Tag: autoimmunity

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a hyper-regulated immune system driven by an interplay between regulatory T cells and chronic human herpesvirus infections

Abstract:

Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause. Given these observations, the regulatory CD4+ T cells (Tregs) show promise to be good candidates for the underlying pathology due to their known capacity to suppress the immune responses not only to body components but also against infections. Here we discussed the overlooked role of these cells in the chronicity of Human Herpes Virus 6 (HHV6), Herpes Simplex 1 (HSV1) and Epstein-Barr virus (EBV), as often reported as triggers of ME/CFS.

Using simulations of the Cross-regulation model for the dynamics of Tregs, we illustrated that mild infections might lead to a chronically activated immune responses under control of Tregs if the responding clone has a high autoimmune potential. Such infections promote persistent inflammation and possibly fatigue. We then hypothesized that ME/CFS is a condition characterized by a predominance of this type of infections under control of Tregs. In contrast, healthy individuals are hypothesized to trigger immune responses of a virus-specific clone with a low autoimmune potential.

According to this hypothesis, simple model simulations of the CD4+ T-cell repertoire could reproduce the increased density and percentages of Tregs observed in patients suffering from the disease when compared to healthy controls. A deeper analysis of Tregs in the pathogenesis of ME/CFS will help to assess the validity of this hypothesis.

Source: Nuno Sepúlveda, Jorge Carneiro, Eliana M. Lacerda and Luis C. Nacul. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a hyper-regulated immune system driven by an interplay between regulatory T cells and chronic human herpesvirus infections. Front. Immunol. | doi: 10.3389/fimmu.2019.02684. https://www.frontiersin.org/articles/10.3389/fimmu.2019.02684/abstract

Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination?

Abstract:

Fibromyalgia is a disorder characterized by chronic widespread pain and non-pain symptoms, such as fatigue, dysautonomia, and cognitive and sleep disturbances. Its pathogenesis and treatment continue to be the subject of debate. We highlight the role of three mechanisms-autoimmunity, neuroinflammation, and small fiber neuropathy in the pathogenesis of the disease. These mechanisms are shown to be closely interlinked (also on a molecular level), and the review considers the implementation of this relationship in the search for therapeutic options.

We also pay attention to chronic fatigue syndrome, which overlaps with fibromyalgia, and propose a concept of “autoimmune hypothalamopathy” for its pathogenesis. Finally, we analyze the molecular mechanisms underlying the neuroinflammatory background in the development of adverse events following HPV vaccination and suggesting neuroinflammation, which could exacerbate the development of symptoms following HPV vaccination (though this is hotly debated), as a model for fibromyalgia pathogenesis.

Source: Ryabkova VA, Churilov LP, Shoenfeld Y. Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination? Int J Mol Sci. 2019 Oct 18;20(20). pii: E5164. doi: 10.3390/ijms20205164. https://www.mdpi.com/1422-0067/20/20/5164 (Full article)

Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial and poorly undersood disabling disease. We present epidemiological, clinical and experimental evidence that ME/CFS constitutes a major type of adverse effect of vaccines, especially those containing poorly degradable particulate aluminum adjuvants.

Evidence has emerged very slowly due to the multiplicity, lack of specificity, delayed onset, and frequent medical underestimation of ME/CFS symptoms. It was supported by an epidemiological study comparing vaccinated vs unvaccinated militaries that remained undeployed during Gulf War II.

Affected patients suffer from cognitive dysfunction affecting attention, memory and inter-hemispheric connexions, well correlated to brain perfusion defects and associated with a stereotyped and distinctive pattern of cerebral glucose hypometabolism. Deltoid muscle biopsy performed to investigate myalgia typically yields macrophagic myofasciitis (MMF), a histological biomarker assessing longstanding persistency of aluminum agglomerates within innate immune cells at site of previous immunization. MMF is seemingly linked to altered mineral particle detoxification by the xeno/autophagy machinery.

Comparing toxicology of different forms of aluminum and different types of exposure is misleading and inadequate and small animal experiments have turned old dogma upside down. Instead of being rapidly solubilized in the extracellular space, injected aluminum particles are quickly captured by immune cells and transported to distant organs and the brain where they elicit an inflammatory response and exert selective low dose long-term neurotoxicity. Clinical observations and experiments in sheep, a large animal like humans, confirmed both systemic diffusion and neurotoxic effects of aluminum adjuvants. Post-immunization ME/CFS represents the core manifestation of “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA).

Copyright © 2019. Published by Elsevier B.V.

