Biomedical subjects

Patrick Y Lee

Publications and source records attributed to Patrick Y Lee.

At least 37 records · Page 2Linked to original sources

PubMed2005

Can chronic use of anti-inflammatory agents paradoxically promote chronic inflammation through compensatory host response?

A higher relative risk of thrombotic cardiovascular complications has recently emerged in studies evaluating the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as rofecoxib, celecoxib, and naproxen. Direct pro-thrombotic effects of selective cyclooxygenase-2 inhibition were originally speculated to be the potential mechanism behind these results, but this proposal fails to explain the pro-thrombotic effects of non-selective NSAIDs. We hypothesize that the paradoxical pro-inflammatory, pro-thrombotic effects associated with chronic use of anti-inflammatory agents are attributable to compensatory host response rather than direct effects of the drugs. Chronic pharmacologic inhibition of inflammation may induce physiologic dependence, and cessation of therapy has been shown to produce rebound effects in aspirin, statins, and other immunomodulatory agents. By down-regulating inflammatory pathways in a pulsatile fashion, chronic use of NSAIDs may promote compensatory up-regulation of these same pathways and shift the host baseline equilibrium towards an inflammatory state. The host may be susceptible to inflammation between intermittent doses and after withdrawal of therapy. Inflammation is a promoter of adrenergia and thrombosis, and the constellation of these effects may predispose to excess risk of acute cardiovascular events.

Animals↗

PubMed2005

The link between T helper balance and lymphoproliferative disease.

Lymphoproliferative disorders comprise a heterogeneous group of neoplasms whose behaviors range from indolent to very aggressive. The increased incidence seen in the context of immunodeficiency provides evidence that the host immune system plays a vital role in their pathogenesis. We believe that T-helper (Th)-2 dominant states favor development of lymphoproliferative disorders, including lymphoma, and conversely T-helper (Th)-1 immunity protects against lymphoproliferative disease. The age distribution of lymphomas favors childhood and post-reproductive senescence, suggesting that exposure to these periods of Th-2 bias constitutes a key risk factor for developing the disease. The tendency of lymphomas to arise in Th-2 biased locations such as mucosal interfaces, immunoprivileged sites, and regions of B-cell differentiation may likewise reflect a corresponding spatial predilection. Various clinical conditions or treatments that shift Th1/Th2 balance, including HIV infection, transplant-related immune suppression, and autoimmune disorders, can also influence the status of lymphoproliferative diseases.

Homeostasis↗

PubMed2005

The incorporation of iodine in thyroid hormone may stem from its role as a prehistoric signal of ecologic opportunity: an evolutionary perspective and implications for modern diseases.

To optimize fitness under conditions of varying Darwinian opportunity, organisms demonstrate tremendous plasticity in their life-history strategies based on their perception of available resources. Higher-energy environments generally promote more aggressive life-history strategies, such as faster growth, larger adult size, greater genetic variation, shorter lifespan, larger brood sizes, and offspring ratio skewed towards the larger-sized gender. While numerous mechanisms regulate life-history plasticity including genetic imprinting, methylation, and growth factors, evidence suggests that thyroid hormone plays a central role. Given the pivotal adaptive role of thyroid hormone, the teleology of its dependence on dietary iodine for production remains unexplained. We hypothesize that iodine may have emerged as a substrate for production of thyroid hormone in prehistoric ecosystems because the former represented a reliable proxy for ecologic potential that enabled the latter to modulate growth, reproduction, metabolic rate, and lifespan. Such a scenario may have existed in early marine ecosystems where ocean-surface vegetation, which concentrates iodine for its antimicrobial and antioxidant properties, formed the basis of the food chain. Teleologic parallels can be drawn to the food-chain accumulation of antimicrobials that also exhibit antioxidant properties and promote adult size, brood size, and offspring quality by modulating central hormonal axes. As each higher species in the food chain tunes its life-history strategy based on iodine intake, the coupling of this functional role of iodine with its value as a resource signal to the next member of the food-chain may promote runaway evolution. Whereas predators in prehistoric ecosystems successfully tuned their life-history strategy using iodine as a major input, the strategy may prove maladaptive in modern humans for whom the pattern of iodine intake is decoupled from resource availability. Iodine acquired through sodium iodide supplementation may independently contribute to some biologic dysfunctions currently attributed to sodium.

Animals↗

PubMed2005

Adventitial dysfunction: an evolutionary model for understanding atherosclerosis.

