e. a site which is sheltered from the immune system. The anterior chamber and cornea of the eye, the brain and the uterus are other examples. The cornea, for instance, is sheltered from the immune system due to low exposure to vasculature, but if the cornea is breached by injury or infection, the immune system gains access to this site and may view actual self antigens as foreign, and may mount immunological attack. Similarly the release of heart-muscle antigens after myocardial infractions has been shown to lead on occasion to the formation of autoantibodies. 12/19/2014 [email protected]
- 18. 3. Formation ofnew antigens Sometimes ‘new’ antigens, also known as neoantigens, are formed by modification of self antigens by chemical binding with another reactive molecule; this may result in provocation of the immune system and subsequent immunological attack which is similar to that seen in autoimmune tissues damage. For Example- Several drugs are capable of binding to erythrocyte cell surfaces in the body, creating neoantigens – examples of such drugs include penicillin, cephalosporin, salicylic acid, sulfonamide and streptomycin These neoantigens on erythrocyte surfaces may stimulate the production of antibodies which may bind to erythrocytes and cause complement- mediated lysis of erythrocytes, a condition called drug-induced hemolytic anemia. 12/19/2014 [email protected]
- 19. Some autoimmune responsesare kept under control by the action of suppressor cells; loss of this suppressor function can result in a lack of control over this response and subsequent autoimmunity. This has been proposed to be one mechanism for the induction of autoantibodies against nucleic acids and chromosomal proteins seen in systemic lupus erythematous ( SLE) Aside from peripheral tolerance maintained by regulatory T cells, other factors such as hormones and cytokines may be involved in restraining potentially autoreactive cells under normal conditions. Presumably a deficiency in any of these hormones (e.g. steroids) and cytokines (e.g. transforming growth factor –Beta) may increase susceptibility to autoimmunity, by allowing the restrained cells to get activated. 4. Loss of Suppressor Function 12/19/2014 [email protected]
- 20. 5. Epitope Spreading Sometimesinfections in tissues can result in the induction of defensive immune reactions that are geared to destroy the microbes, but in doing so, result in damage to neighboring tissues. This damage to an unintended target (i.e. host tissues) is often referred to as ‘innocent bystander’ damage For example – Infections of areas rich in myelin, such as the myelin sheath that encloses neuronal axons can result in the triggering of immune responses that cause innocent bystander destruction of the myelin sheath; this may result in the activation of new responses to myelin itself leading to further destruction of this important barrier and subsequent infiltration by immune molecules and cells. 12/19/2014 [email protected]
- 21. 6. Cytokine Dysregulation Somecytokines such as interferon-Y can induce the expression of class II HLA molecules on cells that do not normally express these molecules; when class II HLA molecules are induced inappropriately, these molecules may then present self antigens that are not normally presented to T cell, leading to response against self For Example- Pancreatic Beta cells of individuals with insulin- dependent diabetes mellitus express high levels of class II HLA molecules, whereas healthy Beta cells do not express class II HLA molecules. Thyroid cells from those with Graves’ disease have been shown to express Class II molecules on their cell membranes. Class II HLA molecules are normally expressed only on antigen-presenting cells (i.e. Macrophages, Dendritic cells (DC) and B-cells) and the inappropriate expression of these molecules on pancreatic cells or thyroid cells, induced by inappropriate production of the cytokine IFNYy, may lead to the activation of T helper cells to peptides from pancreatic cells or thyroid cells respectively. This would further lead to the activation of B cells or cytotoxic T cells against self antigens. 12/19/2014 [email protected]
- 22. 7. Polyclonal Activationof B cells Several viruses and bacteria can induce non-specific polyclonal activation of B lymphocytes ; If B cells specific for self antigens are activated randomly autoantibodies can be produced. For example- In infectious mononucleosis caused by the Epstein-Barr virus, several autoantibodies are induced by non –specific polyclonal B cell activation. This pool of autoantibodies often includes rheumatoid factor, anti- nuclear antibodies and antibodies to T cells and B cells. 12/19/2014 [email protected]
- 23. Immunological tolerance forself antigens is generally effective in preventing autoimmune reactivity against self, mechanisms of tolerance are not always successful and that tolerance can be bypassed or breached. When tolerance is bypassed, autoantibodies and /or autoreactive T cells can be generated and when these are produced, autoimmune disease may result. Autoimmune diseases affect 5-7% of adults and have a major health and socio-economic impact considering their debilitating effects. 12/19/2014 [email protected]
- 24. 12/19/2014 [email protected] 24 Environment GeneticFactor •Gender •Ethnic Origin •Host Defense Genes (TLR7, FcR, TNF) •Immune Response Genes (HLA- DR, PTPN22, CTLA4, IL10, FcRIIB) Pathways influencing the development and perpetuation of autoimmune diseases.
- 25. 12/19/2014 [email protected] 25 ThankYou For Your Precious Time
- 26. Thymus Hormones Antibodies White Blood Cells BoneMarrow Spleen Lymphatic System Complement System Human Immune System 12/19/2014 [email protected]