We left off in our last blog (#5) with innate immunity converting into adaptive immunity as it advances in the disruption of homeostasis and produces “dysregulation” of the overall immune system. At this point in the process, any one of four mechanisms can occur. First, if the removal of the antigen occurs, “feedback inhibition” reduces the innate immune stimulus and decreases the production of antibodies and cytokines, effectively reducing and reversing dysregulation. Second, neuroendocrine and neurogenic pathways modulate cytokine production and control the immune response. This complex neurological control mechanism is the ultimate regulatory hierarchy for chronic inflammation (CI) as well, and will be discussed in the Blog (#17). The third mechanism is when TREG reduces TH cells and produces a commensurate reduction in B-cell activity (which you will recall from innate immunity is controlled by TH cells). And finally, the fourth mechanism is a very complex genetic mechanism creating a system of idiotype antigen-specific B cells called the “Idiotype-anti-idiotype Regulatory Circuit”. This is a process that self-generates through genetic cloning, creating its own immunogenic stimuli that induce anti-idiotype-specific antibodies (“antibodies 1, 2, etc.”). This system has strong implications in cancer therapy and we’ll postpone further discussion on it until the blog (#33) on cancer.
Failure to remove an offending antigen in a timely manner or malfunction of any one of the four mechanisms described above can lead to a pathophysiological response resulting in a clinical effect you have heard about and undoubtedly experienced yourself, called “acute inflammation.” At this point, adaptive immunity is now in a race to eliminate the bad guy (antigens), a competition in which, in most cases (given an otherwise healthy person), the combined innate and adaptive immune systems will win. If, however, the underlying health of the patient is not adequate enough to sustain the activity of the adaptive immune response, things could begin to deteriorate further. All those T’s
and B’s and so on now begin to initiate four types of “hypersensitivity reactions” (also referred to as “overreactions” because the immune system is now going beyond its protective functions) we mentioned in the later part of the innate immune system discussion (Blog #5). These four overreactions are induced by different types of antigen categories and each is characterized by specific cellular responses and “types” of immunoglobulin antibodies (Figure 1.6). We won’t describe each reaction here (later in Blog #14), but simply indicate that one or more of these reactions will precipitate the next phase of immunity, acute inflammation, and its associated “inflammatory cascade” (Figure 2.1) of pharmacological components and their subsequent clinical manifestations synonymous with acute inflammation including vasodilation, edema, infiltration, ulceration (Figure 2.2).
Acute inflammation can be considered a healing or protective adaptive immune process reacting to foreign antigenic invasion. Nonetheless, the fundamental treatment for acute inflammation is the removal of the offending antigen in a timely manner and amelioration of clinical sequelae like cold for vasoconstriction (to reduce vascular diapedesis) and steroids for infiltration (Figure 2.3 and 2.4). Failure to do so can lead to more destructive manifestations of ulceration, tissue loss, and even the potential for DNA disturbance. Once again, the physiological (even physical) stress creating
disequilibrium and a “dysregulated” in tissues or organ systems in the inflammatory cascade create the potential for a “clinical autoimmune cycle” (Figure 5.1). And the most serious consequence of acute inflammation is the risk of the adaptive immune response lapsing into a CI process over days and weeks.
But, whereas acute inflammation is only one pathogenic route to CI, there are other causes, most of which remain idiopathic. And as we discussed in Blog #2 (and again later in Blog #14), albeit similar in name, CI, beyond duration, introduces an entirely distinct pathophysiology, histopathology, pharmacology, and unremitting clinical course.
Discussion Questions:
The four types of hypersensitivity reactions we mentioned are precursors to acute inflammation. One of those (Type 1) is associated with IgE antibodies. From your basic science background, can you identify the specific antigen responsible for this reaction and its classic clinical response?
Notwithstanding the fact that acute inflammation is a healing and protective function of immunity, it is nonetheless treated aggressively. Can you give some reasons for such a paradox?
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