Endothelial and smooth muscle dysfunctions are widely implicated in the pathogenesis of atherosclerosis. Modern mechanical and pharmacologic treatments aim to remodel abnormalities of the vessel intima and media. We hypothesize that adventitial dysfunction comprises the dominant source of atherosclerosis by originating many endothelial and smooth muscle abnormalities. The autonomic nervous system innervates the adventitia, and autonomic dysfunction induces many end-organ dysfunctions including inflammation and thrombosis. The link between diabetes and atherosclerosis may operate through adventitial autonomic neuropathy. Smoking may promote atherosclerosis by inducing adventitial autonomic dysfunction related to nicotine-mediated compensatory upregulation of sympathetic bias independent of endothelial injury induced by purported tobacco toxins. While hypertension is thought to cause atherosclerosis, the two conditions may instead represent independent consequences of autonomic dysfunction. The link between aging and atherosclerosis may operate through adventitial dysfunction induced by autonomic dysregulations. Exercise may ameliorate atherosclerosis by restoring adventitial autonomic function, thereby normalizing adventitial regulation of medial and intimal biology. Feed-forward adventitial vascular baroreceptor and chemoreceptor dysregulation may further exacerbate atherosclerosis as intimal plaque interferes with these sensors. Since penetrating external physical injury likely represented a dominant selective force during evolution, the adventitia may be preferentially equipped with sensors and response systems for vessel trauma. The convergent response of adrenergia, inflammation, and coagulation, which is adaptive for physical trauma, may be maladaptive today when different stressors trigger the cascade. Endoluminal therapies including atherectomy, angioplasty, and stent deployment involve balloon expansion that traumatizes all layers of the vessel wall. These interventions may paradoxically reinitiate the cascade of atherogenesis that begins with adventitial dysfunction and leads to restenosis. Methods to reduce adventitial trauma, a maladaptive trigger of adventitial dysfunction, may reduce the risk of restenosis. We envision novel mechanical and biopharmaceutical solutions that target the adventitia to prevent or treat atherosclerosis including novel drug delivery strategies, exo-stents that wrap vessels, and neuromodulation of vessels.

Animals↗

PubMed2005

Integrating the theories of Darwin and Bernoulli: maladaptive baroreceptor network dysfunction may explain the pathogenesis of aortic aneurysms.

Current treatment options for aortic aneurysms are suboptimal and their pathogenic mechanisms remain unclear. We propose the existence of a coordinated multi-node baroreceptor network that measures pressures at all vascular bifurcations and enables system-wide hemodynamic coordination and vasomotor regulation, in accordance with the principle of Bernoulli. While the presence of baroreceptors at bifurcations remains unknown, behavior at the level of systems predicts their existence, possibly as glomus cell derivatives. We propose that pressure misregistration among sensor nodes at different vascular bifurcations can precipitate feed-forward dysfunctions that promote thrombosis, inflammation, and vasomotor dysregulation resulting in aneurysm formation. One example of this phenomenon is aortic aneurysm, which is currently attributed to focal anatomic defects. As plaque builds in the infrarenal aorta, the increased blood velocity through this segment can widen the difference between pressures sensed at the iliac and the renal artery bifurcations. Due to the Bernoulli effect, this change creates an incorrect impression of reduced dynamic pressure at the kidneys. The erroneous perception of hypovolemia can induce a pernicious cycle of maladaptive adrenergia and associated coagulation and thrombosis, particularly in the infrarenal aortic segment as the body attempts to normalize renal perfusion. Atherosclerosis can further exacerbate baroreceptor dysfunction by interfering with sensor biology in feed-forward fashion. Hypertension may be a consequence as well as a source of atherosclerosis and aneurysm. The described system may have evolved when trauma-related hypovolemia was a far more prevalent driver of natural selection but may be rendered maladaptive in the setting of modern stressors. Failure to address these factors may explain the suboptimal long-term outcomes with current surgical and endovascular treatments for aneurysms. Implications for other potential sensor networks including chemoreceptors and lymphoid tissues at bifurcating biologic branch-points such as vessels, airways, nerves, lymphatics, and ducts are discussed. Our framework may also provide a new basis for understanding thoracic aneurysm, renovascular dysfunctions, coronary artery disease, carotid artery disease, pulmonary embolism, portal hypertension, venous thrombosis, biliary disease, pancreatic disease, and neurologic disease. Novel treatment paradigms based on drugs or interconnected networks of devices that modulate sensors are envisioned. Improving the interface between sensors and their substrate information by techniques such as minimally traumatic atherectomy or thrombectomy may also restore appropriate sensor function. Lessons learned from bifurcation sensors and their potential maladaptations may generalize to other types of branching systems including botany, civil engineering, and Pitot tube aeronautics.

