Tag: autoantibodies

Characterizing Sjögren-Associated Fatigue: A Distinct Phenotype from ME/CFS

Abstract:

Fatigue is the most commonly reported and debilitating extraglandular symptom of primary Sjögren′s syndrome (pSS). Fatigue and exertional intolerance are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We aimed to characterize fatigue and further symptoms among pSS patients and to determine whether there is a symptom overlap in pSS and ME/CFS.
In 19 patients with pSS, we assessed pSS symptom severity and disease activity via questionnaires as well as the Canadian Consensus Criteria (CCC) for ME/CFS. Hand grip strength (HGS) and levels of α1-, α2-, β1-, β2-, M3- and M4-receptor-autoantibodies were measured. A subgroup of pSS patients exhibited severe fatigue and had higher severity of pain (p = 0.045), depression (p = 0.021) and sleep disturbances (p = 0.020) compared to those with less fatigue.
Four of eighteen pSS patients fulfilled the CCC. HGS parameters strongly correlated with fatigue severity (p < 0.05), but strength fully recovered one hour after exertion in contrast to ME/CFS. Levels of β1-, β2- and M4-receptor-autoantibodies were elevated and correlated significantly with disease activity assessed by the ESSDAI (p < 0.05), but not fatigue severity.
Only a minor subgroup of pSS patients fulfills the CCC, and post exertional malaise (PEM) is atypical, as it is primarily triggered by mental/emotional but not physical exertion. HGS assessment is an objective measure to assess overall fatigue severity.
Source: Kim L, Kedor C, Buttgereit F, Heidecke H, Schaumburg D, Scheibenbogen C. Characterizing Sjögren-Associated Fatigue: A Distinct Phenotype from ME/CFS. Journal of Clinical Medicine. 2023; 12(15):4994. https://doi.org/10.3390/jcm12154994 https://www.mdpi.com/2077-0383/12/15/4994 (Full text)

Autoantibody production is enhanced after mild SARS-CoV-2 infection despite vaccination in individuals with and without long COVID

Abstract:

Long COVID patients who experienced severe acute SARS-CoV-2 infection can present with humoral autoimmunity. However, whether mild SARS-CoV-2 infection increases autoantibody responses and whether vaccination can decrease autoimmunity in long COVID patients is unknown.

Here, we demonstrate that mild SARS-CoV-2 infection increases autoantibodies associated with systemic lupus erythematosus (SLE) and inflammatory myopathies in long COVID patients with persistent neurologic symptoms to a greater extent than COVID convalescent controls at 8 months post-infection. Furthermore, high titers of SLE-associated autoantibodies in long COVID patients are associated with impaired cognitive performance and greater symptom severity, and subsequent vaccination/booster does not decrease autoantibody titers.

In summary, we found that mild SARS-CoV-2 infection can induce persistent humoral autoimmunity in both long COVID patients and healthy COVID convalescents, suggesting that a reappraisal of vaccination and mitigation strategies is warranted.

Source: Visvabharathy L, Zhu C, Orban ZS, Yarnoff K, Palacio N, Jimenez M, Lim PH, Penaloza-MacMaster P, Koralnik IJ. Autoantibody production is enhanced after mild SARS-CoV-2 infection despite vaccination in individuals with and without long COVID. medRxiv [Preprint]. 2023 Apr 12:2023.04.07.23288243. doi: 10.1101/2023.04.07.23288243. PMID: 37090595; PMCID: PMC10120795. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120795/ (Full text)

Free-water-corrected diffusion and adrenergic/muscarinic antibodies in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background and purpose: Free-water-corrected diffusion tensor imaging (FW-DTI), a new analysis method for diffusion MRI, can indicate neuroinflammation and degeneration. There is increasing evidence of autoimmune etiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We used FW-DTI and conventional DTI to investigate microstructural brain changes related to autoantibody titers in patients with ME/CFS.

Methods: We prospectively examined 58 consecutive right-handed ME/CFS patients who underwent both brain MRI including FW-DTI and a blood analysis of autoantibody titers against β1 adrenergic receptor (β1 AdR-Ab), β2 AdR-Ab, M3 acetylcholine receptor (M3 AchR-Ab), and M4 AchR-Ab. We investigated the correlations between these four autoantibody titers and three FW-DTI indices-free water (FW), FW-corrected fractional anisotropy (FAt), and FW-corrected mean diffusivity-as well as two conventional DTI indices-fractional anisotropy (FA) and mean diffusivity. The patients’ age and gender were considered as nuisance covariates. We also evaluated the correlations between the FW-DTI indices and the performance status and disease duration.

Results: Significant negative correlations between the serum levels of several autoantibody titers and DTI indices were identified, mainly in the right frontal operculum. The disease duration showed significant negative correlations with both FAt and FA in the right frontal operculum. The changes in the FW-corrected DTI indices were observed over a wider extent compared to the conventional DTI indices.

Conclusions: These results demonstrate the value of using DTI to assess the microstructure of ME/CFS. The abnormalities of right frontal operculum may be a diagnostic marker for ME/CFS.

