Tag: immunoglobulins

HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms

Abstract:

Due to the wide scope and persistence of COVID-19´s pandemic, post-COVID-19 condition represents a post-viral syndrome of unprecedented dimensions. SARS-CoV-2, in line with other infectious agents, has the capacity to activate dormant human endogenous retroviral sequences ancestrally integrated in human genomes (HERVs). This activation was shown to relate to aggravated COVID-19 patient´s symptom severity.

Despite our limited understanding of how HERVs are turned off upon infection clearance, or how HERVs mediate long-term effects when their transcription remains aberrantly on, the participation of these elements in neurologic disease, such as multiple sclerosis, is already settling the basis for effective therapeutic solutions. These observations support an urgent need to identify the mechanisms that lead to HERV expression with SARS-CoV-2 infection, on the one hand, and to answer whether persistent HERV expression exists in post-COVID-19 condition, on the other.

The present study shows, for the first time, that the HERV-W ENV protein can still be actively expressed long after SARS-CoV-2 infection is resolved in post-COVID-19 condition patients. Moreover, increased anti-SARS-CoV-2 immunoglobulins in post-COVID-19 condition, particularly high anti-SARS-CoV-2 immunoglobulin levels of the E isotype (IgE), seem to strongly correlate with deteriorated patient physical function (r=-0.8057, p<0.01).

These results indicate that HERV-W ENV antigenemia and anti-SARS-CoV-2 IgE serology should be further studied to better characterize post-COVID-19 condition pathogenic drivers potentially differing in subsets of patients with various symptoms. They also point out that such biomarkers may serve to design therapeutic options for precision medicine in post-COVID-19 condition.

Source: Giménez-Orenga K, Pierquin J, Brunel J, Charvet B, Martín-Martínez E, Perron H, Oltra E. HERV-W ENV antigenemia and correlation of increased anti-SARS-CoV-2 immunoglobulin levels with post-COVID-19 symptoms. Front Immunol. 2022 Oct 27;13:1020064. doi: 10.3389/fimmu.2022.1020064. PMID: 36389746; PMCID: PMC9647063.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9647063/ (Full text)

The autoimmune aetiology of unexplained chronic pain

Abstract:

Chronic pain is the leading cause of life years lived with disability worldwide. The aetiology of most chronic pain conditions has remained poorly understood and there is a dearth of effective therapies. The WHO ICD-11 has categorised unexplained chronic pain states as ‘chronic primary pains’ (CPP), which are further defined by their association with significant distress and/or dysfunction. The new mechanistic term, ‘nociplasticic pain’ has been developed to illustrate their presumed generation by a structurally intact, but abnormally functioning nociceptive system.

Recently, researchers have unravelled the surprising, ubiquitous presence of pain-sensitising autoantibodies in four investigated CPP indicating autoimmune causation. In persistent complex regional pain syndrome, fibromyalgia syndrome, chronic post-traumatic limb pain, and non-inflammatory joint pain associated with rheumatoid arthritis, passive transfer experiments have shown that either IgG or IgM antibodies from patient-donors cause symptoms upon injection to rodents that closely resemble those of the clinical disorders. Targets of antibody-binding and downstream effects vary between conditions, and more research is needed to elucidate the molecular and cellular details.

The central nervous system appears largely unaffected by antibody binding, suggesting that the clinically evident CNS symptoms associated with CPP might arise downstream of peripheral processes. In this narrative review pertinent findings are described, and it is suggested that additional symptom-based disorders might be examined for the contribution of antibody-mediated autoimmune mechanisms.

Source: Goebel A, Andersson D, Helyes Z, Clark JD, Dulake D, Svensson C. The autoimmune aetiology of unexplained chronic pain. Autoimmun Rev. 2022 Mar;21(3):103015. doi: 10.1016/j.autrev.2021.103015. Epub 2021 Dec 10. PMID: 34902604. https://www.sciencedirect.com/science/article/abs/pii/S1568997221002974 (Full text)

Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome

Abstract:

Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which – combined with age, history of asthma bronchiale, and five symptoms during primary infection – is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.

Source: Cervia C, Zurbuchen Y, Taeschler P, Ballouz T, Menges D, Hasler S, Adamo S, Raeber ME, Bächli E, Rudiger A, Stüssi-Helbling M, Huber LC, Nilsson J, Held U, Puhan MA, Boyman O. Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome. Nat Commun. 2022 Jan 25;13(1):446. doi: 10.1038/s41467-021-27797-1. PMID: 35078982. https://www.nature.com/articles/s41467-021-27797-1 (Full text)

Back to the Future? Immunoglobulin Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

The findings of controlled trials on use of intravenous immunoglobulin G (IV IgG) to treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are generally viewed as representing mixed results. On detailed review, a clearer picture emerges, which suggests that the potential therapeutic value of this intervention has been underestimated.