Animals↗

PubMed2004

Sudden death among infants and adults: companion disorders of maladaptive sympathetic bias.

Sudden infant death syndrome is the leading cause of death in infancy, but its pathophysiological mechanism has been elusive. Sudden death in adults is a common phenomenon, but the etiology in many cases remains unknown at autopsy. We hypothesize that maladaptive sympathetic bias is the explanatory mechanism that links many cases of sudden demise among adults and infants as companion syndromes. Normally, sympathetic response occurs as an adaptation to physiologic demands of the body through various autonomic reflex arcs such as chemoreceptors. Sympathetic response can become chronic and maladaptive when the normal sympathetic response fails to correct the precipitating physiologic trigger, leading to chronic activation of autonomic reflex arcs. In conditions such as infant sleep apnea or adult heart failure, a pernicious cycle of sympathetic bias may result. Chronic sympathetic bias increases susceptibility to sudden fatal arrhythmias, QT-related and otherwise, in the setting of an exaggerated adrenergic challenge. Examples of such adrenergic stressors include trauma, hypoxia, hypercapnia, acidosis, sleep arousal, illness, medical procedures, and physical activity, all of which have associations with sudden death. Our hypothesis may not only help explain the survival benefits of drugs such as beta-blockers and devices such as synchronization therapy, but also portend new application of similar therapies for many conditions of sympathetic bias.

Adult↗

PubMed2004

Conditions of aging as manifestations of sympathetic bias unmasked by loss of parasympathetic function.

We propose a unifying hypothesis that many clinical consequences of aging are pleiotropic manifestations of the loss of parasympathetic function that occurs during post-reproductive senescence. The loss of parasympathetic function unmasks the baseline sympathetic bias inherent in the end-organs, resulting in the familiar signs of aging including tachycardia, constipation, insomnia, erectile dysfunction, fluid retention, and systemic inflammation. These consequences in turn may contribute to many of the common diseases associated with aging including type-2 diabetes, Alzheimer's, atherosclerosis, and cancer. Maintenance and restoration of parasympathetic function may enable upstream control over the deleterious aspects of inherent end-organ adrenergic bias.

Aging↗

PubMed2004

Acute coronary syndromes and heart failure may reflect maladaptations of trauma physiology that was shaped during pre-modern evolution.

We hypothesize that the pathophysiology of many cardiovascular diseases reflects a maladaptation of the triad of trauma response: adrenergia, inflammation, and coagulation. During biologic evolution, trauma has likely been a prevailing factor in natural selection. Components of the trauma triad act to limit hemorrhage, defend wounds against microorganisms, and initiate reconstruction. Response pathways that enable survival after trauma confer obvious adaptive advantages especially if the individual goes on to reproduce. Modern humans have shaped their own ecologic environment in such a way that the incidence of trauma has waned and previously unseen pathologies have emerged. Manifestations of modern diet, changing lifestyles, and extended lifespan have suddenly created new pathologic challenges to our prehistoric physiologic system. During our evolutionary heritage, endothelial injury and end-organ hypoxia were likely exclusively associated with physical trauma and the responses of the trauma triad were appropriate. Today, endothelial injury is more often precipitated by distinctly modern stressors such as hypertension, smoking, diabetes, and dyslipidemia. The once-adaptive trauma response can maladaptively initiate dangerous, self-propelling cycles of adrenergia, inflammation, and coagulation. Acute coronary syndromes perhaps best exemplify this phenomenon. Congestive heart failure, which often ensues, can similarly be seen as a maladaptation of the trauma triad. Whereas end-organ hypoxia was once commonly associated with trauma, now hypoxia is more often attributable to distinctly modern stressors such as pump failure. The fluid conservation and inflammation that results from the trauma triad was clearly adaptive in our prehistoric past, but in congestive heart failure the response is maladaptive, engendering self-propelling exacerbations of pump failure and vascular disease. Our maladaptive trauma response hypothesis portends new diagnostic and therapeutic paradigms for cardiovascular diseases and has ramifications for many other conditions such as stroke, venous thrombosis, vasculitis, aortic disease, arterial disease, pulmonary embolism, and restenosis.

Acute Disease↗

PubMed2004

Many diseases may reflect dysfunctions of autonomic balance attributable to evolutionary displacement.

