What are the mechanisms that may be involved in the pathogenesis of autoimmune disease
Several mechanisms have been hypothesized. All center upon a genetically predisposed host who has had one or more environmental exposures that, over time, trigger the autoimmune process. The environmental trigger or triggers are usually not identifiable since they may have occurred years before the first clinical symptom develops (see previous question). More than one of the following possible mechanisms may contribute to the development of autoimmunity:
• Superantigens: these are foreign antigens, particularly of bacterial or viral origin, that are capable of binding to the TCR (typically V region of β chain) and MHC class II molecule outside the antigen-binding groove and, in turn, bind the two together. In the case of T cells, superantigens do not need to be processed and subsequently presented in the antigen-binding cleft of MHC molecules in order to stimulate T-cell activation. B-cell superantigens also exist that bind to regions of surface Ig that are common to various subtypes and cause polyclonal B-cell activation without the need for T-cell help.
• T-B cell discordance with abnormal receptor-mediated feedback and suppression: T cells responding normally to a foreign antigen release cytokines to augment the immune response. Self-reactive B cells in proximity are stimulated by the cytokine milieu. If these autoreactive B cells have defective receptors that do not respond to inhibitory signals needed to maintain self-tolerance, then they will survive, contribute to the inflammation, and become self-perpetuating. Additionally, abnormal Treg and Breg suppressive function can contribute to this autoimmune process.
• Molecular mimicry: an exogenous antigen may share structural similarities with a host antigen. Antibodies produced against this antigen can bind the host antigen causing amplification of the immune response.
• Cytokine dysregulation: innate immune system activation releases cytokines that activate the adaptive immune system. Excessive or defective cytokine production could result in an aberrant immune response and/or activation of anergic self-reactive T cells.
• Defective apoptosis: accelerated apoptosis of cells with increased release of self-antigens and/or defective presentation of apoptotic cell antigens to lymphocytes could lead to abnormal lymphocyte activation including self-reactive T and B cells.
• Epitope spreading: occurs when the immune reaction changes from targeting the primary epitope to also targeting other epitopes.
• Cryptic epitope exposure: the innate immune response is activated by an invading pathogen. The inflammatory response causes tissue damage with release of self-antigens whose epitopes the immune system has not previously developed tolerance to. The adaptive immune system is recruited and continually stimulated by exposure to the new self-antigen released by the host tissue.