Source: Kimura Y, Sato W, Maikusa N, Ota M, Shigemoto Y, Chiba E, Arizono E, Maki H, Shin I, Amano K, Matsuda H, Yamamura T, Sato N. Free-water-corrected diffusion and adrenergic/muscarinic antibodies in myalgic encephalomyelitis/chronic fatigue syndrome. J Neuroimaging. 2023 May 27. doi: 10.1111/jon.13128. Epub ahead of print. PMID: 37243973. https://pubmed.ncbi.nlm.nih.gov/37243973/

Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis

Abstract:

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes.

Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy.

This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.

Source: Achleitner, M., Steenblock, C., Dänhardt, J. et al. Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02084-1 https://www.nature.com/articles/s41380-023-02084-1 (Full text)

Modulation of Beta-Adrenergic Autoantibodies Over Time in Post-Viral ME/CFS is Related to Fatigue and Pain Symptoms

Abstract:

Background: Myalgic encephalomyelits/chronic fatigue syndrome (ME/CFS) is an acquired disease with symptoms of fatigue and pain. In pathogenesis, the induction of autoantibodies (AAB) against G-protein coupled receptors (GPCR), such as β-adrenergic receptors (β-AdR), has been suspected. GPCR-AAB correlate with symptom severity and autonomic dysfunction in ME/CFS.

Objectives: To describe symptoms and treatment of a patient presenting with infection-triggered ME/CFS demonstrating that levels of β-AdR-AAB underlie modulation over time, correlating with the severity of symptoms.

Methods: At T1 and T2, GPCR-AAB were measured and questionnaires assessing symptom severity were completed. TSHDS-IgM-AAB were tested, and SF density was analyzed via skin probe.

Results: At T2, elevated levels of β-AdR-AAB were found, corresponding with an aggravation of fatigue and pain symptoms. Elevated TSHDS-IgM-AAB were found, which corresponded with reduced fiber density from the skin probe.

Conclusions: The levels of β-AdR-AAB in post-infectious ME/CFS can be modulated. Future studies might target interventions to reduce these AAB.

Source: Busch L, Schriek C, Paul M, Heidecke H. Modulation of Beta-Adrenergic Autoantibodies Over Time in Post-Viral ME/CFS is Related to Fatigue and Pain Symptoms. Isr Med Assoc J. 2023 Apr;25(4):259-264. PMID: 37129123. https://pubmed.ncbi.nlm.nih.gov/37129123/

Long COVID in autoimmune rheumatic diseases

Abstract:

Consequences of Corona Virus Disease-19 (COVID-19) in patients with rheumatic diseases (RDs) are clinically diverse. SARS-CoV-2 infection has been associated with various autoimmune and rheumatic manifestations over the past three years. Emerging evidence points to the possibility of Long COVID predisposition in rheumatic patients due to the changes in immune regulatory response. The aim of this article was to overview data on the pathobiology of Long COVID in patients with RDs.

Related risk factors, clinical characteristics, and prognosis of Long COVID in RDs were analyzed. Relevant articles were retrieved from Medline/PubMed, Scopus, and Directory of Open Access Journals (DOAJ). Diverse mechanisms of viral persistence, chronic low-grade inflammation, lasting production of autoantibodies, endotheliopathy, vascular complications, and permanent tissue damage have been described in association with Long COVID. Patients with RDs who survive COVID-19 often experience severe complications due to the immune disbalance resulting in multiple organ damage. Regular monitoring and treatment are warranted in view of the accumulating evidence.

Source: Fedorchenko Y, Zimba O. Long COVID in autoimmune rheumatic diseases. Rheumatol Int. 2023 Mar 30:1–11. doi: 10.1007/s00296-023-05319-0. Epub ahead of print. PMID: 36995436; PMCID: PMC10061411. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061411/ (Full text)

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

Abstract:

We measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants with COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided subacute/convalescent sera (6-76 weeks post-admission).

Compared to 60 controls, brain injury biomarkers (Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in patients with altered consciousness. Tau and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness, and correlated with brain injury biomarker levels. Inflammatory mediators were lower than acute levels in convalescent sera, but levels of CCL2, CCL7, IL-1RA, IL-2Rα, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with Tau levels even at this late time point.

When compared to acute COVID-19 patients with a normal GCS, network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens).

In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFNγ, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase and persists late after COVID-19, and may be driven by a para-infectious process involving a dysregulated host response.

Source: Benedict D. Michael, Cordelia Dunai, Edward J. Needham, Kukatharmini Tharmaratnam, Robyn Williams, Yun Huang, Sarah A. Boardman, Jordan Clark, Parul Sharma, Krishanthi Subramaniam, Greta K. Wood, Ceryce Collie, Richard Digby, Alexander Ren, Emma Norton, Maya Leibowitz, Soraya Ebrahimi, Andrew Fower, Hannah Fox, Esteban Tato, Mark Ellul, Geraint Sunderland, Marie Held, Claire Hetherington, Franklyn Nkongho, Alish Palmos, Alexander Grundmann, James P. Stewart, Michael Griffiths, Tom Solomon, Gerome Breen, Alasdair Coles, Jonathan Cavanagh, Sarosh R. Irani, Angela Vincent, Leonie Taams, David K. Menon. Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses. medRxiv 2023.04.03.23287902; doi: https://doi.org/10.1101/2023.04.03.23287902 (Full text available as PDF file)

Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course

Abstract:

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes.

Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration.

Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

Source: Muri J, Cecchinato V, Cavalli A, Shanbhag AA, Matkovic M, Biggiogero M, Maida PA, Moritz J, Toscano C, Ghovehoud E, Furlan R, Barbic F, Voza A, De Nadai G, Cervia C, Zurbuchen Y, Taeschler P, Murray LA, Danelon-Sargenti G, Moro S, Gong T, Piffaretti P, Bianchini F, Crivelli V, Podešvová L, Pedotti M, Jarrossay D, Sgrignani J, Thelen S, Uhr M, Bernasconi E, Rauch A, Manzo A, Ciurea A, Rocchi MBL, Varani L, Moser B, Bottazzi B, Thelen M, Fallon BA, Boyman O, Mantovani A, Garzoni C, Franzetti-Pellanda A, Uguccioni M, Robbiani DF. Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course. Nat Immunol. 2023 Mar 6. doi: 10.1038/s41590-023-01445-w. Epub ahead of print. PMID: 36879067. https://www.nature.com/articles/s41590-023-01445-w (Full text)

Autoantigen profiling reveals a shared post-COVID signature in fully recovered and Long COVID patients

Abstract:

Some individuals do not return to baseline health following SARS-CoV-2 infection, leading to a condition known as Long COVID. The underlying pathophysiology of Long COVID remains unknown. Given that autoantibodies have been found to play a role in severity of COVID infection and certain other post-COVID sequelae, their potential role in Long COVID is important to investigate. Here we apply a well-established, unbiased, proteome-wide autoantibody detection technology (PhIP-Seq) to a robustly phenotyped cohort of 121 individuals with Long COVID, 64 individuals with prior COVID-19 who reported full recovery, and 57 pre-COVID controls.

While a distinct autoreactive signature was detected which separates individuals with prior COVID infection from those never exposed to COVID, we did not detect patterns of autoreactivity that separate individuals with Long COVID relative to individuals fully recovered from SARS-CoV-2 infection. These data suggest that there are robust alterations in autoreactive antibody profiles due to infection; however, no association of autoreactive antibodies and Long COVID was apparent by this assay.

Source: Bodansky A, Wang CY, Saxena A, Mitchell A, Takahashi S, Anglin K, Huang B, Hoh R, Lu S, Goldberg SA, Romero J, Tran B, Kirtikar R, Grebe H, So M, Greenhouse B, Durstenfeld MS, Hsue PY, Hellmuth J, Kelly JD, Martin JN, Anderson MS, Deeks SG, Henrich TJ, DeRisi JL, Peluso MJ. Autoantigen profiling reveals a shared post-COVID signature in fully recovered and Long COVID patients. medRxiv [Preprint]. 2023 Feb 9:2023.02.06.23285532. doi: 10.1101/2023.02.06.23285532. PMID: 36798288; PMCID: PMC9934805. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934805/ (Full text)

The relationship between chronic immune response and neurodegenerative damage in long COVID-19

Abstract:

In the past two years, the world has faced the pandemic caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2), which by August of 2022 has infected around 619 million people and caused the death of 6.55 million individuals globally. Although SARS-CoV-2 mainly affects the respiratory tract level, there are several reports, indicating that other organs such as the heart, kidney, pancreas, and brain can also be damaged.

A characteristic observed in blood serum samples of patients suffering COVID-19 disease in moderate and severe stages, is a significant increase in proinflammatory cytokines such as interferon-α (IFN-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6) and interleukin-18 (IL-18), as well as the presence of autoantibodies against interferon-α (IFN-α), interferon-λ (IFN-λ), C-C motif chemokine ligand 26 (CCL26), CXC motif chemokine ligand 12 (CXCL12), family with sequence similarity 19 (chemokine (C-C motif)-like) member A4 (FAM19A4), and C-C motif chemokine ligand 1 (CCL1). Interestingly, it has been described that the chronic cytokinemia is related to alterations of blood-brain barrier (BBB) permeability and induction of neurotoxicity.

Furthermore, the generation of autoantibodies affects processes such as neurogenesis, neuronal repair, chemotaxis and the optimal microglia function. These observations support the notion that COVID-19 patients who survived the disease present neurological sequelae and neuropsychiatric disorders. The goal of this review is to explore the relationship between inflammatory and humoral immune markers and the major neurological damage manifested in post-COVID-19 patients.

Source: Elizalde-Díaz JP, Miranda-Narváez CL, Martínez-Lazcano JC, Martínez-Martínez E. The relationship between chronic immune response and neurodegenerative damage in long COVID-19. Front Immunol. 2022 Dec 16;13:1039427. doi: 10.3389/fimmu.2022.1039427. PMID: 36591299; PMCID: PMC9800881. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800881/ (Full text)