When, for some unknown reason, the body incorrectly identifies itself (i.e., self) as foreign (i.e., non-self), effectively, the body becomes an “antigen” and generates a process referred to as “autoantigenicity.” This process initiates an adaptive immune response directed at itself. Stated another way, the immune system has the potential to produce an “autoimmune response.”
There are several theories as to the cause(s) of the idiosyncratic autoimmune responses, but whatever the cause(s), the response has created an entirely separate disease category referred to as “autoimmune disease.” Despite the fact that the etiology of this disease category remains unknown or at least open to multiple hypotheses, its pathogenesis (development) and thus, its therapeutic strategies are similar to those of chronic inflammation (CI) in that CI is the immunological basis and process responsible for this category of immune disease
The etiologies of autoimmune diseases and those of CI are virtually identical (see Blog #14 and 18), thus making the two entities synonymous, one with a clinical label (autoimmune disease) and one as a pathological classification (CI). The first etiology is “a prolonged inflammatory process from failure to eliminate an antigen.” Continued or unabated antigen stimulus will lead to CI and its clinical sequalae as discussed in Blog #14 and 18, and stress antigenicity as described in Blog #3 and elsewhere.
The second autoimmune etiology is abnormalities (inherent or mutational) in the patient’s genome that can make it susceptible to dysregulation. Complicated interactions between neural, genetic variants, genetic mutations, and epigenetics (non-altered DNA modifications of phenotype gene expression) can produce a multitude of pathways that lead to autoimmune diseases.
The third etiology is environmental factor(s) or stress eliciting an autoimmune response. Combined with inherited alleles that an individual might possess for a specific gene (the genotype), a given environmental factor can produce a “phenotype trigger” or something to produce the clinical manifestations of autoimmune disease. Consider the person who has smoked all their life without ever experiencing the classic, associated diseases (respiratory, cardiovascular, carcinogenic). One (like an aging, inveterate smoker) would use this as an argument that smoking is not a risk factor. On the contrary, that individual “rolled the dice” (unknowingly) on not having the specific gene(s) and alleles to induce a smoke-related disorder, and he/she won the gamble. But epidemiologic studies have unequivocally concluded that there is a greater risk of having one or more “phenotype triggers” for smoking-induced disorders than not. The free-will choices we make regarding of what we will or will not expose ourselves to (i.e., risks) range from people’s common sense (or lack thereof) to practicing good personal and public health measures (e.g., smoking, or of late, wearing a mask, and vaccination during an infectious pandemic). Maybe routine DNA screening in the future will help us make better decisions.
The fourth autoimmune etiology is the increasing release and accumulation of proinflammatory cytokines or endogenous (internal) autoantigens, including such things as metabolic and immune byproducts. This pathophysiologic phenomenon was described in some detail back in Blogs #3 and 14 in our discussion of the “clinical autoimmune cycle” or “death hypothesis.”
Finally, the fifth (and probably not the last) etiology of autoimmune disease is “rogue B cells” and epitope spreading. Antigens have small sites on their surfaces called epitopes or “antigenic determinants” that bind to a genetically predetermined corresponding receptor on the surface of the B cell (from the “antibody-encoding gene” introduced in Blog #7). These B-cell receptors and epitopes are programmed genetically through the major histocompatibility complex (MHC) on the T cells (specifically, Th MHC Class 2 CD4 and MHC Class 1 Tc CD8) again, as described in Blog #10). When toll-like receptors (TLRs or the “sentry cells”) signal MHCs, the B cells undergo changes in their genes to produce antibodies that create strong attachments to the antigens’ epitopes and generate plasma cells that proceed to produce large amounts of antibodies. During this rapid proliferation and dispersion (or “spreading”) of antibodies, some B cells become genetically (aberrantly) altered and begin to mistake “self” as antigenic. These autoantibody B cells are called “rogue B cells” and their migration is called “epitope spreading.” This spreading is what produces the clinical picture of the many autoimmune diseases whose signs and symptoms “spread” insidiously (Machiavellian-like) or gradually over time, from one organ to another. It is theorized that this “rogue B-cell-epitope spreading” phenomenon is a product of dual genetic influences (messages) to the immune system, some of which incite, but other which silence the immune system, thus reducing autoantigenic effects (yet another immune paradox).
Discussion Questions:
Explain the positive and negative consideration of phenotype triggers as they relate to cigarette smoking.
Rogue B cells and epitope spreading provide a strong correlation with autoimmune diseases. Can you identify the types of diseases associated with epitope spreading and give some examples?
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