Autoantibodies in COVID-19: Pathogenic Mechanisms and Implications for Severe Illness and Post-Acute Sequelae

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, has led to a wide range of acute and chronic disease manifestations. While most infections are mild, a significant number of patients develop severe illness marked by respiratory failure, thromboinflammation, and multi-organ dysfunction. In addition, post-acute sequelae—commonly known as long-COVID—can persist for months. Recent studies have identified the emergence of diverse autoantibodies in COVID-19, including those targeting nuclear antigens, phospholipids, type I interferons, cytokines, endothelial components, and G-protein-coupled receptors. These autoantibodies are more frequently detected in patients with moderate to severe disease and have been implicated in immune dysregulation, vascular injury, and persistent symptoms. This review examines the underlying immunological mechanisms driving autoantibody production during SARS-CoV-2 infection—including molecular mimicry, epitope spreading, and bystander activation—and discusses their functional roles in acute and post-acute disease. We further explore the relevance of autoantibodies in maternal–fetal immunity and comorbid conditions such as autoimmunity and cancer, and we summarize current and emerging therapeutic strategies. A comprehensive understanding of SARS-CoV-2-induced autoantibodies may improve risk stratification, inform clinical management, and guide the development of targeted immunomodulatory therapies.

1. Introduction

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has profoundly impacted global health, social systems, and economies since its emergence in December 2019 (Worldometer, 2025) [1]. The virus is primarily transmitted via respiratory droplets and aerosols, producing a broad spectrum of clinical manifestations. While most infected individuals experience mild symptoms or remain asymptomatic, a significant proportion develop severe or critical illness requiring hospitalization and intensive care. As of early 2025, COVID-19 has led to over 700 million reported cases and more than 7 million deaths globally, establishing itself as one of the most consequential health crises in modern history [2].

The clinical course of COVID-19 is highly heterogeneous. While many patients recover uneventfully, approximately 10–15% develop severe disease characterized by hypoxemia, pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ dysfunction. Severe disease is frequently associated with a dysregulated immune response marked by excessive production of pro-inflammatory cytokines—a phenomenon referred to as the “cytokine storm.” This hyperinflammatory state promotes endothelial injury, coagulopathy, and systemic organ damage, all of which contribute to increased mortality [3,4,5,6].

Beyond the acute phase, a significant subset of individuals experience persistent symptoms lasting weeks to months, a condition now referred to as post-acute sequelae of SARS-CoV-2 infection (PASC) or long-COVID. Symptoms such as fatigue, dyspnea, cognitive impairment (“brain fog”), myalgia, and chest pain have been widely reported even among patients who had mild acute illness. The underlying mechanisms remain incompletely defined but are thought to involve chronic immune activation, lingering viral reservoirs, autoimmunity, and neuroinflammatory processes [7,8].

The continued emergence of viral variants, including Delta and Omicron, has further complicated pandemic control efforts. These variants exhibit increased transmissibility and partial immune escape, necessitating updated public health strategies. Although vaccination has significantly reduced hospitalization and mortality rates, immune evasion by emerging variants and global disparities in vaccine coverage pose ongoing challenges [9,10].

Following infection, SARS-CoV-2 primarily targets respiratory epithelial cells via interaction between the viral spike (S) protein and the host’s angiotensin-converting enzyme 2 (ACE2) receptor, which is widely expressed in the lungs, heart, kidneys, and gastrointestinal tract. This binding facilitates viral entry, replication, and subsequent cellular injury. The host immune response initiates with the activation of innate immunity, particularly through pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) that detect viral RNA. This is followed by the activation of adaptive immunity, characterized by antigen-specific T- and B-cell responses and the production of neutralizing antibodies [11,12,13].

Antibodies are crucial for combating viral infections, including COVID-19, by neutralizing the virus and preventing its entry into host cells. In COVID-19, antibodies, especially those targeting the spike protein of SARS-CoV-2, are associated with a reduced risk of severe disease and reinfection [14]. They play a central role in providing immunity by recognizing and neutralizing the virus. However, in some patients, the immune response becomes dysregulated, resulting in the production of autoantibodies that target host tissues. These autoantibodies are thought to be a key driver in the development of long-COVID, a condition where persistent symptoms continue long after the acute phase of the infection [15].

Given this background, understanding the immune dysregulation underpinning COVID-19 is essential. In particular, autoantibodies—antibodies that target host self-antigens—have emerged as key mediators of COVID-19 pathogenesis. These antibodies can impair immune regulation, exacerbate inflammation, and directly damage tissues. Their presence has been associated with increased disease severity, thrombotic complications, and the development of long-COVID. This review aims to explore the mechanisms driving the production of autoantibodies in SARS-CoV-2 infection, their specific targets, and their functional consequences in both acute and chronic phases of disease. A better understanding of these processes may help guide the development of targeted therapies and diagnostic tools to mitigate the long-term burden of COVID-19 [16,17].

2. Autoantibodies and Their Role in COVID-19 Pathogenesis

2.1. Mechanisms of Autoantibody Production in COVID-19

Autoantibodies observed in COVID-19 patients are thought to arise from a breakdown in immune tolerance driven by intense systemic inflammation and immune dysregulation. Several immunopathological mechanisms underlie this process, notably molecular mimicry, epitope spreading, and bystander activation [18,19].

