chuka_lis (chuka_lis) wrote,
chuka_lis
chuka_lis

Аутоиммунные антитела

Ковид может сопровождаться нарушениями иммунитета- формированием аутоимунных антител, наряду с антителами к белкам коронавируса. В исследовании медиков из США обнаружилось, что примерно у 50% госпитализированных (а значит тяжелых, тк тут госпитализируют не просто так), формируются новые антитела к собственной соединительной ткани, цитокинам (включая интерфероны и интерлейкины) или ДНК. Проявления активности этих аутоантител могут выглядеть как симптомы миозита, ревматизма, системного склероза, склеродермы, васкулита, волчанки, Крона и пр. Иногда это могут быть и аутоантитела к рецепторам АСЕ2, или запускающие тромбоз, или антитетла к анитгенам эндокринных желез (щитовидки).
Титры антител к коронавирусу и к своим антигенам  у больных нарастали синхронно, и со временем появлялись новые аутоантитела (тк у больных брали множественные образцы для анализа, начиная с первых дней госпитализации, в период с 2 по 59 день). Так же данные сравнивали с титрами у конроля (у которых все похоже, но без ковида), где картина была другой..
Так же, отмечу, почти у всех больных, участвующих в исследовании, на момент госпитализации или через день-два (когда брали анализ)  уже вырабатывались антитела к белкам коронавиурса, и у некоторых это были IgG в большом количестве.
Замечу,  что аутоиммунные нарушения, могут проявляться как долгий ковид с его разнообразием симптомов (так же как и поражения органов и тканей вирусом, который персистирует, достижимый (или не очень) для иммунитета, и вызывает воспалительную реакцию).
В статье (в дискуссии), обсуждается, кстати, момент- что развитию аутоиммунитета может способствовать и длительная болезнь сама по себе тоже, тк когда по первым мишеням ответ иммунитета пришелся "мимо" (вирус все еще размножается), организм "ищет" дальше, как бы достать эту заразу, при этом порой вырабатывая антитела на неструктурные белки или не самые типичные антигенные эпитопы, которые могут и мимикрировать.
Дальше будет выдержка из статьи и абстракт.  С подробностями.
Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, is associated with many different clinical features that are commonly found in autoimmune diseases, including arthralgias, myalgias, fatigue, sicca, and rashes1-3. Less common manifestations of autoimmunity have also been observed in COVID-19 patients, including thrombosis, myositis, myocarditis, arthritis, encephalitis, and vasculitis3. These clinical observations, and the increasing proportion of “recovered” patients with persistent post-COVID-19 symptoms (so-called “long haulers”, or “long COVID”) suggest that inflammation in response to SARS-CoV-2 infection promotes tissue damage in the acute phase and potentially some of the long-term sequelae4-6. Autoantibodies, a hallmark of most but not all autoimmune disorders, have been described in COVID-19 patients. In the earliest report, approximately half of hospitalized patients at an academic hospital in Greece had high levels of serum autoantibodies, often associated with clinical findings such as rashes, thrombosis, and vasculitis7. Serum anti-nuclear antibodies (ANA) were detectable in approximately one third of patients7. Woodruff et al. reported that 23 of 48 (44%) of critically-ill COVID-19 patients have positive ANA tests8,9. Zuo described an even higher prevalence of thrombogenic autoantibodies, reporting that up to 52% of hospitalized COVID-19 patients have anti-phospholipid antibodies. They further showed that autoantibodies have the capacity to cause clots in mouse models10. In a large autoantibody screen, Gruber et al. demonstrated that Multisystem Inflammatory Syndrome in Children (MIS-C) patients develop autoantibodies, including autoantibodies against the lupus antigen SSB/La11. SSB/Ro autoantibodies have also been described12. The apparent link between clinical manifestations resembling those seen in patients with classifiable autoimmune diseases, and those observed in COVID-19 patients, has prompted searches for candidate target autoantigens that may be useful for diagnosis and for improving understanding of COVID-19 pathogenesis. Samples were obtained from 147 hospitalized patients infected by SARS-CoV-2, some of which were collected longitudinally, in three geographically distinct locations. Our results demonstrate that a large cadre of autoantigens are targeted by circulating antibodies in a substantial proportion of hospitalized patients with COVID-19, but less commonly in uninfected healthy controls (HC). Our studies confirm emerging reports of IgG autoantibodies in hospitalized COVID-19 patients and demonstrate that a significant subset of patients develop new-onset autoantibodies that could place them at risk for progression to symptomatic, classifiable autoimmunity in the future.
Discussion We have used a multiplexed, bead-based platform to identify circulating antibodies in hospitalized patients with COVID-19 and have generated integrated results from three different protein microarrays to discover COVID-19 associated autoantigens and link them to anti-viral responses. Our studies have led to several important findings that provide further insights into COVID-19 pathogenesis. First, we found that approximately half of hospitalized COVID-19 patients develop serum autoantibodies against one or more antigens on our array even though only a quarter of all patients are ANA+. Increased levels of autoantibodies are not simply a reflection of hypergammaglobulinemia because they are produced out of proportion to total IgG serum concentration. In most individuals, only a small number of autoantigens are targeted, which is more consistent with a sporadic loss of self-tolerance than a global increase in autoantibody production. Second, the autoantibodies we discovered are found in relatively rare connective tissue diseases that are not typically measured in clinical labs, and some are predicted to be pathogenic. Third, a surprisingly large number of ACA were identified, far more than just the interferon autoantibodies described recently21. Fourth, antibodies recognizing nonstructural SARS-CoV-2 proteins were identified that correlate positively with autoantibodies. Finally, and perhaps most importantly, some autoantibodies are newly triggered by SARS-CoV-2 infection, suggesting that severe COVID-19 can break tolerance to self.
