Tag: IGG

Transfer of IgG from Long COVID patients induces symptomology in mice

Abstract:

SARS-CoV-2 infections worldwide led to a surge in cases of Long COVID, a post-infectious syndrome. It has been hypothesized that autoantibodies play a crucial role in the development of Long COVID and other syndromes, such as fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, we tested this hypothesis by passively transferring total IgG from Long COVID patients to mice.

Using Glial Fibrillary Acidic Protein (GFAP) and type-I interferon expression, we stratified patients into three Long COVID subgroups, each with unique plasma proteome signatures. Remarkably, IgG transfer from the two subgroups, which are characterized by higher plasma levels of neuronal proteins and leukocyte activation markers, induced pronounced and persistent sensory hypersensitivity with distinct kinetics. Conversely, IgG transfer from the third subgroup, which are characterized by enriched skeletal and cardiac muscle proteome profiles, reduced locomotor activity in mice without affecting their motor coordination.

These findings demonstrate that transfer of IgG from Long COVID patients to mice replicates disease symptoms, underscoring IgG’s causative role in Long COVID pathogenesis. This work proposes a murine model that mirrors Long COVID’s pathophysiological mechanisms, which may be used as a tool for screening and developing targeted therapeutics.

Source: Hung-Jen Chen, Brent Appelman, Hanneke Willemen, Amelie Bos, Judith Prado, Chiara. E. Geyer, Patrícia Silva Santos Ribeiro, Sabine Versteeg, Mads Larsen, Eline Schüchner, Marije K. Bomers, Ayesha H.A. Lavell, Amsterdam UMC COVID-19 biobank, Braeden Charlton, Rob Wüst, W. Joost Wiersinga, Michèle van Vugt, Gestur Vidarsson, Niels Eijkelkamp, Jeroen den Dunnen. Transfer of IgG from Long COVID patients induces symptomology in mice. bioRxiv 2024.05.30.596590; doi: https://doi.org/10.1101/2024.05.30.596590 https://www.biorxiv.org/content/10.1101/2024.05.30.596590v1.full (Full text)

A causal link between autoantibodies and neurological symptoms in long COVID

Summary:

Acute SARS-CoV-2 infection triggers the generation of diverse and functional autoantibodies (AABs), even after mild cases. Persistently elevated autoantibodies have been found in some individuals with long COVID (LC). Using a >21,000 human protein array, we identified diverse AAB targets in LC patients that correlated with their symptoms.

Elevated AABs to proteins in the nervous system were found in LC patients with neurocognitive and neurological symptoms. Purified Immunoglobulin G (IgG) samples from these individuals reacted with human pons tissue and were cross-reactive with mouse sciatic nerves, spinal cord, and meninges. Antibody reactivity to sciatic nerves and meninges correlated with patient-reported headache and disorientation. Passive transfer of IgG from patients to mice led to increased sensitivity and pain, mirroring patient-reported symptoms. Similarly, mice injected with IgG showed loss of balance and coordination, reflecting donor-reported dizziness. Our findings suggest that targeting AABs could benefit some LC patients.

Source: Keyla Santos Guedes de Sa, Julio Silva, Rafael Bayarri-Olmos, Ryan Brinda, Robert Alec Rath Constable, Patricia A. Colom Diaz, Dong il Kwon, Gisele Rodrigues, Li Wenxue, Christopher Baker, Bornali Bhattacharjee, Jamie Wood, Laura Tabacof, Yansheng Liu, David Putrino, Tamas L. Horvath, Akiko Iwasaki. A causal link between autoantibodies and neurological symptoms in long COVID. medRxiv 2024.06.18.24309100; doi: https://doi.org/10.1101/2024.06.18.24309100 https://www.medrxiv.org/content/10.1101/2024.06.18.24309100v1.full-text (Full text)

Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID

Abstract:

During the COVID-19 pandemic it was widely described that certain individuals infected by SARS-CoV-2 experience persistent disease signs and symptoms, Long COVID, which in some cases is very severe with life changing consequences. To maximize our chances of identifying the underpinnings of this illness, we have focused on 121 of the most severe cases from >1000 patients screened in specialized clinics in Sweden and Belgium. We restricted this study to subjects with objective measures of organ damage or dysfunction, >3 months following a verified, but mild-to-moderate SARS-CoV-2 infection.

