Hi, the body APCs keep presenting self cells to MHC II because the body has lost capacity to differentiate between self cells and non self cells which is the hallmark for the autoimmune diseases as seen in the lupus disease.

It is complicated. See the paper linked below (Fig.1). https://academic.oup.com/rheumatology/article/56/suppl_1/i55/3091367

1. Apoptosis is increased in CD4 cells from lupus patients creating a bigger load of self-antigens to be potentially taken and presented by APCs. This load excess is not a risk during healthy apoptosis

2. Different biochemical modifications occurring during apoptosis expose cryptic self-antigens more likely to trigger autoimmune responses. So, the load of newly exposed self-antigens is increased in lupus compared to healthy subjects

3. Lupus patients may have an increased number of autoreactive T cell clones that survived the negative selection process during their thymic development

4. Peripheral control of these surviving autoreactive clones may be hampered by defective Treg function, also described in lupus patients

You ask an excellent question, Penny. As the preceding contributors suggest, there may be several tolerance mechanisms that fail in order to explain any autoimmune disease. Autoreactive T cells would have to be a necessary player in this process. However, even if autoreactive T cells come to reside in the periphery (which undoubtedly occurs normally at least for organ-/tissue-specific antigens), it would be unlikely they would respond to cognate self-antigen even if inadvertently presented on MHC because of the absence of costimulation. Generally, “pathogen-associated molecular pattern”, molecules thought to be unique to prokaryotes or viruses, provide this costimulation to APCs (“signal 0”), resulting in increased MHC class II, B7 and cytokine expression. It has been suggested that co-incident infection would provide PAMPs while simultaneously taking up and presenting self-peptides. Without such an event it had been argued, self-antigen derived from apoptotic cells would be inert. However, increasing evidence suggests that some receptors for these PAMPs do have capacity to respond to self materials if present in sufficient amounts – TLR9 responds to CpG islands in mammalian DNA, TLR7 to small nuclear RNAs, microRNA or possibly mitochondrial RNA, and TLR4 to certain monocyte-derived Ca++-binding cytokines and to HSP-60. In addition recent literature suggests that “signal 0” may also be provided by “damage-associated molecular patterns” released by necrotic cells such as uric acid, histones, or HMGB1 engaging “receptors for advanced glycation end products” on innate immune cells, particularly dendritic cells and perhaps macrophage. These self-molecules may provide the co-stimulation for APCs necessary to activate naïve autoreactive T cells.

Thank you so much for all your wonderful responses!

althogh of these brillient suggestion,s still the "exact" mechanis,m need more research for a complicated disease "SLE"

I agree with the above points but there is also the contribution of sequestered antigens; rare internal cellular proteins that are not usually exposed to APC and to which the immune system has not been made tolerant to through the process of peripheral T cell selection and destruction of auto-reactive immature T cells in the thymus.

The argument that self reactive proteins would be inert is something to be tested. Logically apoptosis of large numbers of cells could lead to release of sequestered proteins on a scale that immunogenic epitope presentation on APC could be at a high enough density to activate auto-immune T cells. This would be especially true in the presence of inflammation or other activation of the innate immune system, as suggested by Robert, which would provide signal 0.

Self-molecules that are normally sequestered from direct contact with TCRs or BCRs would, in theory, be more likely to induce an immune response if inadvertently and productively exposed to immune cells for the reasons expressed by Dr. Gieni. This is probably why organ/tissue-specific autoimmune diseases are more common than systemic (non-tissue-specific) autoimmune diseases – most organ/tissue-specific self-antigens are not accessible during T-and B-cell development so central lymphocyte tolerance is not induced. But there would normally have to be a coincident “signal 0” inflammatory event, and it is likely that one or more intrinsic defects in the peripheral tolerance machinery would be necessary to account for a sustained autoimmune response. A limited understanding of such defects has been described in autoimmune-prone mice and have been therapeutically manipulated in people to promote tumor-specific immunity, but, as Dr. Redwan points out, the exact nature of these tolerance defects are largely unknown. And while the amount of exposed self-antigen might be relevant, as suggested by Dr. Gieni, this may not be the crucial determinant of an autoimmune response. If it were just the amount of debris from dead cells that determined autoimmune risk, things like traumatic injury or even surgery should be predictors of autoimmune disease in otherwise normal people; there is no evidence for this, as far as I know.