Source: Gherardi RK, Crépeaux G, Authier FJ. Myalgia and chronic fatigue syndrome following immunization: macrophagic myofasciitis and animal studies support linkage to aluminum adjuvant persistency and diffusion in the immune system. Autoimmun Rev. 2019 May 3. pii: S1568-9972(19)30109-0. doi: 10.1016/j.autrev.2019.05.006. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31059838

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity.

Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients.

Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.

Source: Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M, Scheibenbogen C; European Network on ME/CFS (EUROMENE). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease. Autoimmun Rev. 2018 Jun;17(6):601-609. doi: 10.1016/j.autrev.2018.01.009. Epub 2018 Apr 7. https://www.sciencedirect.com/science/article/pii/S1568997218300880 (Full article)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology.

In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients.

Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.

Source: Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S1, Murovska M, Scheibenbogen C; European Network on ME/CFS (EUROMENE). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease. Autoimmun Rev. 2018 Apr 7. pii: S1568-9972(18)30088-0. doi: 10.1016/j.autrev.2018.01.009. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29635081

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME

Abstract:

Introduction: Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases.

Methods: 10 patients with post-infectious CFS/ME and elevated ß2 autoantibodies were treated with IA with an IgG-binding column for 5 days. We assessed severity of symptoms as outcome parameter by disease specific scores. Antibodies were determined by ELISA and B cell phenotype by flow cytometry.

Results: IgG levels dropped to median 0.73 g/l (normal 7–16 g/l) after the 4th cycle of IA, while IgA and IgM levels remained unchanged. Similarly, elevated ß2 IgG antibodies rapidly decreased during IA in 9 of 10 patients. Also 6 months later ß2 autoantibodies were significantly lower compared to pretreatment. Frequency of memory B cells significantly decreased and frequency of plasma cells increased after the 4th IA cycle. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting moderate to marked improvement for 6–12+ months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening.

Conclusions: IA can remove autoantibodies against ß2 adrenergic receptor and lead to clinical improvement. B cell phenotyping provides evidence for an effect of IA on memory B cell development. Data from our pilot trial warrants further studies in CFS/ME.

Source: Carmen Scheibenbogen, Madlen Loebel, Helma Freitag, Anne Krueger, Sandra Bauer, Michaela Antelmann, Wolfram Doehner, Nadja Scherbakov, Harald Heidecke, Petra Reinke, Hans-Dieter Volk, Patricia Grabowski. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLOS ONE. Published: March 15, 2018 https://doi.org/10.1371/journal.pone.0193672 (Full article)

Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model

Abstract:

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease.

A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension.

A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Source: Jonas Blomberg, Gerhard Gottfries, Amal Elfaitouri, Muhammad Rizwan and Anders Rosén. Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Hypothesis and Theory Article, Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229 (Full article)

On chronic fatigue syndrome and nosological categories

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disease which presents with pronounced disabling fatigue, sleep disturbances, and cognitive impairment that negatively affects patients’ functional capability. CFS remains a poorly defined entity and its etiology is still in question. CFS is neither a novel diagnosis nor a new medical condition. From as early as the eighteenth century, a constellation of perplexing symptoms was observed that resembled symptoms of CFS. Commencing with “febricula” and ending with CFS, many names for the disease were proposed including neurocirculatory asthenia, atypical poliomyelitis, Royal Free disease, effort syndrome, Akureyri disease, Tapanui disease, chronic Epstein-Barr virus syndrome, and myalgic encephalitis. To date, it remains unclear whether CFS has an autoimmune component or is a condition that precedes a full-blown autoimmune disease.

Research suggests that CFS may overlap with other diseases including postural orthostatic tachycardia syndrome (POTS), autoimmune syndrome induced by adjuvants (ASIA), and Sjögren’s syndrome. Additionally, it has been postulated that the earliest manifestations of some autoimmune diseases can present with vague non-specific symptoms similar to CFS. Sometimes only when exposed to a secondary stimulus (e.g., antigen) which could accelerate the natural course of the disease would an individual develop the classic autoimmune disease. Due to the similarity of symptoms, it has been postulated that CFS could simply be an early manifestation of an autoimmune disease. This paper will provide a historical background review of this disease and a discussion of CFS as an entity overlapping with multiple other conditions.

Source: Sharif K, Watad A, Bragazzi NL, Lichtbroun M, Martini M, Perricone C, Amital H, Shoenfeld Y. On chronic fatigue syndrome and nosological categories. Clin Rheumatol. 2018 Feb 7. doi: 10.1007/s10067-018-4009-2. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29417255

Do anorexia, irritable bowel syndrome, chronic fatigues share a common cause?