Our analysis is consistent with the propositions that: (1) IgG is highly effective for a proportion of patients with severe and well-characterised ME/CFS; (2) responders can be predicted with a high degree of accuracy based on markers of immune dysfunction. Rigorous steps were taken in the research trials to record adverse events, with transient symptom exacerbation commonly experienced in both intervention and placebo control groups, suggesting that this reflected the impact of participation on people with an illness characterised by post-exertional symptom exacerbation. Worsening of certain specific symptoms, notably headache, did occur more commonly with IgG and may have been concomitant to effective treatment, being associated with clinical improvement.

The findings emerging from this review are supported by clinical observations relating to treatment of patients with severe and very severe ME/CFS, for whom intramuscular and subcutaneous administration provide alternative options. We conclude that: (1) there is a strong case for this area of research to be revived; (2) pending further research, clinicians would be justified in offering a course of IgG to selected ME/CFS patients at the more severe end of the spectrum. As the majority of trial participants had experienced an acute viral or viral-like onset, we further suggest that IgG treatment may be pertinent to the care of some patients who remain ill following infection with SARS-CoV-2 virus.

Source: Brownlie H, Speight N. Back to the Future? Immunoglobulin Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Healthcare (Basel). 2021 Nov 12;9(11):1546. doi: 10.3390/healthcare9111546. PMID: 34828592. https://pubmed.ncbi.nlm.nih.gov/34828592/

Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems.

Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30.

Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3-11 were significantly associated with ME/CFS without sr-IBS.

In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774-0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806-0.846) and ME/CFS without sr-IBS (AUC = 0.754-0.780).

Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.

Source: Milivojevic M, Che X, Bateman L, et al. Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS. PLoS One. 2020;15(7):e0236148. Published 2020 Jul 21. doi:10.1371/journal.pone.0236148 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236148 (Full text)

Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment.

Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p = 0.011). There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab.

A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up. Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab.

Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p = 0.03). In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6-9.5 g/L, IgA 1.8-1.5 g/L, and IgM 0.97-0.70 g/L.

Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B-cell regulatory effects on T-cell or NK-cell subsets are not the main mechanisms for the observed improvements in ME/CFS symptoms observed in the two previous trials. The modest increase in serum BAFF levels at baseline may indicate an activated B-lymphocyte system in a subgroup of ME/CFS patients.

 

Source: Lunde S, Kristoffersen EK, Sapkota D, Risa K, Dahl O, Bruland O, Mella O, Fluge Ø. Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome. PLoS One. 2016 Aug 18;11(8):e0161226. doi: 10.1371/journal.pone.0161226. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990178/ (Full article)

 

Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a severe disease characterized by various symptoms of immune dysfunction. CFS onset is typically with an infection and many patients suffer from frequently recurrent viral or bacterial infections. Immunoglobulin and mannose binding lectin (MBL) deficiency are frequent causes for increased susceptibility to infections.

In this study we retrospectively analysed 300 patients with CFS for immunoglobulin and MBL levels, and B-cell subset frequencies. 25% of the CFS patients had decreased serum levels of at least one antibody class or subclass with IgG3 and IgG4 subclass deficiencies as most common phenotypes.

However, we found elevated immunoglobulin levels with an excess of IgM and IgG2 in particular in another 25% of patients. No major alteration in numbers of B cells and B-cell subsets was seen. Deficiency of MBL was found in 15% of the CFS patients in contrast to 6% in a historical control group. In a 2nd cohort of 168 patients similar frequencies of IgG subclass and MBL deficiency were found. Thus, humoral immune defects are frequent in CFS patients and are associated with infections of the respiratory tract.

Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

 

Source: Guenther S, Loebel M, Mooslechner AA, Knops M, Hanitsch LG, Grabowski P, Wittke K, Meisel C, Unterwalder N, Volk HD, Scheibenbogen C. Frequent IgG subclass and mannose binding lectin deficiency in patients with chronic fatigue syndrome. Hum Immunol. 2015 Oct;76(10):729-35. doi: 10.1016/j.humimm.2015.09.028. Epub 2015 Sep 30. https://www.ncbi.nlm.nih.gov/pubmed/26429318

 

Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is considered as a neuroimmunological disease but the etiology and pathophysiology is poorly understood. Patients suffer from sustained exhaustion, cognitive impairment and an increased sensitivity to pain and sensory stimuli. A subset of patients has frequent respiratory tract infections (RRTI). Dysregulation of the sympathetic nervous system and an association with genetic variations in the catechol-O-methyltransferase (COMT) and glucocorticoid receptor genes influencing sympathetic and glucocorticoid metabolism were reported in CFS. Here, we analyzed the prevalence of SNPs of COMT and glucocorticoid receptor-associated genes in CFS patients and correlated them to immunoglobulin levels and susceptibility to RRTI.

METHODS: We analyzed blood cells of 74 CFS patients and 76 healthy controls for polymorphisms in COMT, FKBP5 and CRHR1 by allelic discrimination PCR. Serum immunoglobulins were determined by immunoturbidimetric technique, cortisol levels by ECLIA.