Molecular mimicry is a proposed mechanism by which viral antigens that share sequence or structural similarity with host proteins may elicit cross-reactive immune responses. In the context of SARS-CoV-2, several in silico analyses have identified candidate regions of sequence homology between viral proteins—particularly the spike glycoprotein—and various human proteins, including angiotensin-converting enzyme 2 (ACE2), heat shock proteins (HSPs), and other conserved elements [18]. While these findings raise the possibility that molecular mimicry could contribute to autoantibody production in genetically predisposed individuals, experimental validation—such as competitive binding assays or functional studies demonstrating cross-reactivity—is still lacking. Therefore, the role of molecular mimicry in SARS-CoV-2-induced autoimmunity remains a hypothesis that warrants further investigation.

Epitope spreading is a well-characterized mechanism in chronic autoimmune diseases such as systemic lupus erythematosus (SLE), wherein immune responses initially targeting specific epitopes expand to include additional, often self-derived, antigens. Although direct evidence for epitope spreading in COVID-19 is limited, severe cases are characterized by intense inflammation, extensive tissue damage, and the release of intracellular antigens, which may provide a substrate for broader autoreactivity. Notably, studies have identified extrafollicular B-cell responses in severely ill COVID-19 patients, bearing transcriptional and phenotypic resemblance to those observed in SLE [19]. These atypical B-cell activation pathways may set the stage for dysregulated antibody production, though whether they lead to true epitope spreading in the short course of acute infection remains to be determined.

Bystander activation refers to the nonspecific stimulation of autoreactive B- and T-cells within an inflammatory environment, a mechanism commonly implicated in viral infections. In the context of COVID-19, the systemic cytokine surge and disrupted antigen presentation may compromise immune tolerance, enabling the expansion of self-reactive lymphocytes. However, emerging evidence suggests that this process may be more complex and pathogenic than initially presumed. Studies have demonstrated molecular mimicry and cross-reactivity between SARS-CoV-2 proteins and human tissue antigens, indicating that bystander activation may occur alongside or be amplified by antigen-specific mechanisms [20,21]. Additionally, post-pandemic analyses have revealed shifts in autoimmunity biomarkers, reinforcing concerns that COVID-19 may trigger or exacerbate autoimmune conditions at the population level [22]. These observations underscore the necessity of distinguishing bystander activation from other overlapping mechanisms, such as epitope spreading and molecular mimicry, to clarify their contributions to the autoimmune sequelae of COVID-19 [23].

Bystander activation refers to the nonspecific activation of autoreactive B- and T-cells in the inflammatory milieu, a mechanism frequently observed in viral infections. In COVID-19, systemic cytokine elevation and dysregulated antigen presentation may override normal checkpoints for immune tolerance, allowing for the escape and expansion of self-reactive lymphocytes [20,21,22,23].

The convergence of these mechanisms—occurring in a setting of intense inflammation, tissue destruction, and prolonged immune activation—creates a permissive environment for the emergence of pathogenic autoantibodies. These antibodies may persist beyond the acute phase, contributing to the long-term sequelae observed in many COVID-19 survivors.

Before addressing the diverse types of autoantibodies and their potential pathogenic roles, it is essential to recognize that autoantibody production, whether induced by infection, vaccination, or other immune-altering events, may not be inherently pathological. The generation of distinct sets of idiotypes in response to changes in immune status—such as those associated with atopic diseases [24,25,26,27], allergies [28,29,30,31,32,33,34,35,36,37,38], infections [39], or even mere exposure to pathogens without overt infection [40]—suggests a more nuanced role for autoantibodies in immune regulation. Recent studies have demonstrated that these idiotype repertoires vary significantly across donor groups stratified by immunological background, with evidence indicating that both human and murine idiotypes can mediate immunomodulatory effects [30,41]. These effects may promote or suppress inflammatory responses, implying a context-dependent role for autoantibodies in maintaining or disrupting immune homeostasis—a concept encapsulated in the “hooks without bait” hypothesis [42].

In this regard, it becomes increasingly clear that not all autoantibody responses are detrimental; rather, they may represent adaptive or regulatory mechanisms shaped by evolutionary pressures. Nonetheless, in the context of COVID-19, particular attention must be given to the subset of autoantibodies that exhibit pathological potential. SARS-CoV-2 infection has been linked to the emergence of autoantibodies that target critical self-antigens, including those involved in coagulation, endothelial integrity, and immune signaling pathways. Such autoantibodies are thought to contribute to the hyperinflammatory state, thrombotic complications, and prolonged symptomatology observed in severe and long-COVID cases. Therefore, while acknowledging the broader immunological landscape of autoantibody function, the present discussion will focus specifically on those antibodies with the capacity to act as mediators of immune pathology in COVID-19.

In addition to classical pathways of autoreactivity, we propose that a persistent disruption of the idiotype–anti-idiotype network may represent a novel mechanism sustaining long-term autoantibody production beyond viral clearance. The generation of anti-idiotype antibodies with structural mimicry to host receptors, such as ACE2, could lead to autoreactive cascades and sustained immune dysregulation. This paradigm, which has been insufficiently explored in COVID-19, may help explain the chronicity of certain autoantibody responses.

