Layperson Version
The Enemy Within Us
Blog #14:Chronic inflammation- “Enemy #1” (Part 1: Etiologies and pathogenesis)
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 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 or 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 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.
Blog #15:Chronic inflammation (CI)- “Enemy #1” (Part 2: Pharmacology and pharmacodynamics)
We started our last blog (#14) on chronic inflammation (CI) by describing its differences with acute inflammation. They included the causes of CI; its types of overreactions triggered by the immune cells; its chemical or pharmacologic differences; and finally, its clinical presentation. We really covered only the first and second difference, namely the causes and the cellular immune overreactions of CI. So we have a lot more work to do. Let’s get through CI’s chemical, pharmacology and pharmacodynamics in this blog and then finish up with the clinical and immunotherapeutic considerations of CI in Blog #15.
The pharmacology of CI includes a vast array of chemicals, enzymes, hormones and other reactive proteins as part of the inflammatory cascade. All of their functions are controlled in large part by the brain and we’ll be discussing them more in Blog #17. Meanwhile, the chemical actions that drive the immune response, or the pharmacodynamic process, is another portion of the CI reactions. All sorts of chemical mediators or “immunomodulators” that are actively amplifying, supplementing or suppressing CI reactions are producing the therapeutic effects we’ll be discussing in the next blog. The active immune cells in the process are generating some very potent chemicals of their own like interleukins, cytokines and one in particular protein called tumor necrosis factor alpha or TNA-a responsible for a wide range of signals that lead to those unique CI reactions we mentioned previously, like necrosis, fibrinization, and apoptosis. An interesting feature of this TNA-a protein is its multiple functions as a proinflammatory chemical that can resist infection and it also plays a role in cancer treatments. As such, numerous drugs have been developed to inhibit TNA-a to control inflammation and conversely, drugs to stimulate it to treat infection and cancer. Confusing? Indeed, it’s a delicate balancing act when modulating these pharmacologic agents in immunotherapies. But this whole area of CI pharmacology and pharmacodynamics illustrates CI’s role in all disease processes.
Allow me to dive just a little deeper for a moment into the pharmacodynamics of CI for some more robust, albeit complex, but worthwhile information. Think back to those WBCs that were activated by APCs (remember antigen presenting cells from back in Blog #5?) and immune chemicals that escaped from the blood vessels to fight a disease process site(s). On activation, one of those WBCs, the neutrophil, is being strengthened by all those mediators to aggressively help destroy the antigen by a powerful process called phagocytosis. This neutrophil process adds significantly to cytokines, TNF-a, T- and B-lymphocytes and antibodies that are attempting tto mediate inflammation along with those hypersensitivity overreactions (the Type 1 to 4 reactions from Blog #5). Meanwhile, adding to the inflammatory process are circulating blood platelets playing a role in the inflammatory process by adhering to the vessel walls forming thrombus; and other types of unique cells like mast cell giving off histamine and other inflammatory mediators producing the classic IgE allergic response (from Type I hypersensitivity). Quite a demonstration of biochemistry and, in fact, the basis for our in-depth immunotherapy upcoming discussion in Blog #21. What was the old DuPont saying? “Better living through chemistry.” Oops! I’m giving away my age?
Blog #16:Chronic inflammation (CI)- “Enemy #1” (Part 3: A multisystem pathology)
Other than my ad nauseum repetition of “Chronic inflammation (CI) being the basis of all diseases,” our discussions up to this point regarding CI have really only referenced the relatively obvious disease categories of allergy, infection, and immune diseases that are existentially related to CI. So let’s take a look at some other highly prevalent disease categories (cardio/cerebrovascular disease, musculoskeletal disease and injury, and neurologic and neurodegenerative diseases) and see what their direct and indirect relationships might be to CI.
Several landmark clinical studies have been done on the role of CI in the incidence of heart attacks and strokes. The findings in the studies show that a sustained low level of inflammation promotes the accumulation of cholesterol or plaques in the coronary and cerebral arteries, serious problem called atherogenesis. This can trigger a continuing inflammatory response with the immune system interpreting these plaques as being abnormal and foreign responding by creating a sort of barrier against them. Once this happens, the plaques loosen and blood clots and thrombi can cause heart attacks and strokes. Myocarditis, an inflammation of the heart muscle (myocardium), has also been shown to be a risk in infectious diseases, especially COVID-19. This can happen to those even with low blood cholesterol levels but who have elevated levels of inflammatory markers in the blood. A recent clinical trial proved that targeting inflammation without changing cholesterol levels can have a significant impact in reducing the likelihood of heart attacks and strokes by 15%.
Data have shown that inflammation has a central and stimulating effect on the development of atherosclerosis leading to increased risk of cardiovascular disease (CVD). Factors that produce dysfunctions in blood vessel walls (remember that effect as one of the causes of CI in Blog #13?) create cellular accumulations and increased production of tumor necrosis factor (TNF-a) and other interleukins (ILs) associated with the CI process and this becomes yet another cause of plaque formation (atherogenesis). There is strong evidence that anti-inflammatory biologic drugs, such as anti-TNF-a and anti-IL-6 agents, could control atherogenesis and ameliorate CVD risk. New research shows that reduced mortality and morbidity using biologic anti-IL-1b therapy to treat men and women who have had a prior heart attack provides proof of CI as contributing to the development of CVD.
