autoimmunity notes (2).pdf

AUTOIMMUNITY VETS2007 Chiara Palmieri ([email protected]) Autoimmunity is a specific immune response to self-antigens. It reflects a loss of immunological tolerance to self-antigens or cellular antigens (self-tolerance) and is characterised by abnormal or excessive activity of self-reactive immu...

AUTOIMMUNITY VETS2007 Chiara Palmieri ([email protected]) Autoimmunity is a specific immune response to self-antigens. It reflects a loss of immunological tolerance to self-antigens or cellular antigens (self-tolerance) and is characterised by abnormal or excessive activity of self-reactive immune effector cells. What is Self-tolerance (immunological tolerance)? It is the ability of the immune system to tolerate the self-antigens that comprise the tissues of the body. In order to achieve self-tolerance, potentially autoreactive T and B lymphocytes must be brought under control. The mechanisms of self-tolerance can be broadly classified into two groups: central and peripheral tolerance. 1) Central tolerance: immature self-reactive T and B lymphocyte clones that recognise selfantigens during their maturation in the thymus (T cells) and bone marrow (B cells) are killed or rendered harmless. This occurs during the development and maturation of T and B cells in the primary lymphoid organs.  T-cell development and maturation: T cells are created within the bone marrow and exported via the blood to the thymus for their final development and maturation. Thymic maturation is a very wasteful process, as some 99% of immature T cells that enter the thymus do not leave, but instead die by apoptosis. The first change to an early thymic immigrant is that the immature T cells forms and expresses a TCR. Additionally, this early cortical cell will co-express the CD4 and CD8 molecules, a phenomenon that generally is restricted to thymic T cells, as mature T cells express either one (but not both) of these markers. The immature T cells must pass two “examinations” before it is allowed to leave the thymus and enter the periphery. In the first examination, called “positive selection”, the immature T cell must prove that it has created a TCR capable of interacting with peptide antigen presented to that T cell by an MHC molecule. Within the thymic cortex are numerous thymic epithelial cells. These display surface membrane MHC I and II molecules that contain peptide fragments of self-antigens. Thymic epithelial cells have a high level of autophagy enabling them to present a wide range of normal tissue antigens. Each immature T cell must test out its TCR to ensure that it can interact with the MHC-peptide complex, but only by having a moderateaffinity interaction. Cells that have such a functional TCR pass the test of positive selection and are permitted to move on to the second examination. Cells that fail to mount such an interaction by having produced a TCR with no or low affinity for peptideMHC, dye by “neglect”. The positively selected T cells then move into the medulla of the thymic lobule where they undertake the second examination, called negative selection. In this test the immature T cell meets a thymic dendritic cell displaying MHC I or II molecules containing peptides derived from a wide array of self-proteins. In this  examination, the T cell must prove that its TCR is incapable of responding to these self-antigens with high affinity. Cells that do not carry high-affinity autoreactive TCRs will pass this test and progress to the final stage of maturation. Cells that fail will be instructed to undergo apoptosis. B-cell maturation: immature bone marrow B cells undergo a process similar to the negative selection of developing intrathymic T cells. Contact of the BCR with selfantigen may lead to deletion by apoptosis of that cell. Alternatively, the B cell may undergo further gene rearrangements within the light chain and express a new BCR. If this new receptor is still self-reactive, the cell will be deleted but if not, the cell will be exported for further maturation in the periphery (receptor editing). Central tolerance, however, is imperfect. Not all self-antigens may be present in the thymus, and hence T cells bearing receptors for such autoantigens escape into the periphery. There is similar “slippage” in the B-cell system. Self-reactive lymphocytes that escape negative selection can inflict tissue injury unless they are deleted or muzzled in the peripheral tissues. 2) Peripheral tolerance includes those mechanisms controlling autoreactive cells that escape to the periphery:    Anergy = functional inactivation of lymphocytes that encounter antigen. Because costimulatory molecules (B7-1, B7-2) are not expressed or are weakly expressed on resting dendritic cells in normal tissues, the encounter between autoreactive T cells and their specific self-antigens displayed by these dendritic cells may lead to anergy. Anergy also affects mature B cells in peripheral tissues. It is believed that if B cells encounter self-antigen in peripheral tissues, especially in the absence of specific helper T cells, the B cells become unable to respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting in their death. Suppression by regulatory T cells. A population of T cells called regulatory T cells functions to prevent immune reactions against self-antigens. Regulatory T cells develop mainly in the thymus, as a result of recognition of self-antigens, but they may also be induced in peripheral lymphoid tissues. The best-defined regulatory T cells are CD4+ cells that express high levels of CD25 and a transcription factor called FOXP3. Their inhibitory activity is mediated in part by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, which inhibit lymphocyte activation and effector functions. Deletion by apoptosis. T cells that recognise self-antigens may receive signals that promote their death by apoptosis. Two mechanisms of deletion of mature T cells have been proposed. It is postulated that if T cells recognise self-antigens, they may express a pro-apoptotic member of the Bcl family, called Bim, without antiapoptotic members of the family like Bcl-2 and Bcl-x. Unopposed Bim triggers apoptosis by the mitochondrial