Latent viral immune inflammatory response model for chronic multisymptom illness

Abstract

A latent viral immune inflammatory response (LVIIR) model is presented which integrates factors that contribute to chronic multisymptom illness (CMI) in both the veteran and civilian populations. The LVIIR model for CMI results from an integration of clinical experience with a review of the literature in four distinct areas: (1) studies of idiopathic multisymptom illness in the veteran population including two decades of research on Gulf War I veterans with CMI, (2) new evidence supporting the existence of chronic inflammatory responses to latent viral antigens and the effect these responses may have on the nervous system, (3) recent discoveries concerning the role of vitamin D in maintaining normal innate and adaptive immunity including suppression of latent viruses and regulation of the immune inflammatory response, and (4) the detrimental effects of extreme chronic repetitive stress (ECRS) on the immune and nervous systems.

The LVIIR model describes the pathophysiology of a pathway to CMI and presents a new direction for the clinical assessment of CMI that includes the use of neurological signs from a physical exam, objective laboratory data, and a new proposed latent viral antigen–antibody imaging technique for the peripheral and central nervous system. The LVIIR model predicts that CMI can be treated by a focus on reversal of immune system impairment, suppression of latent viruses and their antigens, and healing of nervous system tissue damaged by chronic inflammation associated with latent viral antigens and by ECRS.

In addition, the LVIIR model suggests that maintaining optimal serum 25 OH vitamin D levels will maximize immune system suppression of latent viruses and their antigens and will minimize immune system inflammation. This model also emphasizes the importance of decreasing ECRS to improve immune system function and to minimize nervous system injury from excess serum glucocorticoid levels. The proposed model supports growing evidence that increasing omega 3 essential fatty acid levels in nervous system tissues may decrease inflammation in the nervous system and improve neural plasticity and recovery from neuronal injury.

Introduction

The latent viral immune inflammatory response (LVIIR) model describes a pathway to chronic multisymptom illness in both military and civilian populations and may stimulate new methods for the clinical evaluation and treatment of individuals with these conditions. The term “chronic multisymptom illness” (CMI) was first developed by the US Center for Disease Control and Prevention in 1994 to define an idiopathic symptom complex that was based on a factor analysis of symptoms frequently reported by veterans returning from the first Gulf War [1], [2]. CMI’s were defined by the presence for at least 6 months of one or more symptoms from two symptom clusters: (a) general fatigue, mood, and cognitive disorders, and (b) musculoskeletal pain.

The LVIIR model is also used to explain an expanded list of signs and symptoms of idiopathic illnesses affecting veteran and civilian populations. Examples of other idiopathic illnesses might include mental health disorders such as post-traumatic stress disorder (PTSD), anxiety, and depression associated with physical symptoms and idiopathic physical conditions including pain syndromes, rashes, headaches, irritable bowel syndrome, sleep disorders, and cardiac arrhythmias. The LVIIR model suggests that, when CMI extends from affecting the nervous system to other organ systems or tissues of the body, it may become an idiopathic multisystem illness. This paper proposes that a CMI may be influenced by the interaction of several simultaneous factors such as; non viral antigenic stimulation of the immune system, neural toxins, medications that suppress the immune system, CNS post concussive changes, nutritional deficiencies, and pre-morbid mental health conditions.

The latent viral immune inflammatory response (LVIIR) model was developed as the result of combining clinical experience with a review of the literature in four distinct areas. (1) A brief review of idiopathic multisymptom illness in the veteran population since the US Civil War including two recent decades of research on veterans involved in conflicts in Western Asia including Kuwait, Iraq and Afghanistan. (2) New evidence supporting chronic inflammatory responses in the nervous system to latent viral antigens including those of the herpetic family of viruses and the effect that these responses may have on the nervous system. (3) Recent discoveries concerning the role of vitamin D in maintaining normal innate immunity, normal adaptive immunity, and the suppression of latent viruses. (4) The detrimental effects of extreme chronic repetitive stress (ECRS) on the immune system and the nervous system. In addition, the LVIIR model’s explanation of CMI is based on the extensive clinical experience of the first two authors in treating service members deploying to and returning from the war zones in Afghanistan and Iraq, in veterans at a Department of Veterans Affairs, VA Medical Center, and in civilian populations including children.