We hypothesize that many ailments are attributable to dysfunctions of autonomic balance. The autonomic system is a primitive, highly-adaptive response system that allows differential allocation of biologic effort under varying conditions. The autonomic system, however, can execute a response that is inappropriate for the system stressor due to evolutionary displacement. Evolutionary displacement is a situation in which a trait that evolved as an adaptive response to certain conditions now faces a new set of conditions. Modern human evolution since the Pleistocene era is characterized by substantial evolutionary displacement, brought on in large part by the accelerating ability of humans to change their own environment. In the setting of evolutionary displacement, previously adaptive systems such as the autonomic system can be rendered unhelpful or even counterproductive. Emergence of chronic conditions, maladaptation of the trauma response, and extension of human lifespan are examples of evolutionary displacements that can induce inappropriate sympathetic bias in hosts. We postulate that many diseases are manifestations of this general phenomenon. Implications for existing and future therapeutic strategies are discussed.

Biological Evolution↗

PubMed2004

Autonomic dysfunction may be an under-recognized cause of female fertility disorders.

Female conditions of impaired fertility comprise a heterogeneous group of disorders that are attributed to various anatomic, hormonal and immunologic disturbances. We hypothesize that autonomic dysfunction may be a previously unrecognized factor in female fertility disorders. Emerging physiologic and molecular evidence suggests that autonomic balance varies during normal menstrual cycles with a shift to sympathetic bias during the luteal phase. Furthermore, many diseases associated with autonomic dysfunction show catamenial variations in patterns consistent with a shift to sympathetic bias occurs during the second half of normal menstrual cycles. The shift to sympathetic bias during the normal luteal phase may be an evolutionary adaptation to address the immunologic and physiologic demands for successful implantation and gestation. Through direct modulation of the lymphoid system and activation of the cortisol pathway, sympathetic bias promotes a shift to relative T helper (Th)-2 biased immunity which may favor maternal tolerance of the embryo by attenuating Th-1 mediated interference of implantation. Indeed, a growing body of evidence has implicated abnormal Th balance in fertility disorders, but the link has been attributed to factors other than autonomic function, such as hormonal factors. After implantation, maternal sympathetic bias may further support gestation through physiologic changes necessary to maintain placental perfusion pressure. We propose that insufficient shift to sympathetic bias during the luteal phase, which manifests in inadequate shift towards Th-2 bias and down-regulation of Th-1 function, may be the mechanism of impaired fertility in certain patients. Our hypothesis portends new potential methods to treat fertility disorders by modulating autonomic balance.

Autonomic Nervous System Diseases↗

PubMed2004

Tumors may modulate host immunity partly through hypoxia-induced sympathetic bias.

Hypoxia can occur in solid tumors when oxygen demand from rapid tumor growth outstrips the blood supply. Once thought to be merely a consequence of tumor physiology, more recent evidence suggests that hypoxia may also be a tumor adaptation to promote its own survival. For example, hypoxic conditions generate local transcriptional changes that enhance angiogenesis and glycolysis, processes that directly promote tumor growth. We hypothesize that maladaptive local chemoreceptor host response to hypoxia may contribute to a shift in immune balance that favors cancer survival. Specifically, we propose that hypoxia in the tumor microenvironment activates local adrenergic activity which in turn inhibits Th1 function while favoring Th2 function. Th1 function is vital to the host defense against cancer, and Th1 depletion is associated with increased cancer risk. In our view, the sympathetic bias induces Th2 bias independent of the direct immunomodulatory effects of tumor-derived cytokines. The hypoxia-induced local adrenergic response may be part of a broad tumor adaptation that enables its evasion of host immune surveillance. That the host response of Th2 bias is so reflexively linked to hypoxia may reflect the likelihood that trauma, rather than modern diseases such as cancer, were the most common causes of hypoxia during our teleologic past when natural selection shaped our biologic pathways. Validation of our hypothesis may shed more light on the biology of cancer and reveal novel diagnostic and therapeutic strategies.

Adaptation, Physiological↗

PubMed2004

Modulation of host immunity by HIV may be partly achieved through usurping host autonomic functions.