pathway. A second mechanism of activation-induced death of CD4+ T cells and B cells involves the Fas-Fas ligand system. Lymphocytes as well as many other cells express the death receptor Fas (CD95), a member of the TNF-receptor family. Fas ligand (FasL), a membrane protein that is structurally homologous to the cytokine TNF, is expressed mainly on activated T lymphocytes. The engagement of Fas by FasL induces apoptosis of activated T cells. It is postulated that if self-antigens engage antigen receptors of self-reactive T cells, Fas and FasL are co-expressed,  leading to elimination of the cells via Fas-mediated apoptosis. Self-reactive B cells may also be deleted by FasL on T cells engaging Fas on the B cells. Antigen sequestration: antigens that are not expressed in the thymus or are cryptic in nature have the potential to induce a self-reactive immune response. Cells may never be exposed to self-antigens as they remain sequestered (immunologically privileged sites). The sequestering of antigens may occur through the blood-brain barrier, an absence of lymphatic drainage or the limited ability to express MHC molecules. For example, in the testes, new antigens may appear only at puberty – long after the T cell system has developed and become tolerant to autoantigens (therefore, injury to the testes may permit proteins from damaged tissues to reach the blood stream, encounter antigen-sensitive cells and stimulate autoimmunity). A mechanism for the eye is referred to as the anterior chamber-associated immune deviation (ACAID), thought in part to be the result of inhibitory cytokines produced by the cells of the iris and ciliary body. AUTOIMMUNITY AND AUTOIMMUNE DISEASES Most autoimmune diseases are organ specific and target autoantigens related to a single body system or organ, but some are multisystemic and involve two or more body systems. In veterinary medicine, they are most prevalent in the dog. Some examples are: autoimmune haemolytic anaemia, autoimmune thrombocytopaenia, autoimmune neutropaenia, the spectrum of pemphigus disorders, autoimmune polyarthritis, myasthenia gravis, lymphocytic thyroiditis, diabetes mellitus and SLE. Autoimmunity is a multifactorial process involving a range of interlinked predisposing and triggering factors. The key elements of the autoimmune response are: 1. An immunological imbalance/dysfunction of the self-tolerance 2. An appropriate genetic background: o particular breeds of dog are susceptible to autoimmune diseases and these often occur within pedigree lines o the genes most strongly linked to the occurrence of autoimmunity are those of the MHC but the underlying mechanism is unknown 3. Predisposing factors including age, gender, lifestyle and diet: for example, these disease most commonly occur in middle to older age animals. This is related to the immunosenescence and the reduction in cell-mediated immune function with relatively more CD8+ cells and fewer CD4+ T cells. If the declining population of CD4+ cells includes natural Treg, this could clearly account for an increased onset of autoimmune reactivity. 4. Environmental factors such as exposure to UV irradiation, chemicals or infectious agents or other triggers factors:  E.g.: exposure to UV light for the development of canine nasal CLE (cutaneous lupus erythematosus): it is proposed that UV light might modify the antigenic structure of target autoantigens within the skin.  E.g. trimethoprim-sulphonamides are particularly recognised as triggers of IMHA (immune-mediated haemolytic anaemia), thrombocytopaenia and neutropaenia. In these cases the drug may be acting as a hapten, which by binding to the membrane of the target cell directly forms a target for an immune response. Alternatively, by modifying the structure of a self-protein the drug forms a novel drug-protein structure that is also capable of inducing an immune response.  Infectious agents might trigger autoimmune responses by a variety of different mechanisms:  Infections may upregulate the expression of costimulators on APCs. If these cells are presenting self-antigens, the result may be a breakdown, the result may be a breakdown of anergy and activation of T cells specific for the self antigen.  The microrganisms can attach to the membrane of a host cell or infects that cell, leading to expression of microbial antigen on the cell surface. An appropriate adaptive immune response is made to the infectious agent, but this also non-specifically destroys the host cell that carries the organism (innocent bystander effect). Alternatively, the infectious agent changes the structure of the antigens making it target for an immune response. This effect may be important in diseases such as feline infectious anaemia where circulating erythrocytes are parasitised by the surface membrane-dwelling organism Mycoplasma haemofelis.  Some autoimmune diseases involve circulating immune complex deposition in antigen-excess type III hypersensitivity. The antigenic component of such complexes may be derived from a microorganism.  The appropriate immune response to an infectious agent may extend inadvertently to self-tissue through the phenomenon of “bystander activation”. The inflammatory response might lead to damage of self-tissue, with structural modifications of selfantigens or to release of previously hidden antigens.  Molecular mimicry: microbial antigens and self-antigens might share regions of peptide sequence. B cells may be triggered by a foreign epitope that cross-reacts with an autoantigen. For example, the parasite Trypanosoma cruzi contains antigens that cross-react with mammalian neurons and cardiac muscle. Individuals infected with the parasite make autoantibodies that can cause nervous system and heart disease. In summary, the factors that lead to a loss of self-tolerance and the development of autoimmunity include: (1) inheritance of susceptibility genes that may disrupt different tolerance pathways (2) infections that may change tissue antigens and activate APCs and lymphocytes in the tissue (3) immunological imbalance with reduced function or activation of Treg cells (4) tissue injury with release of new antigens (5) environmental factors (UV light, drugs)