Irritable bowel syndrome, chronic fatigue syndrome and anorexia nervosa may all have a common origin according to researchers.

They speculate that all three disorders may be caused by antibodies to the body’s own nerve cells because of a mistake by the immune system following infection.

At the moment, the ultimate cause of these illnesses remains a mystery.

Writing in Medical Hypotheses, Dr Jim Morris from the University Hospitals of Morecambe Bay NHS Trust, Dr Sue Broughton and Dr Quenton Wessels from Lancaster University say current explanations are unsatisfactory.

“Psychological factors might be important, but are unconvincing as the primary or major cause.

“There might, for instance, be an increased incidence of physical and sexual abuse in childhood in those who go on to manifest functional disorders. It is easy to see how this could influence symptoms in adults but it stretches credulity to imagine abuse as the sole and sufficient cause of the functional disorder.”

It is already well known that women are more at increased risk of autoimmune disease especially ones in which antibodies to the body’s own cells are thought to play a role, like thyroid disease, pernicious anemia and myasthenia gravis.

The researchers said: “The female to male ratio in these conditions is of the order of 10. The female excess in Irritable Bowel Syndrome, Chronic Fatigue Syndrome and Anorexia Nervosa is equally extreme and therefore this fits with the idea that auto-antibodies to nerve cells could be part of the pathogenesis of these conditions.”

The formation of auto-antibodies is found mostly among women and increases with age, which could be why these disorders are more common in midlife. Even with anorexia, which reaches a peak at the age of 30, auto-antibodies have been found in the bodies of patients.

There are also links with infection in that the onset of IBS commonly follows an episode of infectious diarrhea while chronic fatigue syndrome can be triggered by infectious mononucleosis and viral hepatitis.

Even anorexia could be influenced by secretions from bacteria affecting the brain, triggering the production of antibodies which affect mood and motivation.

“Auto-antibodies acting on the (brain’s) limbic system could induce extremes of emotion including disgust and fear. These then become linked, in the minds of adolescent girls, to culturally determined ideas of what is, and what is not, the ideal body shape and size. It is then a small step for disgust and fear to be directed to food and obesity which the fashion industry currently demonizes.”

If their idea is proven, the researchers suggest that these disorders may be amenable to treatment using pooled immunoglobulin from the blood of healthy people, especially in severe cases of anorexia where life is threatened. It should also be possible to identify and eliminate from the gut the bacteria which are triggering auto-antibodies.

Journal Reference: J.A. Morris, S.J. Broughton, Q. Wessels. Microbes, molecular mimicry and molecules of mood and motivation. Medical Hypotheses, 2016; 87: 40 DOI:10.1016/j.mehy.2015.12.011

 

Source: Lancaster University. “Do anorexia, irritable bowel syndrome, chronic fatigues share a common cause?.” ScienceDaily. ScienceDaily, 25 April 2016. https://www.sciencedaily.com/releases/2016/04/160425100204.htm

 

Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity

Abstract:

Myalgic encephalomyelitis (ME) is a complex, heterogeneous illness of unknown etiology. The search for biomarkers that can delineate cases from controls is one of the most active areas of ME research; however, little progress has been made in achieving this goal. In contrast to identifying biomarkers that are directly involved in the pathological process, an immunosignature identifies antibodies raised to proteins expressed during, and potentially involved in, the pathological process. Although these proteins might be unknown, it is possible to detect antibodies that react to these proteins using random peptide arrays.

In the present study, we probe a custom 125,000 random 12-mer peptide microarray with sera from 21 ME cases and 21 controls from the USA and Europe and used these data to develop a diagnostic signature. We further used these peptide sequences to potentially uncover the naturally occurring candidate antigens to which these antibodies may specifically react with in vivo.

Our analysis revealed a subset of 25 peptides that distinguished cases and controls with high specificity and sensitivity. Additionally, Basic Local Alignment Search Tool (BLAST) searches suggest that these peptides primarily represent human self-antigens and endogenous retroviral sequences and, to a minor extent, viral and bacterial pathogens.

 

Source: Singh S, Stafford P, Schlauch KA, Tillett RR, Gollery M, Johnston SA, Khaiboullina SF, De Meirleir KL, Rawat S, Mijatovic T, Subramanian K, Palotás A, Lombardi VC. Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity. Mol Neurobiol. 2016 Dec 15. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27981498