Tag: autoantibodies

A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.

We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.

Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.

Source: Wirth K, Scheibenbogen C. A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors. Autoimmun Rev. 2020 Apr 1:102527. doi: 10.1016/j.autrev.2020.102527. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32247028

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)

The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE

Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a common and severe disease with a considerable social and economic impact. So far, the etiology is not known, and neither a diagnostic marker nor licensed treatments are available yet. The EUROMENE network of European researchers and clinicians aims to promote cooperation and advance research on ME/CFS. To improve diagnosis and facilitate the analysis of clinical trials surrogate markers are urgently needed. As a first step for developing such biomarkers for clinical use a database of active biomarker research in Europe was established called the ME/CFS EUROMENE Biomarker Landscape project and the results are presented in this review. Further we suggest strategies to improve biomarker development and encourage researchers to take these into consideration for designing and reporting biomarker studies.

Source: Carmen Scheibenbogen, Helma Freitag, Julià Blanco, Enrica Capelli, Eliana Lacerda, Jerome Authier, Mira Meeus, Jesus Castro Marrero, Zaiga Nora-Krukle, Elisa Oltra, Elin Bolle Strand, Evelina Shikova, Slobodan Sekulic and Modra Murovska. The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE. Journal of Translational Medicine201715:162. https://doi.org/10.1186/s12967-017-1263-z https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1263-z (Full article)

Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor

Abstract:

BACKGROUND: Numerous associations between brain-reactive antibodies and neurological or psychiatric symptoms have been proposed. Serum autoantibody against the muscarinic cholinergic receptor (mAChR) was increased in some patients with chronic fatigue syndrome (CFS) or psychiatric disease. We examined whether serum autoantibody against mAChR affected the central cholinergic system by measuring brain mAChR binding and acetylcholinesterase activity using positron emission tomography (PET) in CFS patients with positive [CFS(+)] and negative [CFS(-)] autoantibodies.

METHODOLOGY: Five CFS(+) and six CFS(-) patients, as well as 11 normal control subjects underwent a series of PET measurements with N-[(11)C]methyl-3-piperidyl benzilate [(11)C](+)3-MPB for the mAChR binding and N-[(11)C]methyl-4-piperidyl acetate [(11)C]MP4A for acetylcholinesterase activity. Cognitive function of all subjects was assessed by neuropsychological tests. Although the brain [(11)C](+)3-MPB binding in CFS(-) patients did not differ from normal controls, CFS(+) patients showed significantly lower [(11)C](+)3-MPB binding than CFS(-) patients and normal controls. In contrast, the [(11)C]MP4A index showed no significant differences among these three groups. Neuropsychological measures were similar among groups.

CONCLUSION: The present results demonstrate that serum autoantibody against the mAChR can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.

 

Source: Yamamoto S, Ouchi Y, Nakatsuka D, Tahara T, Mizuno K, Tajima S, Onoe H, Yoshikawa E, Tsukada H, Iwase M, Yamaguti K, Kuratsune H, Watanabe Y. Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS One. 2012;7(12):e51515. doi: 10.1371/journal.pone.0051515. Epub 2012 Dec 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519853/ (Full article)

 

Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence?

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous syndrome of unknown etiology and physiopathology. CFS patients complain about disabling fatigue, depression, difficulty with memory, and concomitant skeletal and muscular pain. Interestingly enough, there is certain overlap between CFS symptoms, autoimmune rheumatic disease, and infectious diseases.

Certain neuroendocrine-immune abnormalities have also been described, and autoantibodies commonly described in some autoimmune diseases have been found in CFS patients as well. An increasing number of autoantibodies, mainly directed against other nuclear cell components, have been illustrated. Likewise, an association between some infectious agents, antibody production, and later CFS onset has been reported. Similarly, vaccination is depicted as playing an important role in CFS onset.

Recently, a case report pointed toward a causal association between silicone breast linkage, hepatitis B virus vaccination, and CFS onset in a previous healthy woman. Such findings suggest that there is a likely deregulation of the immune system influenced by specific agents (infections, vaccination, and products, such as silicone).

Evidence suggests that CFS is a complex disease in which several risk factors might interact to cause its full expression. Thus, although different alterations have been found in CFS patients, undoubtedly the main feature is central nervous system involvement with immunological alterations. Therefore, a new term neuro-psycho-immunology must be quoted. New studies based on this concept are needed in order to investigate syndromes, such as CFS, in which immunological alterations are thought to be associated with concomitant psychological and health disturbances.

 

Source: Ortega-Hernandez OD, Shoenfeld Y. Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence? Ann N Y Acad Sci. 2009 Sep;1173:600-9. doi: 10.1111/j.1749-6632.2009.04799.x. https://www.ncbi.nlm.nih.gov/pubmed/19758205

 

Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome(CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression

Abstract:

Major depression and chronic fatigue syndrome (CFS) are accompanied by signs of oxidative and nitrosative stress (O&NS) and an inflammatory response. Phosphatidyl inositol (Pi) is thought to play a role in depression. The aim of the present study is to examine whether depression and CFS are characterized by an IgM-mediated immune response directed against Pi. Toward this end, this study examines the serum IgM antibodies directed against Pi in 14 patients with major depression, 14 patients with CFS, 14 subjects with partial CFS, and in 11 normal controls.

We found that the prevalence and mean value for the serum IgM levels directed against Pi were significantly greater in patients with major depression and CFS than in normal controls and patients with partial CFS. There were significant and positive correlations between serum IgM levels directed against Pi and two symptoms of the FibroFatigue Scale, i.e. fatigue and depression.

