The concept of stress as the cause of “all” immune responses was a bit of an epiphany as I wrote The Paradox of the Immune System. I always felt that stress produces a loss of homeostasis (the “yin and yang” phenomenon in human biology) and thus, notwithstanding that it’s not a substance (synonymous with “non-self” antigens), stress should be considered an antigen because of its dysregulation or destabilization of normal physiology (i.e., loss of homeostasis). So my thinking focused on external (exogenous) considerations like environmental factors and intrinsic (endogenous) human factors like mental and emotional stress. Then, thanks to the work and articles of a preeminent immunology scholar, Dr. Polly Matzinger, I came to realize that additional “dangerous” stress related factors also escaped the immunologic T-cell tolerance associated with body’s unceasing innate and acquired immune responses (lots more on those in Chapters 1 and 2).
Some of these factors include cellular injury and debris, other non-physiological events in a tissue, or defects in the body’s handling of dying, injured or stressed cells (a process called apoptosis), all antigenic in nature and producing a disruption of homeostasis. Dr. Matzinger referred to this in her research as the “danger hypothesis.” Beyond the enumerated “dangerous” exogenous factors, I began to recognize that the continual endogenous, biologic and physiologic effects from whatever causes, were also a source of recurring homeostatic imbalance and thus, an inherent source of antigenicity. I call this the “clinical autoimmune cycle” because it produces a continual systemic “antigenic stimulus” with or without a non-self antigenic source.
Taking these novel theses to their logical conclusion regarding the human immune system, you can appreciate an omnipresent, prevailing immunogenic stimulus with the potential to produce chronic inflammation (CI). If we accept the concept of CI as the basis of “all” disease” (as explained in the prior blog), this immunologic progression of stress antigenicity (the clinical autoimmune cycle) establishes the premise of stress, be it exogenous or immune-induced endogenous, physiologic stimuli as the ultimate, rudimentary etiology of autoimmune diseases, cancers and in fact, the eventual cause of all diseases. So why then, given that all human organisms experience this inherent antigenic stress stimulus, aren’t all humans in a constant state of clinical or subliminal “disease”? Could it be that, in fact, we are in some continual stage of dysregulation controlled by cellular, humoral, cytokinetic factors, or genetic mutations yet undetermined? Certainly, more research must be conducted to identify immunomodulating forces that amplify or mitigate human disease in the presence of stress antigenicity.
Discussion Questions:
Should stress (exogenous and/or endogenous) be considered an antigen (or antigenic) and if so, why?
Is the “danger hypothesis” (immunity being a function of bodily tissue cells, rather adaptive or innate immune systems [Matzinger P. Autoimmunity: Are we asking the right question? Front Immunol. 2022]) a reasonable, questionable or indefensible theory?
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