We began our discussion of chronic inflammation (CI) way back in Blog #2. You may (or may not) want to relisten or reread that blog before jumping into the deep end. In essence, my message (my hypothesis) is that CI is the basis of all diseases. Besides defining the entity, in this blog, I hope to make my case clear enough to help you understand the thesis and strong enough to make you a “believer.” We’ll start with its pathogenic etiologies; then to its immunologic, and molecular level; then its pharmacology and pharmacodynamics; and finally, its clinical and immunotherapeutic considerations.
Of course, the foundational etiology of CI is an antigenic stimulus leading to adaptive immunopathological dysregulation. When that antigen is a “known” (substance or stress), its removal is the solution (or “cure” if you will). But what about “non-self” antigenicity (exogenous or endogenous), the more insidious etiologies of CI. The postulates here include a congenital or acquired mutation in the patient’s genome; chronic exposure to environmental factors (toxins, pollution, smoking, microbiota [microbiome], etc.); accumulating inflammatory byproducts of cellular and humoral (e.g., proinflammatory cytokines) resulting in persistent inflammatory and neural stimuli, and as described in Blog #3, intrinsic antigenic stress (the “danger hypothesis”); and finally, innate, unknown autoantigenic factor(s). This last etiology will become the basis for our autoimmune discussion starting in Blog #18.
Starting way back in the innate immune discussion (Blog #5), we described the progression of hypersensitivity or overreactions (sometimes referred to as Coomb’s Gell classification, Type I to Type IV) triggered by innate immune T and B lymphocytes, NK, macrophage cells, immune complexes, cytokines, and immunoglobin antibodies. These overreactions produce the inflammatory cascade associated with acute inflammation. But included in the molecular biology of that cascade are a vast array of molecules and cytokines (Figure 2.1 in Blog #9) that can lead indirectly or directly to CI. The distinguishing pathological features of CI from those molecules and cytokines include localized or diffuse (throughout the body) histopathological changes.
These changes produce the following effects: localized accumulations of monocytes, lymphocytes, neutrophils (WBCs), and giant cells (called granulomas) that convert to fibroblasts and produce induration and fibrinization; and caseation (cheesy textured tissue), necrosis (dying tissue), and apoptosis (programmed cell death), all disrupting and destroying tissue (Figure 4.1). Cellular migration associated with surface proteins and chemokines induces a specialized molecule, endothelial leukocytic adhesion molecules (ELAM) which stimulates leukocyte (neutrophil) adhesion to the endothelial vessel walls. As edema loosens cell junctures in the blood vessel walls (perivasculitis), ELAM produces vessel wall permeability (diapedesis) with extravasation (escape from the vessel) of neutrophils. This allows cells and fluid to migrate into tissues and structures while inflammatory substances (proinflammatory cytokines, etc.) continue to accumulate (infiltration) producing a “clinical autoimmune cycle” or the “death hypothesis.
Beyond these histopathological features, cellular dysfunction is producing immunogenomic and proteomic disturbances (disruption of the cellular proteome [remember the “central dogma of molecular biology” from Blog #10?]). As mentioned above, these inflammatory changes are occurring locally as well as diffusely in the body and its genome. Ultimately, regardless of the primary etiology of any disease (infection, immune, cardio/cerebrovascular, neurological, musculoskeletal, metabolic, endocrine, congenital, cancer, and more), the immunohistopathological and physiological changes occurring, particularly in diffuse blood vessel walls (perivasculitis), and in the genome, make CI the basis of all disease. Simply stated, all diseases are ultimately the clinical manifestations of the pathogenesis of CI. That’s my hypothesis (Figure 4.2) and “I’m sticking to it!” And I’ll try to defend it further regarding “all diseases” in Blog #14 to 16 of this discussion on CI.
Discussion Questions:
If CI is the basis for all diseases, what are some of the histopathological and pharmacodynamic reasons for such a hypothesis?
CI can produce local as well as diffuse inflammatory effects throughout the body. If that is the case, what is the mechanism (the pathophysiology that contributes most to the diffuse nature of CI?
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