2.2. Types of Autoantibodies in COVID-19

SARS-CoV-2 infection has been associated with the induction of a broad array of autoantibodies that target self-antigens involved in various physiological systems. These autoantibodies are frequently detected in moderate to severe COVID-19 cases and have been linked to immune dysregulation, endothelial dysfunction, and thromboinflammatory complications. Below are several key autoantibody types that have been consistently reported.

Antinuclear antibodies (ANA): ANAs, which target nuclear components such as histones, DNA, and ribonucleoproteins, have been frequently observed in hospitalized COVID-19 patients. Their presence has been correlated with more severe clinical presentations, including hyperinflammatory syndromes and vascular injury [43,44].

Anti-phospholipid antibodies (aPL): These antibodies target phospholipid-binding proteins such as β2-glycoprotein I and are well-known mediators of thrombosis. In COVID-19, elevated aPL levels have been associated with thromboembolic events, suggesting a role in the hypercoagulable state observed in critically ill patients [45,46].

Anti-platelet antibodies: Antibodies against platelet glycoproteins can enhance platelet activation and aggregation, contributing to thrombocytopenia and thrombotic complications in severe COVID-19. Their detection correlates with platelet consumption and microvascular injury [47,48].

Anti-interferon autoantibodies: Neutralizing autoantibodies against type I interferons (especially IFN-α and IFN-ω) have emerged as critical biomarkers of immune failure in COVID-19. These autoantibodies impair antiviral responses, prolong viral replication, and are found in over 10% of patients with life-threatening disease [49,50,51,52].

Collectively, these autoantibodies not only serve as indicators of disease severity but may also directly contribute to COVID-19 pathophysiology by disrupting immune regulation, promoting coagulation, and impairing viral clearance mechanisms.

2.3. Autoantibodies and Immune Dysregulation

The emergence of autoantibodies in COVID-19 has been increasingly recognized as a key factor contributing to immune dysregulation, particularly in patients with severe disease. These autoantibodies can target essential components of the immune system, disrupting normal regulatory pathways and amplifying pro-inflammatory responses. For example, autoantibodies directed against interleukin-6 (IL-6) or its receptor have been associated with exacerbation of the cytokine storm—a hyperinflammatory state characterized by elevated levels of IL-6, TNF-α, and IL-1β—which contributes to systemic inflammation, multi-organ injury, and high mortality in critically ill patients [3,53].

Additionally, the presence of autoantibodies against type I interferons (IFNs), particularly IFN-α and IFN-ω, has been reported in a significant proportion of patients with life-threatening COVID-19. These autoantibodies impair antiviral responses by neutralizing IFN signaling, thereby allowing uncontrolled viral replication and increasing susceptibility to severe disease [50,52]. Importantly, such neutralizing anti-IFN autoantibodies have been identified even in patients without prior autoimmune conditions, highlighting their de novo induction during SARS-CoV-2 infection.

Complement dysregulation is another immunopathological mechanism exacerbated by autoantibodies. Autoantibodies targeting components such as C1q, C3, or factor H may impair complement clearance or induce excessive activation, contributing to endothelial injury, microvascular thrombosis, and disseminated intravascular coagulation [48,54]. These effects are particularly relevant in the context of COVID-19-associated coagulopathy and pulmonary intravascular inflammation, which are frequently observed in severe and fatal cases.

Moreover, autoantibodies targeting leukocyte proteins, including CD8 and CD4, have been reported in COVID-19 patients and may contribute to immune cell depletion or functional exhaustion, further compromising antiviral defenses [55]. This complex network of autoreactive antibodies not only aggravates acute disease but may also lay the foundation for chronic immune dysregulation in long-COVID.

Collectively, these findings underscore the central role of autoantibodies in modulating host immunity during SARS-CoV-2 infection. Their presence correlates with increased disease severity, dysfunctional antiviral responses, and immune-mediated tissue damage—positioning them as both markers and mediators of immune dysregulation in COVID-19.

2.4. Proteomic Profiling of SARS-CoV-2-Induced Autoantibodies

A recent study utilized a human proteome microarray encompassing 23,736 unique proteins to identify the targets of SARS-CoV-2-induced IgG autoantibodies in patients with moderate and severe COVID-19. The study found that these autoantibodies recognized a broad array of human proteins, including key immune modulators such as interferon alpha (IFN-α), tumor growth factor beta (TGF-β), interleukin 1 (IL-1), and chemokine CXCL16. Additionally, autoantibodies targeted proteins involved in immune cell signaling, such as CD34, CD47, and BCL2, as well as proteins expressed in various organs, including the brain, liver, lungs, and heart. Notably, the reactivity patterns varied between moderate and severe cases, suggesting that the extent and specificity of autoantibody production may correlate with disease severity and organ involvement [55].

Further investigations into the autoantibody profiles of COVID-19 patients have revealed that SARS-CoV-2 infection can induce a diverse array of autoantibodies targeting various human proteins. For instance, a study by Wang et al. utilized a SARS-CoV-2 proteome peptide microarray to analyze antibody interactions at the amino acid resolution, identifying specific epitopes within viral proteins that elicit strong immune responses [56]. The methodological approach described in this study can be applied to explore potential cross-reactivity between viral and human proteins. In our view, such cross-reactivity may underlie the development of autoantibodies in COVID-19 patients and warrants further investigation using these high-resolution epitope mapping tools.