Approximately 60-80% of all hospitalized COVID-19 patients in our study had at least one ACA, with a greater number of different ACA specificities generated in individual patients than observed for traditional autoantigens. Two recent studies demonstrated that IFN-α and IFN-ω-blocking ACA are found in patients with severe COVID-1921,25. Anti-IFN antibodies with blocking activity were absent in all 663 tested patients with mild COVID-19, strongly linking the presence of anti-IFN to disease pathogenesis and severity21. Another study reported that type I interferon (IFN) deficiency could be a hallmark of severe COVID-1926, while other investigators pointed towards an untuned antiviral immune response due to delayed type I/III interferon expression27. Bastard identified blocking ACA for additional cytokines including IL-6, IL-22, and IL-12p7021. ACA without blocking activity still may be biologically important, for example by potentiating receptor binding or prolonging cytokine half-life28,29. In another recent study, Wang identified autoantibodies against additional secreted and tissue-associated proteins in COVID-19 patients17, some of which were pathogenic when tested in animal models of SARS-CoV-2 infection. Pre-existing IFN-α autoantibodies were recently identified in 4/10 (40%) SLE patients from NIH’s SLE cohort who later became infected with SARS-CoV-232. We have identified ACA in SLE (including anti-BAFF blocking antibodies and anti-IFNα)18, systemic sclerosis30, and a variety of immunodeficiency disorders18,19,31, suggesting that ACA are probably more common than previously appreciated in immune-mediated diseases. Taken together, these earlier studies are consistent with the notion that pre-existing ACA are pathogenic and may place such individuals at increased risk of developing severe COVID-19. What is different about our work from these earlier studies is that we show a change in ACA levels and in the numbers of ACAs over time in many hospitalized individuals with acute COVID-19. Our findings suggest that ACA may also form in response to viral infection or as a consequence of an inflammatory immune response in which high levels of cytokines are generated. In addition to ACAs modulating the immune response and potentially causing more destructive inflammation, autoantibodies have the potential to contribute in a number of other ways to COVID-19 pathogenesis. Several autoantigens we discovered are naturally complexed with a structural RNA molecule which could serve as a ligand for nucleic acid sensors such as Toll Like Receptors (e.g., TLR7, TLR3) in host cells. RNA or DNA released from dying cells could also form immune complexes with viral or self-antigens that can promote autoantibody production. A subset of array-identified autoantigens (e.g., MDA5) are encoded by interferon-inducible genes and would be predicted to be transcribed in response to SARS-CoV-2 infection. Indeed, the acute phase of severe SARS-CoV-2 infection can be accompanied by marked tissue inflammation, cytokine storm (including secretion of interferons), upregulation of interferon signaling pathways, and expression of ACE-2 in vascular endothelium. Although not yet explored for COVID-19-associated autoantibodies or ACA, IgG antibodies that bind SARS-CoV-2 proteins are often IgG1 and have afucosylated glycans. These properties enhance immunoglobulin interactions with the activating Fcγ receptor FcγRIIIa, potentially leading to increased production of inflammatory cytokines such as IL-6 and TNF33. We postulate that a subset of the autoantibodies we have identified contribute to the formation of inflammatory immune complexes in situ, particularly at endothelial surfaces. For example, neutrophil extracellular traps (NETs) have been implicated in COVID-19 patients with vasculitis.34Antineutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV) has been strongly associated with neutrophil activation and generation of proinflammatory NETs containing nucleic acids, histones, and inflammatory peptides35. While we did not observe elevated levels of MPO or PR3, we identified high MFI anti-BPI antibodies in 6% of COVID-19 patients. The detection of autoantibodies to BPI and core as well as linker histones raises the possibility that NETs contribute to the generation of autoantibodies in severe COVID-19, a possibility that is in line with the neutrophilia that accompanies severe acute disease36. Disseminated microvascular coagulopathy and microvascular injury in lung and skin from COVID-19 patients correlate with fibrin deposition and thrombus formation37. SARS-CoV-2 membrane proteins including the spike protein (but not SARS-CoV-2 RNA) colocalize with activated complement in ACE-2+ microvascular endothelia of COVID-19 lung tissue and normal-appearing skin37,38. Magro and colleagues hypothesize that spike protein on the surface of circulating pseudovirions binds to endothelial ACE-2 (whose gene is interferon-inducible), providing a nidus for activation of complement and formation of microthrombi. Anti-C1q (an SLE autoantigen), anti-β2GP1 (which is thrombogenic), anti-BPI, and anti-ACE-2 (if non-blocking)39that were discovered in our screen would be predicted to exacerbate these pathogenic processes40. Severe infection may also result in an “all-hands-on-deck” immune response that results in loss of tolerance due to the presence of pro-inflammatory mediators that may lessen the requirement for T cell help. Some patients with severe acute COVID-19 appear to mount extrafollicular B cell responses that are characterized by expanded B cells and plasmablasts, loss of germinal centers, and loss of expression of Bcl-641,42. Antibody repertoires analyzed from hospitalized COVID-19 patients during acute disease include massive clones with low levels of somatic mutation (SHM)43,44and elongated CDR3 sequences which can be associated with polyreactivity45 and are reminiscent of immune responses seen in acute Ebola46 and salmonella infection47. It has been suggested that these responses resemble SLE flares in which autoreactive B cells are also activated via an extrafollicular, TLR7-dependent pathway8,41,48. Although SARS-CoV-2 genomic RNA could itself serve as a costimulatory TLR7 ligand, many of the autoantigens we have identified also bind to structural RNAs such as the U1-snRNA (found in Sm/RNP complexes), 7S RNA (a component of SRP), and tRNAs (e.g., Jo-1, PL-7, and PL-12) which might activate dendritic cells in a TLR7-dependent manner49,50. One of the most important unanswered questions raised by our studies is why specific molecules are targeted in hospitalized COVID-19 patients. For newly triggered ACA, the most likely explanation is that they arise as a consequence of severe disease along with high levels of viremia, tissue injury, and elevated local levels of pro-inflammatory cytokines and chemokines. However, it is also possible that the presence of ACA could affect the regulation of self-reactive lymphocytes by altering the half-lives of the receptor interactions of the target molecules. For traditional autoantigens, one possibility is that viral proteins or the SARS-CoV-2 RNA genome and self-molecules physically interact, and that the initial immune response to the viral protein in a highly inflammatory microenvironment expands to include self-proteins through linked recognition and intermolecular 26epitope spreading. Another possibility is molecular mimicry in which one or more viral proteins or epitopes cross reacts with self-proteins leading to loss of tolerance and development of autoimmunity51,52 Here, we developed a multiplexed viral protein array that enables simultaneous measurement of antibody responses against 28 different proteins from 13 different viruses. We determined that non-structural proteins are recognized by antibodies in a large proportion of hospitalized COVID-19 patients, suggesting that B cell responses expand over time to involve additional viral molecules. IgG antibody levels against NSP1 and ME correlated positively with the presence of at least one autoantibody. We hypothesize that prolonged inability to eradicate and clear virus expands the adaptive immune response to target non-structural viral proteins, some of which might physically interact or cross-react with autoantigens in the context of an intense local or systemic inflammatory environment, exceeding a threshold for breaking tolerance to self. In contrast, patients who rapidly mount neutralizing antibody responses to the viral spike protein abort “intraviral epitope spreading” and may be less likely to develop autoantibodies. Why anti-SARS-CoV-1 RBD IgG responses associate with autoantibody positive patients is unclear. Future longitudinal studies are needed to determine whether broad B cell responses play any direct pathogenic role in patients with prolonged hospital courses or in patients with long-term sequelae of COVID-19 infection; to correlate anti-viral responses with ACA and autoantibodies over time using much larger COVID-19 cohorts including patients who are asymptomatic or have mild disease; and to explore whether specific SARS-CoV-2 proteins might cross-react with autoantigens discovered in our screens.


Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. We developed three different protein arrays to measure hallmark IgG autoantibodies associated with Connective Tissue Diseases (CTDs), Anti-Cytokine Antibodies (ACA), and anti-viral antibody responses in 147 hospitalized COVID-19 patients in three different centers. Autoantibodies were identified in approximately 50% of patients, but in <15% of healthy controls. When present, autoantibodies largely targeted autoantigens associated with rare disorders such as myositis, systemic sclerosis and CTD overlap syndromes. Anti-nuclear antibodies (ANA) were observed in ~25% of patients. Patients with autoantibodies tended to demonstrate one or a few specificities whereas ACA were even more prevalent, and patients often had antibodies to multiple cytokines. Rare patients were identified with IgG antibodies against angiotensin converting enzyme-2 (ACE-2). A subset of autoantibodies and ACA developed de novo following SARS-CoV-2 infection while others were transient. Autoantibodies tracked with longitudinal development of IgG antibodies that recognized SARS-CoV-2 structural proteins such as S1, S2, M, N and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. COVID-19 patients with one or more autoantibodies tended to have higher levels of antibodies against SARS-CoV-2 Nonstructural Protein 1 (NSP1) and Methyltransferase (ME). We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.

 

Tags: иммунитет, коронавирус, статьи
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