Idiopathic and disabling war related illnesses with similar symptoms and signs have been documented since the US Civil War [3]. They are often described as clinical syndromes for which the underlying causes of the signs and symptoms are not well understood. There are multiple factors associated with CMI and other idiopathic war related illnesses including ECRS, trauma, and some factors unique to specific conflicts [4]. Examples of unique factors might include infection and malnutrition during the US Civil War, exposure to chlorine and mustard gases during World War I, malnutrition and exposure to harsh weather during World War II and the Korean War, exposure to “agent orange” during the Vietnam War, and exposure to concussions from improvised explosive devices, numerous potential toxins, vaccines, and medications during recent wars in Kuwait, Iraq and Afghanistan.

Even with variations in experiences and exposures during different conflicts, chronically disabled veterans have presented with CMI and other idiopathic multisystem illnesses that have similar but perplexing characteristics. Symptoms are present in these illnesses that do not have an apparent medical explanation and laboratory tests, which measure severity and identify the causes of CMI and other multisystem idiopathic illnesses are notably absent. At times, there is progressive disability and, occasionally, signs and symptoms resolve spontaneously. Idiopathic syndromes have been identified in varied locations in the world at different times for at least the past one and one-half centuries. Most of the veterans afflicted with CMI or other idiopathic war related illnesses (i.e., chronic pain syndromes) have sustained some known form of ECRS from exposure to traumatic and stressful experiences. CMI and other idiopathic multisystem illnesses, however, have also appeared in non-deployed service members and in civilian populations [1], [2], [3], [4], [5], [6].

The LVIIR model presents one plausible pathway to idiopathic multisymptom illnesses or clinical syndromes that have occurred in different locations and following different conflicts for the past one and one-half centuries. The LVIIR model may also prove to be consistent with many recent epidemiological, neuropsychological (including PTSD [7]), toxicological, and immunological studies of idiopathic war related illnesses [6], [7], [8], [9].

Latent herpetic viruses have been infecting people for thousands of years [10]. The inflammatory nature of latent herpes zoster and herpes simplex I & II viruses in tissues of the nervous system and in other tissues of the body has been well documented [11], [12], [13], [14], [15]. The LVIIR model proposes that inflammation caused by the interaction of the immune system and latent herpetic viral antigens may be associated with hyper-excitability of sensory ganglia (i.e., herpes zoster neuritis) and of other neurons of the nervous system (i.e., herpes simplex I vestibular neuronitis, etc.) with or without clinically significant replication of either entire latent viruses or their DNA/RNA and with or without recurrent latent viral infection or nerve cell death. Latent herpetic viruses (and possibly latent viral antigens alone) have the ability to travel between sensory ganglia and innervated tissues of the body [16] and may also migrate from neurons of peripheral sensory ganglia to other neurons of the central nervous system.

This hypothesis that latent viral antigens may be present and trigger an immune inflammatory response is supported by a recent study involving varicella zoster virus, glycoprotein E-Specific, CD4⁺ T cells. Circulating gE-specific CD4⁺ T cells were detected at a relatively high frequency in healthy donors with normal immune systems. This finding would be compatible with frequent exposure to replicative cycle antigens in these healthy donors [17]. Varicella zoster virus (VZV) specific T cell responses may be vital in the prevention of latent viral reactivation.

In a mouse model, cytotoxic (killer) Cd8 T cells have been shown to block HSV I reactivation from latency in sensory neurons (trigeminal ganglia). HSV I infected trigeminal ganglia cells, infiltrated with Cd8⁺ T cells, were able to produce HSV I immediate and early proteins, but did not produce HSV I late proteins or infectious virions. Cd8⁺ T cells prevented reactivation of HSV I without destroying the infected neurons [18].

Elevated IgG levels to cytomegalovirus have also been implicated in rapid cognitive decline in older individuals (age 60–100) over a 4 year period [19]. Persistent latent viral DNA/RNA, in the presence or absence of infectious virus replication, can result in the loss of normal cell homeostasis and in an inflammatory response associated with antigenic viral proteins. The antigenic inflammatory response could result in demyelination or oligodendroglia cell death [20].