By performing systems-level immunological testing and comparisons to controls fully convalescent following a similar mild/moderate COVID-19 episode, we identify elevated serological responses to SARS-CoV-2 in severe Long COVID suggestive of chronic antigen stimulation. Persistent viral reservoirs have been proposed in Long COVID and using multiple orthogonal methods for detection of SARS-CoV-2 RNA and protein in plasma we identify a subset of patients with detectable antigens, but with minimal overlap across assays, and no correlation to symptoms or immune measurements.

Elevated serologic responses to SARS-CoV-2 on the other hand were inversely correlated with clonally expanded memory CD8+ T cells, indicating that restrained clonal expansion enables viral persistence, chronic antigen exposure and elevated IgG responses, even if antigen-detection in blood is not universally possible.

Source: Lucie Rodriguez, Ziyang Tan, Tadepally Lakshmikanth, Jun Wang, Hugo Barcenilla, Zoe Swank, Fanglei Zuo, Hassan Abolhassani, Ana Jimena Pavlovitch-Bedzyk, Chunlin Wang, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Yang Chen, Anna James, Jaromir Mikes, Linn Kleberg, Christopher Sundling, Mikael Björnson, Malin Nygren Bonnier, Marcus Ståhlberg, Michael Runold, Sophia Björkander, Erik Melén, Isabelle Meyts, Johan Van Weyenbergh, Qian-Pan Hammarström, Mark M Davis, David R. Walt, Nils Landegren, COVID Human Genetic Effort, Alessandro Aiuti, Giorgio Casari, Jean-Laurent Casanova, Marc Jamoulle, Judith Bruchfeld, Petter Brodin. Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID. medRxiv 2024.02.11.24302636; doi: https://doi.org/10.1101/2024.02.11.24302636 https://www.medrxiv.org/content/10.1101/2024.02.11.24302636v1.full-text (Full text)

Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating, and multi-faceted illness. Heterogenous onset and clinical presentation with additional comorbidities make it difficult to diagnose, characterize, and successfully treat. Current treatment guidelines focus on symptom management, but with no clear target or causative mechanism, remission rates are low, and fewer than 5% of patients return to their pre-morbid activity levels. Therefore, there is an urgent need to undertake robust clinical trials to identify effective treatments.
This review synthesizes insights from clinical trials exploring pharmacological interventions and dietary supplements targeting immunological, metabolic, gastrointestinal, neurological, and neuroendocrine dysfunction in ME/CFS patients which require further exploration. Additionally, the trialling of alternative interventions in ME/CFS based on reported efficacy in the treatment of illnesses with overlapping symptomology is also discussed. Finally, we provide important considerations and make recommendations, focusing on outcome measures, to ensure the execution of future high-quality clinical trials to establish clinical efficacy of evidence-based interventions that are needed for adoption in clinical practice.
Source: Seton KA, Espejo-Oltra JA, Giménez-Orenga K, Haagmans R, Ramadan DJ, Mehlsen J on behalf of the European ME Research Group for Early Career Researchers (Young EMERG). Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives. Journal of Clinical Medicine. 2024; 13(2):325. https://doi.org/10.3390/jcm13020325 https://www.mdpi.com/2077-0383/13/2/325 (Full text)

Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms

Abstract:

Background Autoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objectives To examine whether Long COVID, and its accompanying affective symptoms and CFS are associated with immunoglobulin (Ig)A/IgM/IgG directed at neuronal proteins including myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin, α+β-tubulin, neurofilament protein (NFP), cerebellar protein-2 (CP2), and the blood-brain-barrier-brain-damage (BBD) proteins claudin-5 and S100B.

Methods IgA/IgM/IgG to the above neuronal proteins, human herpes virus-6 (HHV-6) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were measured in 90 Long COVID patients and 90 healthy controls, while C-reactive protein (CRP), and advanced oxidation protein products (AOPP) in association with affective and CFS ratings were additionally assessed in a subgroup thereof.

Results Long COVID is associated with significant increases in IgG directed at tubulin (IgG-tubulin), MBP, MOG and synapsin; IgM-MBP, MOG, CP2, synapsin and BBD; and IgA-CP2 and synapsin. IgM-SARS-CoV-2 and IgM-HHV-6 antibody titers were significantly correlated with IgA/IgG/IgM-tubulin and -CP2, IgG/IgM-BBD, IgM-MOG, IgA/IgM-NFP, and IgG/IgM-synapsin. Binary logistic regression analysis shows that IgM-MBP and IgG-MBP are the best predictors of Long COVID. Multiple regression analysis shows that IgG-MOG, CRP and AOPP explain together 41.7% of the variance in the severity of CFS. Neural network analysis shows that IgM-synapsin, IgA-MBP, IgG-MOG, IgA-synapsin, IgA-CP2, IgG-MBP and CRP are the most important predictors of affective symptoms due to Long COVID with a predictive accuracy of r=0.801.

