Tag: IgM antibodies

Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID

Abstract:

Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions.

Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID. We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS.

Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients. Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.

Source: Zheng Liu, Claudia Hollmann, Sharada Kalanidhi, Arnhild Grothey, Samuel Keating, Irene Mena-Palomo, Stephanie Lamer, Andreas Schlosser, Agnes Kaiping, Carsten Scheller, Franziska Sotzny, Anna Horn, Carolin Nuernberger, Vladimir Cejka, Boshra Afshar, Thomas Bahmer, Stefan Schreiber, Joerg Janne Vehreschild, Olga Milljukov, Christian Schaefer, Luzie Kretzler, Thomas Keil, Jens-Peter Reese, Felizitas A Eichner, Lena Schmidbauer, Peter U Heuschmann, Stefan Stoerk, Caroline Morbach, Gabriela Riemekasten, Niklas Beyersdorf, Carmen Scheibenbogen, Robert K Naviaux, Marshall Williams, Maria E Ariza, Bhupesh Kumar Prusty. Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID. medRxiv 2023.06.23.23291827; doi: https://doi.org/10.1101/2023.06.23.23291827 https://www.medrxiv.org/content/10.1101/2023.06.23.23291827v1 (Full text available as PDF file)

IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and depression are considered to be neuro-immune disorders (Maes and Twisk, BMC Medicine 8:35, 2010). There is also evidence that depression and ME/CFS are accompanied by oxidative and nitrosative stress (O&NS) and by increased autoantibodies to a number of self-epitopes some of which have become immunogenic due to damage by O&NS. The aim of this study is to examine IgM-mediated autoimmune responses to different self-epitopes in ME/CFS versus depression.

We examined serum IgM antibodies to three anchorage molecules (palmitic and myristic acid and S-farnesyl-L-cysteine); acetylcholine; and conjugated NO-modified adducts in 26 patients with major depression; 16 patients with ME/CFS, 15 with chronic fatigue; and 17 normal controls. Severity of fatigue and physio-somatic (F&S) symptoms was measured with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale.

Serum IgM antibodies to the three anchorage molecules and NO-phenylalanine were significantly higher in ME/CFS than in depression. The autoimmune responses to oxidatively, but not nitrosatively, modified self-epitopes were significantly higher in ME/CFS than in depression and were associated with F&S symptoms. The autoimmune activity directed against conjugated acetylcholine did not differ significantly between ME/CFS and depression, but was greater in the patients than controls.

Partially overlapping pathways, i.e. increased IgM antibodies to a multitude of neo-epitopes, underpin both ME/CFS and depression, while greater autoimmune responses directed against anchorage molecules and oxidatively modified neo-epitopes discriminate patients with ME/CFS from those with depression. These autoimmune responses directed against neoantigenic determinants may play a role in the dysregulation of key cellular functions in both disorders, e.g. intracellular signal transduction, cellular differentiation and apoptosis, but their impact may be more important in ME/CFS than in depression.

 

Source: Maes M, Mihaylova I, Kubera M, Leunis JC, Twisk FN, Geffard M. IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression. Metab Brain Dis. 2012 Dec;27(4):415-23. doi: 10.1007/s11011-012-9316-8. Epub 2012 May 22. https://www.ncbi.nlm.nih.gov/pubmed/22614823

 

Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins

Abstract:

There is now some evidence that chronic fatigue syndrome (CFS) is accompanied by signs of oxidative stress and by a decreased antioxidant status. The aim of the present study was to examine whether CFS is accompanied by an immune response to neoepitopes of a variety of modified lipids and proteins indicating damage caused by oxidative and nitrosative stress. Toward this end we examined serum antibodies to fatty acids (oleic, palmitic and myristic acid), by-products of lipid peroxidation, i.e. azelaic acid and malondialdehyde (MDA), acetylcholine, S-farnesyl-L-cysteine, and N-oxide modified amino-acids in 14 patients with CFS, 14 subjects with partial CFS and 11 normal controls.