2.5. Impact of COVID-19-Induced IgG on MAIT Cells and Immune Dysregulation

A recent study examined the effect of IgG antibodies obtained from patients with mild or severe COVID-19 on mucosal-associated invariant T (MAIT) cells, a specialized subset of T-cells that play a key role in the antiviral immune response. MAIT cells are particularly important in the defense against viral infections including SARS-CoV-2, and their depletion or dysfunction can exacerbate disease outcomes [57,58,59]. MAIT cells may also play a role in immunogenicity of vaccines against SARS-CoV-2 where these cells can be harnessed as cellular adjuvants [60].

The study found that IgG antibodies from patients with severe COVID-19 were capable of reducing the frequency of MAIT cells and impairing their ability to produce interferon-gamma (IFN-γ), a critical cytokine in antiviral immunity [61].

These findings suggest that the IgG repertoire induced during severe COVID-19 may directly contribute to immune dysregulation by hindering the antiviral activity of MAIT cells. This dysfunction could play a significant role in the pathogenesis of severe disease, where the immune response is often compromised, and the ability to mount an effective defense against the virus is impaired. In contrast, IgG from patients with mild disease had a less pronounced effect on MAIT cells, highlighting the potential correlation between the extent of immune dysregulation and disease severity. These results underscore the complexity of the immune response in COVID-19 and the potential role of autoantibodies in modulating immune cell function, particularly in the context of severe infection.

The observed reduction in MAIT cells and IFN-γ production may also have implications for long-COVID, as persistent immune dysregulation and a weakened antiviral response could contribute to the chronic symptoms observed in patients with prolonged disease [61]. These findings suggest that IgG antibodies in severe COVID-19 may not only interfere with immune function acutely but could also reprogram immune homeostasis in a way that perpetuates autoreactive phenotypes, potentially supporting long-term autoantibody production.

3. The Role of Autoantibodies in Modulating Disease Severity in COVID-19

3.1. Moderate COVID-19

In moderate cases of COVID-19, the immune system typically mounts an effective antiviral response that limits viral replication and mitigates the need for intensive respiratory support. Nonetheless, emerging data suggest that even in non-severe presentations, autoantibodies contribute to immunopathology and may prolong inflammation or predispose patients to later complications [62].

Several studies have identified aPLs, including lupus anticoagulant and anti-β2 glycoprotein I, in the serum of patients with moderate COVID-19. Although these patients generally do not experience catastrophic thrombotic events, the presence of aPLs has been associated with endothelial activation, increased D-dimer levels, and prolonged clotting times—markers of subclinical coagulopathy and vascular stress [45,63].

Additionally, anti-endothelial cell antibodies (AECAs) have been described in patients with mild to moderate disease, implicating humoral immune responses in the disruption of vascular homeostasis even in the absence of overt thrombosis [64]. These antibodies can enhance leukocyte adhesion, promote cytokine release, and increase vascular permeability, thereby contributing to the inflammatory milieu characteristic of COVID-19.

Furthermore, ANAs—typically associated with systemic autoimmune disorders—have also been reported in patients with moderate disease. While their titers are generally lower than in severe cases, the detection of ANAs may reflect a loss of peripheral immune tolerance triggered by infection-related cellular stress and apoptosis [65]. Their presence has been linked to prolonged symptoms and a higher likelihood of post-acute sequelae, suggesting that autoreactivity is not exclusive to critically ill individuals.

Altogether, these findings indicate that autoantibody production in moderate COVID-19 is not merely a feature of severe disease but may serve as a marker of persistent immune activation with potential clinical consequences. Monitoring for the presence and evolution of these antibodies may offer prognostic insights and guide follow-up care for individuals recovering from moderate illness.

3.2. Severe COVID-19

Severe cases of COVID-19 are characterized by extensive pulmonary injury, systemic inflammation, and multi-organ dysfunction, often requiring intensive care and mechanical ventilation. A hallmark of this disease severity is the presence of a hypercoagulable state, leading to thrombotic complications such as deep vein thrombosis, pulmonary embolism, and microvascular thrombosis [45,66].

Autoantibodies are significantly more prevalent and functionally impactful in severe COVID-19 compared to mild or moderate disease. Among the most well-characterized are aPLs, including lupus anticoagulant, anti-cardiolipin, and anti-β2 glycoprotein I antibodies. These autoantibodies have been strongly associated with thrombotic events, endothelial cell activation, and complement-mediated damage in critically ill patients [45,67].

Additionally, anti-platelet antibodies are detected in patients with severe disease, contributing to enhanced platelet activation and aggregation. This, in turn, promotes microvascular thrombosis and impairs perfusion of vital organs, particularly the lungs and heart [47]. These findings underscore the role of humoral autoimmunity in driving the thromboinflammatory state characteristic of severe COVID-19.

Another major contributor to poor outcomes in this population is the presence of autoantibodies against type I interferons (IFN-α, IFN-ω). These antibodies neutralize the antiviral effects of endogenous interferons, compromising the innate immune response and facilitating prolonged viral replication [49]. Up to 10–15% of patients with life-threatening COVID-19 have been found to carry these neutralizing anti-interferon antibodies, often without prior autoimmune disease history [68]. Their presence has also been linked to delayed viral clearance and increased risk of death.

Collectively, these data suggest that autoantibody-mediated immunopathology is a central component of severe COVID-19. By impairing antiviral immunity and promoting endothelial injury and thrombosis, these autoantibodies contribute to the escalation of inflammation, organ dysfunction, and ultimately, poor clinical outcomes.