Conclusion Brain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.

Source: Abbas F. Almulla, Michael Maes, Bo Zhou, Hussein K. Al-Hakeim, Aristo Vojdani. Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms. medRxiv [Preprint] https://www.medrxiv.org/content/10.1101/2023.10.04.23296554v1 (Full text available as PDF file)

Persistent immune and clotting dysfunction detected in saliva and blood plasma after COVID-19

Abstract:

A growing number of studies indicate that coronavirus disease 2019 (COVID-19) is associated with inflammatory sequelae, but molecular signatures governing the normal versus pathologic convalescence process have not been well-delineated. Here, we characterized global immune and proteome responses in matched plasma and saliva samples obtained from COVID-19 patients collected between 20 and 90 days after initial clinical symptoms resolved.

Convalescent subjects showed robust total IgA and IgG responses and positive antibody correlations in saliva and plasma samples. Shotgun proteomics revealed persistent inflammatory patterns in convalescent samples including dysfunction of salivary innate immune cells, such as neutrophil markers (e.g., myeloperoxidase), and clotting factors in plasma (e.g., fibrinogen), with positive correlations to acute COVID-19 disease severity. Saliva samples were characterized by higher concentrations of IgA, and proteomics showed altered myeloid-derived pathways that correlated positively with SARS-CoV-2 IgA levels.

Beyond plasma, our study positions saliva as a viable fluid to monitor normal and aberrant immune responses including vascular, inflammatory, and coagulation-related sequelae.

Source: Jang H, Choudhury S, Yu Y, Sievers BL, Gelbart T, Singh H, Rawlings SA, Proal A, Tan GS, Qian Y, Smith D, Freire M. Persistent immune and clotting dysfunction detected in saliva and blood plasma after COVID-19. Heliyon. 2023 Jul 4;9(7):e17958. doi: 10.1016/j.heliyon.2023.e17958. PMID: 37483779; PMCID: PMC10362241. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362241/ (Full text)

Divergent Adaptive Immune Responses Define Two Types Of Long Covid

The role of adaptive immune responses in long COVID remains poorly understood, with contrasting hypotheses suggesting either an insufficient antiviral response or an excessive immune response associated with inflammatory damage. To address this issue, we set to characterize humoral and CD4+ T cell responses in long COVID patients prior to SARS-CoV-2 vaccination.

Long COVID patients who were seropositive (LC+, n=28) or seronegative (LC-, n=23) by spike ELISA assay were recruited based on (i) an initial SARS-CoV-2 infection documented by PCR or the conjunction of three major signs of COVID-19 and (ii) the persistence or resurgence of at least 3 symptoms for over 3 months. They were compared to COVID patients with resolved symptoms (RE, n=29) and uninfected control individuals (HD, n=29).

The spectrum of persistent symptoms proved similar in both long COVID groups, with a trend for a higher number of symptoms in the seronegative group (median=6 vs 4.5; P=0.01). The use a highly sensitive S-flow assay enabled the detection of low levels of SARS-CoV-2 spike-specific IgG in 22.7% of ELISA-seronegative long COVID (LC-) patients. In contrast, spike-specific IgG levels were uniformly high in the LC+ and RE groups.

Multiplexed antibody analyses to 30 different viral antigens showed that LC-patients had defective antibody responses to all SARS-CoV-2 proteins tested but had in most cases preserved responses to other viruses. A sensitive primary T cell line assay revealed low but detectable SARS-CoV-2-specific CD4 responses in 39.1% of LC-patients, while response frequencies were high in the LC+ and RE groups. Correlation analyses showed overall strong associations between humoral and cellular responses, with exceptions in the LC-group.

These findings provide evidence for two major types of antiviral immune responses in long COVID. Seropositive patients showed coordinated cellular and humoral responses at least as high as those of recovered patients. In contrast, ELISA-seronegative long COVID patients showed overall low antiviral responses, with detectable specific CD4+ T cells and/or antibodies in close to half of patients (52.2%). These divergent findings in patients sharing a comparable spectrum of persistent symptoms raise the possibility of multiple etiologies in long COVID.