Modulation of host immunity has been observed in human immunodeficiency virus (HIV) infections. HIV is believed to influence host immunity through a variety of mechanisms including direct effects on host T cell survival, indirect effects on cytokine profile through modulation of immune cells, and modulation of endocrine functions that affect immunity such as steroids. We hypothesize that HIV infection may also alter host immunity through modulation of host sympatho-vagal balance. Specifically, we propose that HIV drives autonomic balance towards sympathetic bias, which can contribute to a T helper (Th)2 type immunity. A variety of paraviral syndromes associated with HIV infection such as QT prolongation, cachexia, cardiomyopathy, and lipodystrophy are consistent with evidence of autonomic dysfunction. Immunomodulatory effects of autonomic dysfunction toward Th2 bias are presented. A plausible mechanism by which HIV can influence autonomic balance through hypothalamic manipulation is offered. Shift to Th2 dominance is associated with HIV disease progression and can be viewed as a viral adaptation to promote its own survival. Autonomic remodeling by HIV may exemplify this phenomenon. Our hypothesis has implications for treatment of HIV and its associated syndromes.

Autonomic Nervous System Diseases↗

PubMed2004

Hypertrophic osteoarthropathy may be a marker of underlying sympathetic bias.

Hypertrophic osteoarthropathy (HOA) is a condition that accompanies many seemingly unrelated diseases. It is commonly associated with various clinical conditions such as pregnancy, aging, pulmonary diseases, cancers, and other systemic illnesses. The condition has been attributed to various causes such as platelet abnormalities, hormonal disturbances, and cytokine dysfunction, but the exact underlying mechanism has been elusive. We propose a unifying hypothesis that activation of the adrenergic system is the common thread that links all of the disparate clinical associations of hypertrophic osteoarthropathy. In diseased states, autonomic stimulation may occur as a result of chemoreceptor activation in response to acidosis, hypoxia, or hypercapnia. Examples include sleep apnea, congestive heart failure, renal failure, and tumor-induced hypoxia. In this setting, clinical signs of HOA may be a marker of underlying autonomic dysfunction. Autonomic stimulation may also occur as a normal part of pregnancy or as an abnormal component of aging. The exact pathway linking adrenergic excess to HOA remains to be clarified, but a plausible scenario based on current molecular evidence is offered.

Adrenergic Agents↗

PubMed2004

Modulation of autonomic balance by tumors and viruses.

Autonomic balance, a function generally under host control, is subject to modulation by other signalers. In some cases, modulation of host autonomic function through behavioral and physical stressors exerted by another individual may have negative consequences for the stress recipient by inducing sympathetic bias. Modulation of autonomic function may sometimes benefit one party at the expense of another. Tumors and HIV are examples of illegitimate signalers who may induce host sympathetic bias to promote their own growth and evade host immune surveillance. Paraneoplastic and paraviral syndromes such as hypertrophic osteoarthopathy, QTc prolongation, insomnia, and cachexia could be viewed as epiphenomena related to the tumoral and viral manipulation of host autonomic balance. In a more general framework, other paraneoplastic and paraviral syndromes may represent epiphenomena related to modulation of endocrine, cytokine, and autonomic functions by tumors and viruses to promote their own survival. Spatial distribution of cancers and viruses within the host may reflect affinity for strategic locations that facilitate manipulation of a variety of host functions including autonomic, endocrine, and cytokine regulation. A more general for understanding spatial distribution of diseases based on gradients of autonomic balance in the body are explored. Darwinian perspectives are discussed.

Autonomic Nervous System Diseases↗

PubMed2004

Temporal variation of autonomic balance and diseases during circadian, seasonal, reproductive, and lifespan cycles.

Many diseases show patterns of temporal variation that remain unexplained. We hypothesize that oscillation of autonomic balance over different time intervals plays a role in these variations. In the Darwinian struggle, organisms must perform various functions related to fitness such as survival, energy acquisition, and reproduction in a prioritized fashion. Autonomic systems enable differential allocation of effort to various functions under different conditions, some of which vary in patterns that are predictable such as circadian, menstrual, seasonal, and life cycles. For many species, daytime functions such as seeking food and avoiding predators are achieved with sympathetic activity while night-time functions such as internal processing are achieved with parasympathetic activity. For organisms that maintain thermal homeostasis year-round, cooler temperature seasons may demand sympathetic bias to drive adaptive thermogenesis. Reproduction may necessitate autonomic shift to sympathetic bias during the luteal phase and pregnancy to modulate immune balance towards a more tolerant Th2 bias. Many diseases including infectious, cardiovascular, inflammatory, pulmonary, metabolic, fertility, oncologic, and neurologic conditions also show variation in prevalence over these cycles. The co-variation of autonomic balance and diseases over time intervals suggests that autonomic balance, by its direct effects as well as its indirect effects through modulation of T helper immune balance, plays an under-recognized role in diseases. The theory is extended to the co-variation of autonomic balance and diseases over the lifespan. Termination of organisms during senescence, achieved by emergence of autonomic imbalance and other systemic dysfunctions, is explored from a Darwinian perspective.

