the genesis of autoimmune conditions, or conditions that simulate autoimmune diseases. the most striking of these is the drug-induced lupus erythematosus. usually, withdrawal of the offending drug cures the symptoms in a patient. cigarette smoking is now established as a major risk factor for both incidence and severity of rheumatoid arthritis. this may relate to abnormal citrullination of proteins, since the effects of smoking correlate with the presence of antibodies to citrullinated peptides. pathogenesis of autoimmunity several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental modulation. it is beyond the scope of this article to discuss each of these mechanisms exhaustively, but a summary of some of the important mechanisms have been described: t-cell bypass – a normal immune system requires the activation of b cells by t cells before the former can undergo differentiation into plasma b-cells and subsequently produce antibodies in large quantities. this requirement of a t cell can be bypassed in rare instances, such as infection by organisms producing super-antigens, which are capable of initiating polyclonal activation of b-cells, or even of t-cells, by directly binding to the β-subunit of t-cell receptors in a non-specific fashion. t-cell–b-cell discordance – a normal immune response is assumed to involve b and t cell responses to the same antigen, even if we know that b cells and t cells recognise very different things: conformations on the surface of a molecule for b cells and pre-processed peptide fragments of proteins for t cells. however, there is nothing as far as we know that requires this. all that is required is that a b cell recognising antigen x endocytoses and processes a protein y (normally =x) and presents it to a t cell. roosnek and lanzavecchia showed that b cells recognising iggfc could get help from any t cell responding to an antigen co-endocytosed with igg by the b cell as part of an immune complex. in coeliac disease it seems likely that b cells recognising tissue transglutamine are helped by t cells recognising gliadin. aberrant b cell receptor-mediated feedback – a feature of human autoimmune disease is that it is largely restricted to a small group of antigens, several of which have known signaling roles in the immune response (dna, c1q, iggfc, ro, con. a receptor, peanut agglutinin receptor(pnar)). this fact gave rise to the idea that spontaneous autoimmunity may result when the binding of antibody to certain antigens leads to aberrant signals being fed back to parent b cells through membrane bound ligands. these ligands include b cell receptor (for antigen), igg fc receptors, cd21, which binds complement c3d, toll-like receptors 9 and 7 (which can bind dna and nucleoproteins) and pnar. more indirect aberrant activation of b cells can also be envisaged with autoantibodies to acetyl choline receptor (on thymic myoid cells) and hormone and hormone binding proteins. together with the concept of t-cell–b-cell discordance this idea forms the basis of the hypothesis of self-perpetuating autoreactive b cells. autoreactive b cells in spontaneous autoimmunity are seen as surviving because of subversion both of the t cell help pathway and of the feedback signal through b cell receptor, thereby overcoming the negative signals responsible for b cell self-tolerance without necessarily requiring loss of t cell self-tolerance. molecular mimicry – an exogenous antigen may share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens, and amplify the immune response. the idea of molecular mimicry arose in the context of rheumatic fever, which follows infection with group a beta-haemolytic streptococci. although rheumatic fever has been attributed to molecular mimicry for half a century no antigen has been formally identified (if anything too many have been proposed). moreover, the complex tissue distribution of the disease (heart, joint, skin, basal ganglia) argues against a cardiac specific antigen. it remains entirely possible that the disease is due to e.g. an unusual interaction between immune complexes, complement components and endothelium. idiotype cross-reaction – idiotypes are antigenic epitopes found in the antigen-binding portion (fab) of the immunoglobulin molecule. plotz and oldstone presented evidence that autoimmunity can arise as a result of a cross-reaction between the idiotype on an antiviral antibody and a host cell receptor for the virus in question. in this case, the host-cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host cells. cytokine dysregulation – cytokines have been recently divided into two groups according to the population of cells whose functions they promote: helper t-cells type 1 or type 2. the second category of cytokines, which include il-4, il-10 and tgf-β (to name a few), seem to have a role in prevention of exaggeration of pro-inflammatory immune responses. dendritic cell apoptosis – immune system cells called dendritic cells present antigens to active lymphocytes. dendritic cells that are defective in apoptosis can lead to inappropriate systemic lymphocyte activation and consequent decline in self-tolerance. epitope spreading or epitope drift – when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. in contrast to molecular mimicry, the other epitopes need not be structurally similar to the primary one. epitope modification or cryptic epitope exposure – this mechanism of autoimmune disease is unique in that it does not result from a defect in the hematopoietic system. instead, disease results from the exposure of cryptic n-glycan (polysaccharide) linkages common to lower eukaryotes and prokaryotes on the glycoproteins of mammalian non-hematopoietic cells and organs this exposure of phylogenically primitive glycans activates one or more mammalian innate immune cell receptors to induce a chronic sterile inflammatory state. in the presence of chronic and inflammatory cell damage, the adaptive immune system is recruited and self–tolerance is lost with increased autoantibody production. in this form of the disease, the absence of lymphocytes can accelerate organ damage, and intravenous igg administration can be therapeutic. although this route to autoimmune disease may underlie various degenerative disease states, no diagnostics for this disease mechanism exist at present, and thus its role in human autoimmunity is currently unknown. the roles of specialized immunoregulatory cell types, such as regulatory t cells, nkt cells, γδ t-cells in the pathogenesis of autoimmune disease are under investigation. classification