Source: Jérôme Kervevan, Isabelle Staropoli, Dorsaf Slama, Raphaël Jeger-Madiot, Françoise Donnadieu, Delphine Planas, Marie-Pierre Pietri, Wiem Loghmari-Bouchneb, Motolete A. Tanah, Rémy Robinot, Faroudy Boufassa, Michael White, Dominique SALMON and Lisa A. Chakrabarti. Front. Immunol. Sec. Viral Immunology. Volume 14 – 2023 | doi: 10.3389/fimmu.2023.1221961 https://www.frontiersin.org/articles/10.3389/fimmu.2023.1221961/abstract

Investigating Immune Reactivity to the Intestinal Microbiome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) pathogenesis is thought to be multisystemic, including the immune and gastrointestinal systems. A proportion of patients experience gastrointestinal disturbances with evidence suggesting a leaky gut. It was hypothesised that a leaky gut and microbial translocation causes a breach in immune tolerance, promoting inflammation and autoimmunity.

Aims: A) determine whether severe ME/CFS patients have increased systemic and mucosal immunoglobulin (Ig) reactivity to the intestinal microbiome, and B) determine which intestinal microbes serum IgG was directed against.

Methods: Serum and stool samples were collected from five pairs of severe ME/CFS patients and matched household controls. Enzyme linked immunosorbent assays were developed to quantify IgG in serum, bound and non-bound IgA in stool and serum IgG levels reactive with autologous and heterologous stool bacteria. Flow cytometry methods were developed to quantify both stool microbial load and the proportion of stool microbes reactive with mucosal IgA and serum IgG. A ‘bug FACS’ method was developed to identify and quantify serum IgG reactivity to stool bacteria and fungi.

Results: The main finding was that severe ME/CFS patients have significantly lower levels of serum IgG reactive to heterologous stool bacteria compared to their matched household controls. In addition, severe ME/CFS patients do not have higher levels of serum IgG reactive to heterologous stool bacteria than autologous stool bacteria. Severe ME/CFS patients also have a non-significant increase of IgG binding to Campylobacter jejuni and Pseudomonas viridiflava compared to their matched household controls. Analysis of mucosal IgA found ME/CFS patients with a long disease duration had higher microbe bound IgA concentrations compared to their matched household controls.

Conclusion: This thesis presents results from the first ME/CFS study to investigate serum IgG immune reactivity to stool microbes. Findings suggest ME/CFS patients have an impaired serum IgG immune response to the intestinal microbiome.

Source: Seton, Katharine.  Investigating Immune Reactivity to the Intestinal Microbiome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.  Doctoral thesis, University of East Anglia. https://ueaeprints.uea.ac.uk/id/eprint/90862/

Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease

Abstract:

The coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenged globally with its morbidity and mortality. A small percentage of affected patients (20%) progress into the second stage of the disease clinically presenting with severe or fatal involvement of lung, heart and vascular system, all contributing to multiple-organ failure. The so-called ‘cytokines storm’ is considered the pathogenic basis of severe disease and it is a target for treatment with corticosteroids, immunotherapies and intravenous immunoglobulin (IVIg).

We provide an overview of the role of IVIg in the therapy of adult patients with COVID-19 disease. After discussing the possible underlying mechanisms of IVIg immunomodulation in COVID-19 disease, we review the studies in which IVIg was employed. Considering the latest evidence that show a link between new coronavirus and autoimmunity, we also discuss the use of IVIg in COVID-19 and anti-SARS-CoV-2 vaccination related autoimmune diseases and the post-COVID-19 syndrome.

The benefit of high-dose IVIg is evident in almost all studies with a rapid response, a reduction in mortality and improved pulmonary function in critically ill COVID-19 patients. It seems that an early administration of IVIg is crucial for a successful outcome. Studies’ limitations are represented by the small number of patients, the lack of control groups in some and the heterogeneity of included patients. IVIg treatment can reduce the stay in ICU and the demand for mechanical ventilation, thus contributing to attenuate the burden of the disease.

Source: Danieli MG, Piga MA, Paladini A, Longhi E, Mezzanotte C, Moroncini G, Shoenfeld Y. Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease. Scand J Immunol. 2021 Nov;94(5):e13101. doi: 10.1111/sji.13101. Epub 2021 Sep 16. PMID: 34940980; PMCID: PMC8646640. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646640/ (Full text)

Passive transfer of fibromyalgia symptoms from patients to mice

Abstract:

Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation.

These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.

Source: Andreas Goebel, … , Camilla I. Svensson, David A. Andersson. Passive transfer of fibromyalgia symptoms from patients to mice. J Clin Invest. 2021;131(13):e144201. https://doi.org/10.1172/JCI144201. Published July 1, 2021 https://www.jci.org/articles/view/144201?key=51bf6d85e305f6b62f87 (Full text)