3.3. The Cytokine Storm and Autoantibodies

The cytokine storm represents a critical immunopathological event in severe COVID-19, characterized by the excessive release of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). This hyper-inflammatory state contributes significantly to tissue injury, vascular permeability, and multi-organ failure, particularly affecting the lungs, heart, and kidneys [5].

Autoantibodies targeting cytokines and their receptors may amplify or dysregulate cytokine networks, further exacerbating the systemic inflammation observed in critically ill patients. In particular, autoantibodies against IL-6 and its receptor (IL-6R) have been identified in a subset of patients with severe disease, where they may paradoxically enhance IL-6 signaling by impairing its regulation or by stabilizing immune complexes that prolong cytokine activity [17].

Moreover, anti-TNF-α autoantibodies have been described in severe cases and may disturb the normal feedback mechanisms that limit inflammatory signaling, thus promoting sustained immune activation and endothelial damage [65]. These findings align with observations from autoimmune diseases, where similar autoantibodies are associated with uncontrolled inflammation and organ involvement.

In some patients, anti-IL-1 autoantibodies have also been detected, though their precise function remains less well defined. Depending on their neutralizing or non-neutralizing properties, these antibodies could either attenuate or exacerbate inflammation [69]. Collectively, these humoral immune perturbations contribute to the unrestrained cytokine release syndrome that underpins much of the severe pathology in COVID-19.

These observations reinforce the hypothesis that autoantibody-mediated modulation of cytokine activity is not merely a bystander effect, but a key contributor to the immunopathogenesis of severe and life-threatening COVID-19.

4. Long-COVID and Autoantibodies

4.1. Pathophysiology of Long-COVID

Long-COVID, also referred to as PASC, describes a constellation of persistent symptoms—such as fatigue, cognitive dysfunction (“brain fog”), dyspnea, myalgia, and chest discomfort—that last beyond four weeks after initial infection and may continue for several months. While the mechanisms underlying long-COVID remain incompletely understood, accumulating evidence implicates autoimmunity as a key driver of these prolonged symptoms [15,70,71,72].

Autoantibodies have been identified in patients suffering from long-COVID, targeting a diverse set of self-antigens, including thyroid peroxidase (TPO), endothelial cell antigens, G-protein-coupled receptors (GPCRs), and muscarinic acetylcholine receptors [70,73]. These antibodies can persist after the resolution of viral infection, maintaining a state of low-grade systemic inflammation and contributing to tissue-specific pathology.

For example, anti-GPCR autoantibodies have been associated with autonomic dysregulation and cardiovascular symptoms in long-COVID patients, consistent with findings in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [74,75,76]. Furthermore, persistent activation of autoreactive B-cells, possibly driven by disrupted germinal center responses during acute infection, has been proposed as a source of sustained autoantibody production [77]. These observations underscore the possibility that long-COVID represents, at least in part, a post-infectious autoimmune syndrome.

4.2. Autoantibodies as Predictive Biomarkers of Long-COVID

Given their persistent nature and potential role in symptom pathogenesis, autoantibodies may serve as early biomarkers to identify individuals at risk of developing long-COVID. In longitudinal cohort studies, individuals who developed long-COVID symptoms were more likely to possess autoantibodies targeting nuclear antigens, interferons, phospholipids, and tissue-specific markers at the time of acute infection [78,79].

In particular, anti-thyroid and anti-endothelial autoantibodies have been associated with fatigue, neurocognitive complaints, and microvascular dysfunction in post-COVID patients [80,81]. Detecting such biomarkers in the early phase of disease could facilitate stratification of patients for targeted follow-up or immunomodulatory therapies, such as low-dose corticosteroids or intravenous immunoglobulin (IVIG), depending on the severity and profile of autoreactivity.

Moreover, the development of autoantibody profiling platforms using high-throughput technologies—such as human proteome microarrays—may allow clinicians to screen patients systematically and identify individualized risk signatures for long-COVID [17,55]. The integration of such data into clinical decision-making pipelines could help mitigate the long-term burden of COVID-19 by informing personalized intervention strategies.

5. Therapeutic Implications

5.1. Targeting Autoantibodies in COVID-19 Treatment

Given the central role of autoantibodies in modulating immune dysfunction in COVID-19, various immunomodulatory therapies have been explored with promising outcomes. Plasmapheresis (therapeutic plasma exchange, TPE) has been employed to remove circulating autoantibodies, pro-inflammatory cytokines, and immune complexes. It has shown benefit in cases of severe or refractory COVID-19 with high levels of autoantibodies or autoimmune complications, including autoimmune encephalitis and vasculitis [82,83,84].

Intravenous immunoglobulin (IVIG) is another therapeutic modality with dual effects: it neutralizes pathogenic autoantibodies and exerts anti-inflammatory activity through Fc receptor blockade and cytokine modulation. In COVID-19, IVIG has demonstrated efficacy in reducing disease progression and improving outcomes, particularly in patients with immune-mediated complications [85,86,87].

Monoclonal antibody therapies have also been proposed to target B-cells including autoantibody-producing B-cells or modulate cytokine signaling pathways. These include rituximab, an anti-CD20 monoclonal antibody that depletes B-cells and is currently used in autoimmune diseases and being evaluated in selected COVID-19 cases [88].