RESULTS: Contrary to previous reports, we found no difference between CFS patients and healthy controls in the prevalence of SNPs for COMT, FKBP5 and CRHR1. In patients with the Met/Met variant of COMT rs4680 we observed enhanced cortisol levels providing evidence for its functional relevance. Both enhanced IgE and diminished IgG3 levels and an increased susceptibility to RRTI were observed in CFS patients with the Met/Met variant. Such an association was not observed in 68 non-CFS patients with RRTI.

CONCLUSION: Our results indicate a relationship of COMT polymorphism rs4680 with immune dysregulation in CFS providing a potential link for the association between stress and infection susceptibility in CFS.

 

Source: Löbel M, Mooslechner AA, Bauer S, Günther S, Letsch A, Hanitsch LG, Grabowski P, Meisel C, Volk HD, Scheibenbogen C. Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome. J Transl Med. 2015 Aug 14;13:264. doi: 10.1186/s12967-015-0628-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536662/ (Full article)

 

Treatment of 741 Italian patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a distinctive syndrome characterized by specific symptoms cluster. CFS mostly affects women and often results in severe functional limitation. Its prevalence varies from 0.4 to 2.5% in the general population. In our prior studies on the clinical features of 205 CFS patients we founded immunological and brain abnormalities. In this paper we illustrate our caseload on CFS treatment.

PATIENTS AND METHODS: From January 2000 to December 2005, we evaluated all the patients admitted at the CFS Unit of the Aviano National Cancer Institute, for staging procedures and treatments. Patients not meeting the Fukuda diagnostic criteria were excluded.

RESULTS: 250 male and 491 female (median age 35.5 and 39.3 years, respectively) were enrolled and treated for CFS. As expected, CFS resulted from previous infectious disease in all patients. Female patients showed to be more affected by symptoms than male patients. The treatment schedules followed by the patients included nutritional supplements alone, corticosteroids, antidepressant/sedative drugs, and antiviral/immunoglobulin drugs. Antiviral/ immunoglobulin drugs achieved the best response (15.3% positive responses vs. 8.3% negative responses; OR 0.44, CI 0.26-0.74, p = 0.002). The carrying out of 4 or more treatments showed a protective effect (OR 0.46, CI 0.28-0.77, p = 0.003). This finding was confirmed in the multivariate analysis, adjusted by type of drugs (OR 0.49, CI 0.28-0.84, p = 0.009) and number of treatments carried out (OR 0.51, CI 0.30-0.86, p = 0.01); these two variables were independent.

CONCLUSIONS: These findings show that the antiviral/immunoglobulin approach has a longer positive disease free survival in comparison with other approaches. However, CFS still remains a difficult disease to be effectively treated.

 

Source: Tirelli U, Lleshi A, Berretta M, Spina M, Talamini R, Giacalone A. Treatment of 741 Italian patients with chronic fatigue syndrome. Eur Rev Med Pharmacol Sci. 2013 Nov;17(21):2847-52. http://www.europeanreview.org/article/5782 (Full article available as PDF)

 

Excess of activating killer cell immunoglobulin‑like receptors and lack of HLA-Bw4 ligands: a two‑edged weapon in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is an inflammatory disease of unknown aetiology. Researchers have proposed infectious, neurological and immunological causes of this syndrome. Recently, the xenotropic murine leukemia virus-related virus was detected in 67% of patients with CFS in a US study. This observation is in agreement with one ascertained aspect of the disease: a decreased efficiency in NK cell lytic activity in CFS patients. Here, we analyzed the genomic polymorphism of killer cell immunoglobulin-like receptors (KIRs) and their HLA class I cognate ligands in patients with certified CFS. An excess of KIR3DS1 was found in CFS patients with respect to controls, as well as an increased frequency of the genotype missing KIR2DS5. Forty-four CFS patients and 50 controls also underwent genomic typing for the HLA-ligands. In the patients, a great proportion of KIR3DL1 and KIR3DS1 receptors were found to be missing their HLA-Bw4Ile80 binding motif. We hypothesize that an excess of KIR3DS1, combined with an excess of ligand-free KIR3DL1 and KIR3DS1 receptors, may hamper the clearance of a pathogen via NK cells, thus favouring the chronicity of the infection.

Source: Pasi A, Bozzini S, Carlo-Stella N, Martinetti M, Bombardieri S, De Silvestri A, Salvaneschi L, Cuccia M. Excess of activating killer cell immunoglobulin‑like receptors and lack of HLA-Bw4 ligands: a two‑edged weapon in chronic fatigue syndrome. Mol Med Rep. 2011 May-Jun;4(3):535-40. doi: 10.3892/mmr.2011.447. Epub 2011 Mar 4. https://www.ncbi.nlm.nih.gov/pubmed/21468604