In furtherance of my hypothesis of all diseases being derived from CI, consider the fact that acute inflammation secondary to injury, when not treated early (and sometime even when treated), will convert into CI (e.g., arthritis, bursitis) and the inexorably associated physical (musculoskeletal) “…itis” (inflammation) syndromes. Such conditions (excluding congenital and degenerative “disorders”) are conversions from their primary cause like physical injury, etc. to immunologic disease and resultant CI. Finally, aging is the consequence of the steady, prolonged accumulation of cellular joint damage related to the failure of clearing necrotic and cellular debris over years. The increasing load of these “damage-associated molecular patterns” called DAMPS leads to the release of proinflammatory cytokines (IL-6 and IL-18) causing ongoing low-grade CI. The functional decline of the immune system, including reduction in the length of chromosomes with aging, is referred to as “immunosenescence” and the associated active inflammatory process is called “inflammaging.” The name implies a CI process and that’s “proof of concept” for CI being “the basis of all disease.” I’m sure you’re tired of hearing that by now. Sorry, but you’ll be hearing it a lot more.
Functions and dysfunctions involving the brain, called neurologic and neurodegenerative disorders or diseases, constitute the highly complex relationship between the immune system and the brain or central and peripheral nervous systems. This subject demands its own blog. So let’s make that our next topic for Blog #17, Neuroimmunology.
Blog #17: Neuroimmunology
Buckle up folks. This next blog is a “brain teaser” (pun intended).
Contrary to previous beliefs, the brain is not an “immune-privileged” organ. The nervous system and the immune system share an intimate relationship wherein they modulate each other through sophisticated “bidirectional crosstalk” and very complex neuroendocrine and neurogenic pathways. These neural connections control much of the immunochemical production and reduction (“downregulation”) in the immune responses. This neurological control mechanism is the ultimate regulatory ordering for chronic inflammation (CI). Certain white blood cells (WBCs, specifically macrophages) not associated with the nervous system can infiltrate the central nervous system (CNS or the brain and spinal cord) and maintain a separate identity from the brain’s glial cells that normally function as CNS macrophages. This infiltration of non-CNS macrophages suppresses the glial neural functions (impulse transmission) as the invading macrophages replace the neural (glial) cells. This opens up the possibility for neural-mediated inflammatory reactions. Age-related or genetic CNS diseases that produce this glial macrophage replacement (with non-CNS macrophages) share common hallmarks including cognitive impairment, loss of brain volume, and the possible cause of the “brain fog” associated with the COVID-19 long hauler’s syndrome following acute and CI.
Innate and adaptive immune cells operating in an inflamed CNS produce neurodegeneration. Genome-wide association studies (GWAs, an approach used in genetics research to associate specific genetic variations with particular diseases) can help to identify gene variants that increase the risk of developing neurodegenerative inflammatory diseases. Despite a number of different causes (viral infections, stroke, neoplastic disorders, genetic mutations, trauma, and epigenetics [chemicals affecting genes]), neuronal damage is most frequently associated with chronic activation of an innate immune response in the CNS.
It is well established that the immune system is inextricably involved in shaping the brain during development as well as mediating damage during aging. Research is being conducted on these neuroimmune interactions during development, disease, and with aging. A better understanding of this bidirectional neuroimmune crosstalk will be the key to manipulating these responses and developing effective immunotherapies to reduce the impact of neurodegenerative diseases. Some of these diseases include Alzheimer’s, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, spinocerebellar ataxia, brain trauma, epilepsy, multiple sclerosis, and senile dementia.
As described in previous blog discussions, the body is constantly striving to maintain or reestablish a physiological balance called homeostasis and so too is it in the case with CI. In such cases, the neurological system becomes the main player in a highly complex (you didn’t expect anything less now, did you?) set of cellular and chemical actions and reactions in an effort to downregulate the immune system during CI. The sympathetic nervous system (system that increases heart rate, blood pressure, breathing rate) increases immune cell activity and makes bidirectional systemic immune responses possible, while the parasympathetic nervous system (PNS that slows the heart rate, dilates blood vessels) and the hypothalamic-pituitary-adrenal (HPA) axis generally reduces CI. Negative feedback on certain receptors (glucocorticoid) in the hippocampus can cause cortisol to stop the release of ACTH which can modulate the HPA-axis and increase brain protein (nuclear factor-kappa B or NF-kB, a protein transcription factor) which increases proinflammatory mediators. It has been known for decades that dysregulation of the HPA-axis is associated with depression. Major depressive disorder and depressive symptoms are associated with CI. Uncontrolled or dysregulated immune cells, due to prolonged and exaggerated stress activation, may be a factor in the greater production of NF-kB activity due to reduced cortisol sensitivity. Certain immune chemical mediators also influence the production and metabolism of neurotransmitters such as serotonin and dopamine that play critical roles in mood. These effects can be mitigated with antidepressant serotonin inhibitors combined with nonsteroidal anti-inflammatories. This paragraph really highlights the complexity of the immune-neural relationships. It also highlights the level of confusion the relationship can produce!
Finally, all of these inflammatory (acute and chronic) disturbances in the immune system cause dysregulation (loss of homeostasis) “or stress” in the system. This physiological stress can be considered an autoantigen that began with an antigenic reaction (self versus non-self) and eventually generated a cycle of autoantigenicity (from dysregulation inciting neurogenic and neuroendocrine reactions) collectively referred to as a “clinical autoimmune cycle” or the “danger hypothesis.”