(Selected Tables and Figures referenced, but not present in this blog
can be found in their corresponding Science Version blogs)
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 or my theory 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 in this blog with how it evolves as a disease entity; then to its immunologic, and molecular level; then its biochemical or pharmacology and pharmacodynamics considerations; and finally, its clinical and relationship to immune disease and treatment. Of course, the foundational basis of CI is the good old foreign, non-self, antigenic stimulus leading to adaptive immune 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 of the more subtle or stealthy causes of inflammation? The possibilities here include a congenital or acquired mutation in the patient’s genome; chronic exposure to environmental factors like toxins, pollution, smoking, and even the microbiota of the microbiome; or accumulating inflammatory byproducts of cellular or proinflammatory chemicals resulting from persistent inflammatory and even neurological stimuli to be described further in Blog #17. Remember the intrinsic antigenic stress or the “danger hypothesis” from Blog #3? And finally, innate, unknown autoantigenic factor(s) we’ve introduced in a number of previous blogs. This last potential cause of CI will become the basis for our autoimmune discussions starting in Blog #18. Starting way back in the innate immune discussion in Blog #5, we described the progression of hypersensitivity or overreactions, generally classification as Type I to Type IV and triggered by our good old innate T and B lymphocytes, natural killer cells, macrophage cells, immune complexes, cytokines, and immunoglobin antibodies. These overreactions produce the inflammatory cascade associated with acute inflammation and the inflammatory cascade from Blog #9. But included in the chemistry and biology of that inflammatory cascade are a vast array of molecules and chemicals, like pro-inflammatory cytokines (Figure 2.1 in Blog #9) that can lead indirectly or directly to CI. The distinguishing features of CI from those of acute inflammation include localized versus diffuse, throughout the body, tissue and cellular changes right down to the DNA level. These biological changes produce the following effects: localized accumulations of white blood cells (WBCs) and giant cells, also called granulomas, that convert to course fibrin, aka scarring, and fibroblasts that produce hardening of tissue (induration and fibrinization); and caseation (cheesy textured tissue), necrosis (dying tissue), and apoptosis (programmed cell death). All these abnormal changes are disrupting and destroying tissue (Figure 4.1). Cellular changes associated with surface proteins and chemicals induce a specialized molecule, the endothelial leukocytic adhesion molecules (ELAM) which produces stickiness to blood vessel walls. Edema also loosens the junctures in the blood vessel walls and together these inflammatory changes produce a serious and deleterious condition of the vessels called perivasculitis. This vascular inflammation weakens the blood vessels and causes them to allow WBCs and fluids from the blood to escape into the local tissue or if the vascular process is diffuse, into larger surrounding areas of tissues all the way to entire body involvement. This allows cells and fluid to continue to accumulate, or infiltration tissue producing the “death hypothesis” we mentioned back in Blog #3 or another clinical descriptor, a “clinical autoimmune cycle.” Beyond these cellular and tissue disruptions, the adverse changes and the body’s dysfunction is producing immunogenomic disturbances in protein synthesis (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 cause of any disease, be it infection, immune disease, cardio/cerebrovascular, neurological, musculoskeletal, metabolic, endocrine, congenital, cancer, and other categories, the immunologic consequences of CI, particularly in its diffuse blood vessel wall effects (perivasculitis) and disruption of genomic protein synthesis make CI the basis of all disease. Simply stated, all diseases are ultimately the clinical effects 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 continuing discussion on CI.
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