5.2. Preventing Long-COVID Through Immune Modulation

The prevention and treatment of long-COVID, particularly in patients with evidence of persistent autoimmunity, is an area of active investigation. Immune modulation strategies targeting chronic inflammation and B-cell hyperactivity are under clinical evaluation. B-cell-depleting agents such as rituximab or belimumab could suppress sustained autoantibody production, especially in patients with elevated levels of ANA or anti-endothelial antibodies [89,90].

Cytokine inhibitors, such as tocilizumab (anti-IL-6R), anakinra (IL-1 receptor antagonist), and etanercept (anti-TNF-α), may prevent or reverse the cytokine-driven chronic inflammation seen in long-COVID. These therapies have already demonstrated safety and efficacy in systemic inflammatory diseases and may reduce symptom burden in patients with persistent fatigue, myalgia, or neuroinflammation [91,92,93].

5.3. Future Directions in Autoantibody-Targeted Therapy

Emerging strategies include the use of FcRn inhibitors, which lower IgG half-life by interfering with neonatal Fc receptor recycling. These agents have shown promise in autoimmune diseases such as myasthenia gravis and could be repurposed to mitigate COVID-19-related autoimmunity by reducing total IgG, including pathogenic autoantibodies [94,95].

Janus kinase (JAK) inhibitors—which suppress multiple cytokine pathways simultaneously—have been investigated in severe COVID-19 to mitigate the hyperinflammatory response. Baricitinib and ruxolitinib have demonstrated clinical benefit in reducing hospitalization time and mortality, and their potential role in long-COVID is being explored [96,97,98,99].

Additionally, therapeutic vaccines targeting autoantigen-specific B- or T-cells are being designed to re-establish immune tolerance in chronic autoimmune settings. While still in preclinical development, such approaches may eventually offer targeted and long-lasting resolution of COVID-19-induced autoimmunity [100].

6. Idiotypic Network Disruption and Immune Tolerance Breakdown in COVID-19

The idiotypic network model offers a compelling lens through which to interpret sustained autoreactivity in COVID-19. In this framework, antibodies against SARS-CoV-2 antigens may give rise to anti-idiotype antibodies that mirror structural or functional components of host proteins. These anti-idiotypes, by mimicking the ACE2 receptor or other self-molecules, may bind to native targets, inducing immunological damage and modulating receptor activity [101,102].

Harville and Arthur proposed a theoretical framework in which anti-idiotype antibodies generated in response to SARS-CoV-2 infection or vaccination may mimic host antigens such as ACE2 and contribute to immune dysregulation [101]. While this hypothesis is conceptually aligned with established idiotype network theory, it remains speculative, as direct structural or functional evidence of anti-idiotype antibodies targeting ACE2 is currently lacking. Separately, Arthur et al. reported the presence of anti-ACE2 antibodies in a subset of patients following SARS-CoV-2 infection, suggesting potential autoimmune activity, though the origin and specificity of these antibodies remain to be clarified [102]. Supporting the plausibility of idiotype involvement, Collins et al. observed that sequential mRNA vaccination could elicit anti-ACE2 antibodies in K18-hACE2 transgenic mice, but these findings do not definitively demonstrate an anti-idiotype origin [101].

Collectively, these observations highlight the need for comprehensive idiotype profiling in both natural infection and post-vaccination contexts. Future studies should aim to concurrently characterize anti-spike and anti-ACE2 antibodies and investigate whether their structural complementarity supports an idiotype-mediated mechanism. This disruption of the idiotypic network offers a plausible mechanism for sustained autoreactivity in the post-acute phase of COVID-19. Unlike transient inflammation-induced autoantibody production, anti-idiotype antibodies with host-mimetic properties may maintain a state of functional autoimmunity. Future research should investigate whether this mechanism contributes to the chronicity observed in long-COVID and how it intersects with known tolerance checkpoints. This perspective broadens the conceptual framework for understanding continuous autoantibody generation following viral infections.

7. Pathogenic Relevance of Autoantibody Targets by Subcellular Localization

Autoantibody-mediated diseases often reflect not only the identity of the antigen but its accessibility and localization. In COVID-19, the identification of autoantibody targets within nuclear, cytoplasmic, and membrane compartments suggests that widespread cell death and barrier disruption are key enabling events. In particular, the formation of neutrophil extracellular traps (NETs) during severe infection may release chromatin, histones, and cytoskeletal proteins—potent immunostimulatory structures that drive autoantibody formation [103].

Furthermore, post-translational modifications of intracellular proteins during oxidative stress or apoptosis can generate neoepitopes that are not recognized during immune tolerance development, making them potent triggers of autoreactivity [104]. In this light, the cytoplasmic targeting observed in severe COVID-19 may represent a convergence of cell death, inflammation, and antigenic reshaping.

Beyond immune cells, structural proteins in epithelial and endothelial cells—exposed during respiratory and vascular injury—may also become immunogenic. Proteome analyses have shown reactivity against tight junction proteins, mitochondrial enzymes, and adhesion molecules, which could account for vascular leakage and multi-organ damage [17].

8. Autoantibodies in Neurological Complications of COVID-19

The involvement of autoantibodies in neurological complications of COVID-19 is increasingly well documented. In acute cases, autoimmune encephalitis has been reported with autoantibodies targeting neuronal cell surface proteins such as NMDA and GABA-B receptors, mirroring patterns seen in parainfectious autoimmune syndromes. Post-mortem studies have detected IgG and complement deposition in perivascular spaces of the brain, implicating humoral immunity in microvascular injury [105].