We found that the prevalences and mean values for the serum IgM levels directed against oleic, palmitic and myristic acid, MDA, azelaic acid, S-farnesyl-L-cysteine, and the N-oxide derivates, nitro-tyrosine, nitro-phenylalanine, nitro-arginine, nitro-tryptophan, and nitro-cysteinyl were significantly greater in CFS patients than in normal controls, whereas patients with partial CFS took up an intermediate position. There were significant and positive correlations between the serum IgM levels directed against fatty acids, MDA and azelaic acid and the above N-oxide-derivates and the severity of illness (as measured by the FibroFatigue scale) and symptoms, such as aches and pain, muscular tension and fatigue.

The results show that CFS is characterized by an IgM-related immune response directed against disrupted lipid membrane components, by-products of lipid peroxidation, S-farnesyl-L-cysteine, and NO-modified amino-acids, which are normally not detected by the immune system but due to oxidative and nitrosative damage have become immunogenic.

 

Source: Maes M, Mihaylova I, Leunis JC. Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett. 2006 Oct;27(5):615-21. https://www.ncbi.nlm.nih.gov/pubmed/17159817

 

IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome

Abstract:

BACKGROUND: A unique subset of patients with chronic fatigue syndrome (CFS) and IgM serum antibodies to cytomegalovirus (HCMV) non-structural gene products p52 and CM2 (UL 44 and UL 57) has been described.

PATIENTS AND METHODS: Fifty-eight CFS patients and 68 non-CFS matched controls were studied. Serum antibodies to EBV viral capsid antigen (VCA) IgM and EBV Early Antigen, diffuse (EA, D) as well HVCMV(V), IgM and IgG; VP (sucrose, density purified V); p52 and CM2 IgM serum antibodies were assayed.

RESULTS: Mean age of CFS patients was 44 years (75% women). Control patients were 9 years older (73% women). Serum EBV VCA IgM positive antibody titers were identified in 33 CFS patients (Group A subset EBV VCA IgM 62.3+/-8.3, neg. <20), but were not present in other CFS patients, (Group B subset EBV VCA IgM 6.8+/-0.7) controls (p<0.0001). EBV VCA IgM titers remained positive in CFS patients from Group A for 24-42 months.

CONCLUSION: Serum antibody to EBV VCA IgM may be a specific diagnostic test for a second subset of CFS patients.

 

Source: Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome.  In Vivo. 2004 Mar-Apr;18(2):101-6. http://iv.iiarjournals.org/content/18/2/101.long (Full article)

 

Chronic parvovirus B19 infection resulting in chronic fatigue syndrome: case history and review

Abstract:

The spectrum of disease caused by parvovirus B19 has been expanding in recent years because of improved and more sensitive methods of detection. There is evidence to suggest that chronic infection occurs in patients who are not detectably immunosuppressed.

We report the case of a young woman with recurrent fever and a syndrome indistinguishable from chronic fatigue syndrome. After extensive investigation, we found persistent parvovirus B19 viremia, which was detectable by polymerase chain reaction (PCR) despite the presence of IgM and IgG antibodies to parvovirus B19.

Testing of samples from this patient suggested that in some low viremic states parvovirus B19 DNA is detectable by nested PCR in plasma but not in serum. The patient’s fever resolved with the administration of intravenous immunoglobulin.

 

Source: Jacobson SK, Daly JS, Thorne GM, McIntosh K. Chronic parvovirus B19 infection resulting in chronic fatigue syndrome: case history and review. Clin Infect Dis. 1997 Jun;24(6):1048-51. http://cid.oxfordjournals.org/content/24/6/1048.long (Full article)

 

Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome

Erratum in: J Infect Dis 1995 Dec;172(6):1643.

 

Abstract:

To evaluate the association between human herpesvirus 6 (HHV-6) and chronic fatigue syndrome (CFS), 2 geographically separate groups of CFS patients (125 and 29 patients, respectively) and healthy controls (150 and 15 controls, respectively) were compared, using an EIA, for antibodies to HHV-6 early antigen p41/38 (EA).