Considerable time may be required to reverse synaptic or possibly neural network long-term potentiation and depression changes even after the latent viral immune inflammatory response has resolved. Reversal of changes may also be incomplete in severe cases of a latent viral immune inflammatory response due to irreversible neuronal changes, injury, or even cell death. The role of inflammatory responses in pain was also highlighted in a a recent review [21] of sensory neuron function. Specifically, the researchers concluded that “recent evidence suggests that up regulated expression of inflammatory cytokines in association with tissue damage or infection triggers the observed hyper-excitability of pain sensory nerves”. Furthermore, chemokine and chemokine receptor expression in sensory ganglia may contribute significantly to virus-associated neuropathic pain syndromes [21]. Application of prolonged or intense noxious stimulation to sensory ganglia is thought to rearrange synaptic strength as in long term potentiation [22]. Chronic pain associated with hyperalgesia to pin prick and/or allodynia to touch may be a result of or related to detrimental synaptic plasticity at the sensory, spinal cord, or higher level. Chronic excessive indirect (through the cortex) somatosensory or autonomic afferent nerve input to the limbic system may result in detrimental long term potentiation or long term depression of synapses especially in the hypothalamus, hippocampus, and amygdala. The resulting detrimental neural plasticity changes in the CNS may play a significant role in symptoms (i.e., pain, fatigue, increased startle reflex, sleep problems, rage, PTSD, anxiety, depression, decreased concentration, and decreased short term memory) experienced by veterans with CMI’s or other idiopathic war multisystem illnesses [23], [24], [25], [26].

Further support for a latent viral immune inflammatory response model for CMI comes from our recent retrospective study conducted at a veteran’s hospital [27]. The study reviewed the successful use of long term (6 to 18+ months) antiviral therapy (acyclovir and valacyclovir) in the treatment of US veterans with chronic, often disabling, pain syndromes attributed to atypical herpetic viral reactivation. These pain syndromes were associated with the presence of hyperalgesia to pinprick, subtle or atypical rashes, pain, and burning or itching sensation. The veterans had elevated/positive antibody titers to at-least one herpetic virus including varicella zoster and herpes simplex I & II. One or more of these latent viruses were suspected of causing the veteran’s pain syndromes. Reported improvement in signs and symptoms ranged from 78% to 97% with moderate dose, long term, antiviral therapy (6–18 months)[27].

In another study [28], twelve patients with central nervous system dysfunction including long-standing fatigue were treated with Valganciclovir for 6 months. The patients had symptoms for 1–8 years and had high IgG antibody titers to Human Herpes-6 virus and Epstein Barr Virus. Nine of the 12 patients experienced near resolution of their symptoms and were able to return to full-time work or normal activity levels. IgG antibody titers, in those patients who responded, dropped significantly with treatment.

Also, a case study [29] of three children/adolescents with disabling chronic pain syndromes (greater than 1 year duration) reported such significant improvement in symptoms when treated with long term antiviral therapy (acyclovir or valacyclovir) that they were able to return to school. All three children had elevated IgG antibody titers to varicella zoster and one had elevated IgG antibody titers to HSV I. Two had chronic prominent but atypical rashes which resolved with long-term (greater than 6 months) antiviral therapy. Elevated IgG antibody titers to varicella zoster and herpes simplex I dropped in two individuals for which follow up antibody titers were available. When antiviral medication was stopped, one child experienced acute flare-ups of pain and disability.

When taken together the three studies re-enforce the concept that IgG antibodies to latent viruses can go up without overt signs of acute viral infection and later go down with treatment and/or resolution of symptoms. These studies suggest that some CMI and other chronic idiopathic multisymptom illnesses may have a viral component.

The immune system’s response to latent viruses and their viral antigens may be adversely affected by vitamin D insufficiency and deficiency. Fig. 1 provides a detailed exploration of the different forms of vitamin D in the serum and other tissues of the body in order to explain the relationship between the immune system and vitamin D. Vitamin D₃, cholecalciferol, is formed in the basal layer of the skin under the influence of ultra violet B sunlight. Cholecalciferol is stored in adipose tissue of the body. Vitamin D₃ and its metabolites are also present in the blood serum and are attached to vitamin D binding protein (DPB). As vitamin D₃ passes through the liver, it is converted to 25 OH D₃ and stored in the liver.

Vitamin D₃ is poorly soluble in an aqueous environment and highly soluble in a lipid environment. When vitamin D₃ in the diet and production of vitamin D₃ from skin exposure to ultra violet B sunlight are low, body fat may sequester vitamin D₃ from the serum due to vitamin D₃’s high lipid solubility. Thus a higher percent body fat may contribute to lower serum vitamin D₃ levels when intake and production of vitamin D₃ are low. Vitamin D₃ is transported in vascular and interstitial tissues attached to vitamin D binding protein (DBP) [30]. Plasma concentration of DBP is approximately 20 times greater than the total concentration of vitamin D₃ and its metabolites.