In long-COVID, persistent symptoms such as cognitive dysfunction, sensory abnormalities, and dysautonomia may reflect ongoing low-level neuroinflammation driven by autoreactive antibodies. Autoantibodies against β-adrenergic and muscarinic receptors—previously implicated in chronic fatigue syndrome—have also been reported in long-COVID cohorts, suggesting overlap with post-viral syndromes of unclear etiology [106].

In addition, some patients with long-COVID exhibit abnormal cerebrospinal fluid profiles, including elevated oligoclonal bands and autoantibody indices, even in the absence of direct viral invasion. These findings support the use of antibody screening in neuro-COVID cases and raise the possibility that immunotherapy may benefit select patients with antibody-mediated neurological dysfunction [105].

9. Autoantibody Transfer During Pregnancy: Maternal–Fetal Considerations

SARS-CoV-2 infection during pregnancy introduces the possibility of not only maternal morbidity but also immune-mediated fetal exposure through transplacental IgG transfer. In most cases, this transfer is protective, providing passive immunity to neonates. However, the presence of pathogenic autoantibodies—such as anti-nuclear or anti-phospholipid antibodies—raises concern regarding potential adverse outcomes.

Emerging evidence suggests that maternal SARS-CoV-2 infection may alter placental immunobiology. Studies have identified placental deposition of immune complexes and upregulation of interferon-stimulated genes, which may contribute to growth restriction, preeclampsia-like syndromes, or increased risk of preterm birth [107].

While definitive data on long-term neurodevelopmental outcomes following maternal SARS-CoV-2 infection remain lacking, insights may be gained by comparison with other congenital viral infections. For instance, maternal Zika virus infection has been conclusively linked to congenital neurodevelopmental disorders, including microcephaly and cerebral malformations, as part of the congenital Zika syndrome [108]. Although the pathogenic mechanisms differ, this comparison underscores the importance of monitoring in utero viral exposure and its potential sequelae.

Though definitive data on neurodevelopmental outcomes following maternal COVID-19 are not yet available, longitudinal birth cohorts will be essential to assess whether transient maternal autoimmunity exerts any lasting influence on infant health.

10. Impact of Autoantibodies in COVID-19 Patients with Autoimmunity and Cancer

Cancer patients are at heightened risk of severe COVID-19 due to their compromised immune systems, which may result from both the cancer itself and the immunosuppressive treatments used in cancer therapy. This population is particularly vulnerable to the “cytokine storm” associated with severe COVID-19, which exacerbates inflammation and multi-organ failure. The presence of autoantibodies in these patients can further complicate disease progression, increasing the risk of both COVID-19 complications and cancer recurrence. These autoantibodies may contribute to ongoing inflammation and immune dysregulation, making cancer patients more susceptible to the severe effects of SARS-CoV-2 infection [109].

In addition to immune dysfunction, cancer treatments such as chemotherapy and immunotherapy can suppress immune function, further increasing the vulnerability of cancer patients to COVID-19 [110]. The interaction between COVID-19 and cancer could potentially lead to long-term effects, including an increased risk of cancer recurrence due to chronic low-grade inflammation and tissue damage seen in both COVID-19 and cancer progression [111]. Furthermore, SARS-CoV-2 infection could potentially contribute to the initiation of cancer in previously healthy individuals, raising concerns about the broader impact of the virus on cancer development [111].

Given these overlapping effects, therapeutic strategies that aim to modulate inflammation and autoantibody production in cancer patients with COVID-19 are urgently needed. Targeting inflammation through specialized pro-resolving mediators (SPMs) may provide a novel approach, as SPMs have been shown to reduce the cytokine storm and promote tissue homeostasis without the risks associated with immunosuppressive therapies [109].

11. COVID-19 in the Broader Context of Virus-Induced Autoimmunity

SARS-CoV-2 joins a growing list of viruses capable of disrupting immune tolerance, but its profile of polyclonal B-cell activation and multi-system inflammation may render it particularly potent. Unlike Epstein–Barr virus (EBV), which has strong links to lupus and multiple sclerosis [112], or hepatitis C virus, which predominantly induces cryoglobulinemic vasculitis [113], SARS-CoV-2 appears to break tolerance across a wider range of self-antigens.

Comparative proteomic studies show that COVID-19 patients develop antibodies against nuclear, cytoplasmic, mitochondrial, and membrane-associated proteins—far beyond the typical targets of most virus-associated autoimmune syndromes [17]. This broader autoreactivity may result from both the intensity of immune activation and the diversity of tissue injury seen in severe COVID-19.

These insights offer a new paradigm in viral immunology: that certain infections may not only trigger classical autoimmunity but induce transient, idiotype-driven, or compartment-specific autoreactivity. Understanding this broader continuum will be essential for designing post-viral surveillance strategies and for identifying biomarkers that distinguish transient from persistent autoreactive states. To provide a comprehensive summary,

Table 1. Summary of COVID-19-Associated Autoantibodies: Mechanisms, Clinical Associations, and Disease Severity.