Adaptation, Physiological↗

PubMed2004

Menstrual variation of autonomic balance may be a factor in exacerbations of certain diseases during the menstrual cycle.

Exacerbation of certain medical conditions during specific phases of the menstrual cycle has long been recognized. Mechanisms of the cyclic variations are poorly understood, but are often attributed to fluctuations in reproductive hormones. We hypothesize that normal variations in autonomic balance during the menstrual cycle, which likely evolved as adaptations for reproduction, may contribute to catamenial variations in diseases independent of hormonal variations. Emerging evidence suggests that autonomic balance shifts towards sympathetic bias during the second half of the menstrual cycle. This shift can be seen as an evolutionary adaptation to address the immunologic and physiologic demands for successful implantation and gestation. Through direct modulation of lymphoid system and activation of the cortisol pathway, sympathetic bias promotes a shift to relative T helper (Th)-2-biased immunity which may favor maternal tolerance of the embryo by attenuating Th-1-mediated interference of implantation. Immune variance during the menstrual cycle has been implicated in menstrual fluctuations of many diseases, but until now the immune variance has been attributed to female hormonal changes. We propose that shifts in autonomic balance independently contribute to fluctuations in diseases by modulating the immune system. Still further, we propose that many other diseases fluctuate due to the direct nervous system actions of shifts in autonomic balance. Our hypothesis portends new therapeutic paradigms based on cyclical modulation of autonomic balance to address catamenial variations of medical conditions.

Adaptation, Physiological↗

PubMed2004

Immunomodulatory function of seminal catecholamines may be an adaptation for reproduction.

Catecholamines are found at high concentrations in seminal fluid. The exact functional significance of seminal catecholamines is unknown. We hypothesize that seminal catecholamines perform important immunomodulatory functions that support reproductive success. Specifically, we propose that catecholamines contribute to a local adaptive shift of T helper (Th) balance to Th2 dominance in the maternal reproductive tract to enable the gametes, and possibly the nascent zygote, to evade immune surveillance of the female. Our hypothesis suggests that the Th2 effects of catecholamines are independent of the direct immunomodulatory effects of seminal cytokines such as prostaglandin E2 and transforming growth factor beta1. Potential immunomodulatory functions of other seminal constituents such as aldosterone, oxytocin, vasopressin, and angiotensin remain unexplored and represents a topic of future interest. Seminal stress hormones may play a role in mating dynamics since alpha males typically live in a state of high hormonal stress, Mating with adrenalized alpha males may represent an adaptive Darwinian strategy by females to maximize their reproductive fitness.

Adaptation, Physiological↗

PubMed2004

An "eye" in the gut: the appendix as a sentinel sensory organ of the immune intelligence network.

Neural systems are the traditional model of intelligence. Their complex interconnected network of wired neurons acquires, processes, and responds to environmental cues. We propose that the immune system is a parallel system of intelligence in which the gut, including the appendix, plays a prominent role in data acquisition. The immune system is essentially a virtual unwired network of interacting cells that acquires, processes, and responds to environmental data. The data is typically acquired by antigen-presenting cells (APCs) that gather antigenic information from the environment. The APCs chemically digest large antigens and deconstruct them into smaller data packets for sampling by other cells. The gut performs the same function on a larger scale. Morsels of environmental content that enter the gut are sequentially deconstructed by physical and chemical digestion. In addition to providing nutrients, the componentized contents offer environmental data to APCs in mucosa-associated lymphoid tissues (MALT) that relay the sampled information to the immune intelligence network. In this framework, positioning of the appendix immediately after the ileocecal valve is strategic: it is ideally positioned to sample environmental data in its maximally deconstructed state after small bowel digestion. For single-celled organisms, digestion of the environment has been the primary way to sample the surroundings. Prior to the emergence of complex sensory systems such as the eye, even multi-cellular organisms may have relied heavily on digestion to acquire environmental information. While the relative value of immune intelligence has diminished since the emergence of neural intelligence, organisms still use information from both systems in integrated fashion to respond appropriately to ecologic opportunities and challenges. Appendicitis may represent a momentary maladaptation in the evolutionary transition of sensory leadership from the gut to the eye. Relationships between immune dysfunctions and cognition are explored.

Animals↗