Low serum 25 OH vitamin D₃ levels can lead to secondary hyperparathyroidism [31]. Parathyroid hormone is known to stimulate the kidney’s conversion of serum 25 OH vitamin D₃ to serum 1,25(OH)₂ vitamin D₃, the active form of vitamin D₃ [31]. This may explain why serum 1,25(OH)₂ vitamin D₃ levels can be variable (including paradoxically normal to elevated) in patients with chronic vitamin D deficiency and are an unreliable measure of vitamin D status.

The presence of 1 alpha hydroxylase in many vitamin D target cells of the body (in addition to proximal renal tubular cells) is consistent with autocrine, intracrine, and paracrine functions for 1,25(OH)₂D₃ in the regulation of cell proliferation and differentiation. Both vitamin D activating (25-hydroxylase and 1 alpha-hydroxylase) enzymes and vitamin D metabolizing (24-hydroxylase) enzyme are present in some cells of the immune system including macrophages and mature dendritic cells. Strict regulation of these enzymes within immune system cells is consistent with an autocrine and paracrine role of vitamin D₃ in the immune system [32].

Macrophages and mature dendritic cells of the innate immune system are able to process antigens and then are able to activate and stimulate resting B lymphocytes and T lymphocytes by presenting processed antigens to them [33]. When B and T lymphocytes are activated by these cells and proliferate, both B and T lymphocytes express a 1,25(OH)₂D₃ vitamin D receptor (VDR). When extracellular 25(OH)D₃ levels are normal, macrophages and mature dendritic cells are able to convert adequate 25(OH)D₃ to 1,25(OH)₂D₃ (active vitamin D₃) within their cells. After exportation of the newly processed 1,25(OH)₂D₃ out of these cells, the increased extracellular 1,25(OH)D₃ levels provide negative feedback to activated B and T lymphocytes to limit the proliferation of B lymphocytes, IgG, T lymphocytes and associated inflammatory cytokines of the adaptive immune system [33]. The production of active vitamin D, 1,25(OH)₂D₃, at the site of inflammation permits higher concentrations of active vitamin D than might be achieved through normal diffusion from the serum. This partial uncoupling of interstitial serum 1,25(OH)₂D₃ from serum 1,25(OH)₂D₃ may explain why serum 25(OH)D₃ (rather than serum 1,25(OH)₂D₃) may be the controlling factor for limiting inflammation due to negative feedback by extracellular paracrine 1,25(OH)₂D₃.

When normal serum and interstitial 25 OH vitamin D₃ levels are present, antigenic stimulation of the macrophage/monocyte toll-like receptor 2/1 (TLR2/1) up-regulates these cell’s expression of vitamin D receptor (VDR) and 25 OH vitamin D-1a-hydroxylase (1-OHase). Intracellular 25 OH vitamin D₃ 1a-hydroxylase converts intracellular 25 OH D₃ to 1,25(OH)₂ D₃ which then stimulates the intracellular production of a cathelicidin in monocytes/macrophages. Human cathelicidin is a peptide that induces the destruction of infectious agents and improves innate immunity [34], [35]. Cathelicidin has been shown to have direct antiviral activity against adenovirus and herpes simplex virus in vitro [36].

When serum, interstitial, and monocyte/macrophage intracellular 25 OH vitamin D₃ levels are lower (vitamin D insufficiency/deficiency states), the intracellular production of cathelicidin is decreased and the effectiveness of monocyte/macrophage suppression of infectious agents is compromised. Impaired monocyte/macrophage function combined with an increased but ineffectual, antigen stimulated, B lymphocyte and T lymphocyte response may result in impaired suppression of latent viral antigens/viruses and an increased and chronic latent viral immune inflammatory response.

Dendritic cells of the innate immune system are important for immune system surveillance and dendritic cells also have a vitamin D (VDR) receptor [37]. Cell culture experiments support the hypothesis that vitamin D has significant anti-viral effects especially against enveloped (including herpetic) viruses [38]. Low vitamin D status and the presence of Epstein Barr virus appear to have a detrimental synergistic effect on the immune system facilitating the activation of auto-reactive T cells and increasing the inflammatory reaction to Epstein Barr virus [39].