The results show that an IgM-related immune response directed against Pi may occur in both depression and CFS and may play a role in the pathophysiology of the key symptom of CFS and major depression. It is suggested that the above disorders in Pi result from increased O&NS in both depression and CFS. Autoanti-Pi antibodies may have biological effects, for example, by changing inositol 1,4,5-triphosphate (IP3), phosphatidylinositol-4,5-bisphosphate (PIP2), diacylglycerol and phosphatidylinositol-3,4,5-triphosphate (PIP3) production, thus interfering with intracellular signalling processes. Future research in major depression and CFS should focus on the functional consequences of the immune responses directed against Pi.

 

Source: Maes M, Mihaylova I, Leunis JC. Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome(CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression. Neuro Endocrinol Lett. 2007 Dec;28(6):861-7. https://www.ncbi.nlm.nih.gov/pubmed/18063934

 

Antinuclear antibodies in patients with chronic fatigue syndrome

Abstract:

Significance of antinuclear antibodies (ANA) in the patients with chronic fatigue syndrome (CFS) was reviewed. When indirect immunofluorescence with the HEp-2 cells as the substrates was used, prevalence of the positive ANA was reportedly 15-25%. The ANA titers were low and the immunofluorescent staining patterns were heterogeneous.

One group in the USA reported that ‘nuclear envelope staining pattern’ was found in more than 50% of the patients with CFS. This results, however, have not been confirmed by any other research groups. Clinical significance of the positive ANA in the CFS patients resides in differential diagnoses of systemic lupus erythematosus and other diffuse connective tissue diseases. Recently, several ANAs specific to CFS have been described.

We reported anti-68/48kD protein antibodies utilizing SDS-PAGE/ immunoblot method. These autoantibodies were found in 13% of 114 CFS patients and 0% in healthy subjects (p < 0.05). Hypersomnia and difficulty in concentration were found more frequently in the CFS patients with this specific autoantibody.

 

Source: Nishikai M. Antinuclear antibodies in patients with chronic fatigue syndrome. Nihon Rinsho. 2007 Jun;65(6):1067-70. [Article in Japanese] https://www.ncbi.nlm.nih.gov/pubmed/17561698

 

Evaluation of autoantibodies to common and neuronal cell antigens in Chronic Fatigue Syndrome

Abstract:

People with chronic fatigue syndrome (CFS) suffer from multiple symptoms including fatigue, impaired memory and concentration, unrefreshing sleep and musculoskeletal pain. The exact causes of CFS are not known, but the symptom complex resembles that of several diseases that affect the immune system and autoantibodies may provide clues to the various etiologies of CFS.

We used ELISA, immunoblot and commercially available assays to test serum from subjects enrolled in a physician-based surveillance study conducted in Atlanta, Georgia and a population-based study in Wichita, Kansas for a number of common autoantibodies and antibodies to neuron specific antigens.

Subsets of those with CFS had higher rates of antibodies to microtubule-associated protein 2 (MAP2) (p = 0.03) and ssDNA (p = 0.04). There was no evidence of higher rates for several common nuclear and cellular antigens in people with CFS. Autoantibodies to specific host cell antigens may be a useful approach for identifying subsets of people with CFS, identify biomarkers, and provide clues to CFS etiologies.

 

Source: Vernon SD, Reeves WC.  Evaluation of autoantibodies to common and neuronal cell antigens in Chronic Fatigue Syndrome. J Autoimmune Dis. 2005 May 25;2:5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1177983/ (Full article)

 

Chronic ACTH autoantibodies are a significant pathological factor in the disruption of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome, anorexia nervosa and major depression

Abstract:

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a commonly recognized feature of many pathological conditions. Abnormal adrenal responses to experimental manipulation have been well documented in patients suffering from chronic fatigue syndrome, anorexia nervosa and major depression. Yet no defect of any single organ, gland or brain region has been identified as a cause of these abnormalities. The disruption of the HPA axis that occurs in these conditions can be understood if an interfering factor is present in these patients.

Evidence indicates that this interfering factor is adrenocorticotropin hormone (ACTH) autoantibodies. Chronic high levels of ACTH autoantibodies will significantly disrupt the HPA axis and force the body to compensate for an impaired cortisol response. The resulting effect of chronic ACTH autoantibody interference is the manifestation of adrenocortical insufficient symptoms and psychological disturbances. Some symptoms ofchronic fatigue syndrome, anorexia nervosa and major depression, such as anxiety, are the adverse effects of mechanisms compensating for less effective ACTH due to autoantibodies. Furthermore, these patients engage in extraordinary behaviors, such as self-injury, to increase their cortisol levels. When this compensation is inadequate, symptoms of adrenocortical insufficiency appear.

Corticosteroid supplements have been demonstrated to be an effective treatment for chronic fatigue syndrome, anorexia nervosa and major depression. It allows the patients to have the corticosteroids they require for daily functioning and daily stressors. This therapy will relieve the patients of their symptoms of adrenocortical insufficiency and permit their cortisol-stimulating mechanisms to operate at levels that will not cause pathological problems.

 

Source: Wheatland R. Chronic ACTH autoantibodies are a significant pathological factor in the disruption of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome, anorexia nervosa and major depression. Med Hypotheses. 2005;65(2):287-95. http://www.ncbi.nlm.nih.gov/pubmed/15885924