Sixty percent (93/154) of CFS patients were were positive for HHV-6 EA IgM, 40% (61/154) were positive for IgG, and 23% (35/154) were positive for both. A total of 119 (77%) of the CFS patients were positive for HHV-6 EA IgG or IgM (or both); only 12% (20/165) of the controls had IgG or IgM to HHV-6 EA. These data demonstrate that more CFS patients than controls had elevated levels of HHV-6 EA-specific IgM, perhaps indicating active replication of HHV-6 in CFS.

 

Source: Patnaik M, Komaroff AL, Conley E, Ojo-Amaize EA, Peter JB. Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome. J Infect Dis. 1995 Nov;172(5):1364-7. http://www.ncbi.nlm.nih.gov/pubmed/7594679

 

Coxsackie B virus and postviral fatigue syndrome

Comment on: Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome. [BMJ. 1991]

 

SIR,-Dr N A Miller and colleagues highlight the difficulty of associating a virus (coxsackie B virus) with a disease (postviral fatigue syndrome) when the virus in question is common in the general population.’ In a recent serological survey of the family members of children with insulin dependent diabetes mellitus we also found a high prevalence of IgM antibody specific to enterovirus: 14% of children with recently diagnosed insulin dependent diabetes mellitus, 8% of unaffected siblings, and 18% of parents had the antibody at the time of entry into the study. Serum samples were collected between 1985 and 1987. These seroprevalence figures are higher than those reported among control populations in earlier studies in the United Kingdom-5 5% in children during 19822 and 3-5% in adults during 1979-80.3 Because the assay used in these studies was the same as that used by Dr Miller and colleagues this indicates that enterovirus was endemic during 1985-7, which covers the period of the study of Dr Miller and colleagues.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1675464/pdf/bmj00117-0062c.pdf

 

Source: Muir P, Nicholson F, Banatvala JE, Bingley PJ. Coxsackie B virus and postviral fatigue syndrome. BMJ. 1991 Mar 16;302(6777):658-9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1675464/

 

Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome

Abstract:

OBJECTIVE: To study the association between coxsackie B virus infection and the postviral fatigue syndrome and to assess the immunological abnormalities associated with the syndrome.

DESIGN: Case-control study of patients with the postviral fatigue syndrome referred by local general practitioners over one year.

SETTING: General practitioner referrals in Dunbartonshire, Scotland.

PATIENTS: 254 Patients referred with the postviral fatigue syndrome (exhaustion, myalgia, and other symptoms referable to postviral fatigue syndrome of fairly recent onset–that is, several months) and age and sex matched controls obtained from same general practitioner; 11 patients were rejected because of wrong diagnoses, resolution of symptoms, and refusal to participate, leaving 243 patients and matched controls.

MAIN OUTCOME MEASURES: Detailed questionnaire (patients and controls) and clinical examination (patients) and blind analysis of blood sample at entry and after six months for determination of coxsackie B virus IgM and IgG antibodies and other variables (including lymphocyte protein synthesis, lymphocyte subsets, and immune complexes).

RESULTS: Percentage positive rates for coxsackie B virus IgM at entry were 24.4% for patients and 22.6% for controls and for coxsackie B virus IgG 56.2% and 55.3% respectively; there were no significant differences between different categories of patients according to clinical likelihood of the syndrome nor any predictive value in a fourfold rise or fall in the coxsackie B virus IgG titre in patients between entry and review at six months. The rates of positive antibody test results in patients and controls showed a strong seasonal variation. Of the numerous immunological tests performed, only a few detected significant abnormalities; in particular the mean value for immune complex concentration was much higher in 35 patients and 35 controls compared with the normal range and mean value for total IgM was also raised in 227 patients and 35 controls compared with the normal range.

CONCLUSIONS: Serological tests available for detecting coxsackie B virus antibodies do not help diagnose the postviral fatigue syndrome. Percentage positive rates of the antibodies in patients simply reflect the background in the population as probably do the raised concentrations of total IgM and immune complexes.

 

Source: Miller NA, Carmichael HA, Calder BD, Behan PO, Bell EJ, McCartney RA, Hall FC. Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome. BMJ. 1991 Jan 19;302(6769):140-3. http://www.ncbi.nlm.nih.gov/pubmed/1847316