In August of 2008, an article [40] reviewed a growing body of literature describing the low vitamin D₃ stores in patients with chronic pain and the need for vitamin D₃ supplementation in these patients. A retrospective study [41] of veteran’s charts at the Salisbury, NC. VA Medical Center examined the rate of vitamin D insufficiency and deficiency in a sample of 400 veterans, including those who had chronic disabling pain syndromes. A majority (70.5%) had serum 25 OH vitamin D₃ levels below Lab Corp of America’s lower limits of normal (<32 ng/ml), and 34% were vitamin D deficient (<20 ng/ml). Within the African American subset of veterans in this study, 93% were below the lower limits of normal and 68% were vitamin D deficient. The increased pigmentation in the skin of African Americans may have resulted in greater blocking of ultra violet B sunlight and reduced production of vitamin D₃. In this study, veterans with low serum vitamin D levels were almost twice as likely to develop a chronic pain syndrome compared to veterans with normal vitamin D levels.

A second large study of veterans in six Dept. of Veterans Affairs, medical centers in the Southeastern United States demonstrated wide spread vitamin D deficiency that resulted in high medical costs [42]. This study also reported an especially high risk of vitamin D deficiency in African American veterans. Both studies [41], [42] are consistent in reporting high rates of low serum 25 OH vitamin D₃ levels in the veteran population, thus, chronically low vitamin D levels may be one factor that could contribute to impairment of the immune system and to the development of a latent viral immune inflammatory response.

The effect of severe acute and ECRS on vitamin D metabolism, consumption and storage is not known. Severe acute stress and ECRS with increased glucocorticoid production, however, may impair vitamin D metabolism as has been demonstrated with the use of exogenous corticosteroids including prednisone [43]. ECRS may have particular relevance in the case of idiopathic CMI’s and other idiopathic multisystem illnesses due to its independent negative effects on immune system functioning and on the central nervous system [44], [45].

Overtime, ECRS is known to cause hyperplasia of the adrenal gland, increased glucocorticoid secretion, and atrophy of the thymus gland, which is one source of T lymphocytes [44]. Fig. 2 demonstrates how ECRS may relate to immune system function. Sympathetic fibers of the autonomic nervous system innervate bone marrow, thymus, spleen, and lymph nodes. All lymphocytes have adrenergic receptors. Stimulation of the hypothalamic–pituitary–adrenal axis or of the sympathetic–adrenal–medullary axis by ECRS results in the secretion of adrenal hormones including epinephrine, norepinephrine, and cortisol [46], [47]. Exposure to ECRS, in contrast to acute stress, has been shown to have negative effects on almost all functional measures of the innate and adaptive immune systems [46]. Impairment of the cellular immune response has been shown to often result in higher antibody levels against latent viruses [46], [47], [48].

Delayed-type hypersensitivity reactions have been examined in human participants to evaluate cellular immunity. T lymphocytes recognize an antigen introduced into the skin, then proliferate, secrete cytokines, and start an acute cellular immune system inflammatory reaction to clear the antigen from the skin. Chronic stress has been shown to impair or decrease delayed-type hypersensitivity reactions [49].

It is difficult to directly explain PTSD with its behavioral and psychological manifestations by employing a LVIIR model based on physical signs, laboratory tests, and proposed imaging techniques. However, physical factors, which appear to increase the risk of PTSD may be consistent with the multi-factor LVIIR model. Factors from epidemiological studies [7] that appear to increase the risk of PTSD in veterans and others include: sex (female), age (younger age greater than older age), race and ethnicity (African American and Hispanic individuals).

Specifically, in states of insufficient vitamin D production or intake, a higher percent body fat in females may lead to a greater amount of vitamin D dissolved in lipid tissue thus lowering serum and interstitial 25(OH)D₃ concentrations available for immune system function and regulation. African American and Hispanic individuals often have greater protection from ultra violate B sunlight due to increased pigmentation in the skin. As a result of this natural sun block, they produce vitamin D slowly and generally have low serum vitamin D levels when overall sun exposure to skin is inadequate for sufficient vitamin D production. Finally, there may be two or more possible explanations for the higher risk of PTSD in younger verses older individuals, which are consistent with the LVIIR model. One possible explanation is that there is greater capacity for neural plasticity in the brains of younger individuals making them more susceptible to detrimental synaptic long-term potentiation or depression effects of ECRS or a LVIIR. A second possible explanation is that younger individuals may experience greater glucocorticoid production detrimental to the central nervous and immune system function as part of a response to ECRS or to stress associated with a LVIIR.