Autoantibody Type	Target/Mechanism of Action	Clinical Manifestations	Prevalence by Disease Severity	Refs.
Antinuclear antibodies (ANA)	Target nuclear components (e.g., DNA, histones); reflect loss of immune tolerance	Vascular injury, hyperinflammation, and prolonged symptoms in moderate to severe cases	More common in severe cases	[43,44,65]
Anti-phospholipid antibodies (aPL)	Target β2-glycoprotein I and other phospholipid-binding proteins; prothrombotic	Thromboembolic events, subclinical coagulopathy	Moderate and severe cases	[45,46,63,67]
Anti-platelet antibodies	Bind platelet glycoproteins, promoting activation and aggregation	Thrombocytopenia, microvascular thrombosis	More common in severe cases	[47,48]
Anti-interferon (type I) antibodies	Neutralize IFN-α and IFN-ω, impairing antiviral defense	Poor viral control, prolonged infection, higher mortality	Up to 10–15% in severe cases	[49,50,51,52]
Anti-endothelial cell antibodies (AECAs)	Bind endothelial antigens; increase vascular permeability and leukocyte adhesion	Endothelial activation, vascular inflammation, and microvascular injury	Moderate and severe cases	[64,80,81]
Anti-cytokine antibodies (e.g., IL-6, IL-1, TNF-α)	Interfere with cytokine signaling; may stabilize or neutralize immune complexes	Exacerbation of cytokine storm, systemic inflammation, multi-organ failure	Primarily severe cases	[3,17,53,65,69]
Anti-GPCR and muscarinic receptor antibodies	Target G-protein-coupled and cholinergic receptors involved in autonomic regulation	Fatigue, dysautonomia, cardiovascular symptoms; overlap with chronic fatigue syndrome and long-COVID	Predominantly long-COVID	[70,73,74,75,76]
Anti-CD4/CD8 antibodies	Target T-cell surface markers, possibly leading to depletion or dysfunction	Lymphopenia, immune exhaustion, impaired antiviral immunity	Severe COVID-19	[55]
Anti-thyroid antibodies (e.g., anti-TPO)	Target thyroid peroxidase; associated with autoimmune thyroiditis	Fatigue, endocrine imbalance; potential contributor to long-COVID symptoms	Long-COVID	[70,80]
Anti-C1q, C3, and factor H antibodies	Target complement components; lead to overactivation or impaired clearance	Endothelial damage, complement-mediated microvascular thrombosis	Severe COVID-19	[48,54]

categorizes key autoantibody types reported in COVID-19 by their targets, mechanisms of action, associated clinical outcomes, and prevalence in mild, moderate, or severe disease [43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81]. This table serves as a visual aid to better understand the spectrum of humoral autoreactivity and its pathogenic relevance.

12. Future Directions: Integrating Autoantibody Profiling into COVID-19 Research and Clinical Practice

As the understanding of autoantibodies in COVID-19 continues to evolve, there is growing recognition that routine profiling of humoral autoreactivity could enhance both clinical management and immunological research. Large-scale serological studies and high-throughput proteome microarrays have already demonstrated the feasibility of mapping IgG autoantibody repertoires with cellular and subcellular resolution [17]. These technologies could be adapted to serve as diagnostic and prognostic tools across the COVID-19 disease spectrum.

One key challenge is distinguishing between transient, non-pathogenic autoreactivity and persistent, pathogenic autoantibody responses. Longitudinal cohort studies will be critical in defining time-dependent signatures of autoreactivity, especially in long-COVID. The use of paired serum and clinical metadata could help establish correlations between autoantibody persistence and neurological, cardiovascular, or pulmonary sequelae [71].

Additionally, integrating autoantibody panels into risk stratification models may enhance early identification of patients likely to progress to severe disease. For example, the presence of anti-interferon or anti-endothelial antibodies could serve as early markers of immune dysregulation, justifying pre-emptive immunomodulatory therapy [49].

From a therapeutic standpoint, there is increasing interest in personalized immunotherapy guided by autoantibody profiles. Plasmapheresis, IVIG, and B-cell–depleting agents such as rituximab have been used off-label in selected COVID-19 cases with severe immune dysregulation, but targeted trials are still lacking [82]. Rational selection of candidates based on their antibody repertoires could maximize efficacy and minimize unnecessary immunosuppression. Beyond biomarker development, understanding the contribution of idiotype–anti-idiotype interactions and persistent IgG-mediated immune modulation may be essential for identifying individuals with ongoing autoreactivity and for developing interventions aimed at re-establishing immune equilibrium.

Finally, the tools developed to study autoimmunity in COVID-19 may have broader implications for virology, vaccinology, and public health. The pandemic has provided a unique window into how viral infections reshape immune tolerance, and the lessons learned could inform preparedness for future outbreaks involving other pathogens capable of triggering autoimmunity.

13. Conclusions

Autoantibodies have emerged as pivotal immunological mediators in the pathogenesis of COVID-19, influencing the course of both acute and post-acute disease. Their production, driven by SARS-CoV-2-induced immune dysregulation, tissue damage, and potential disturbances in idiotype–anti-idiotype balance—reflects a profound loss of immunological self-tolerance. The resulting autoreactive IgG repertoire targets a diverse array of human proteins, including nuclear antigens, cytokines, interferons, neural components, endothelial markers, and signaling molecules, many of which are associated with disease severity, thromboinflammatory events, and long-term sequelae.

The subcellular localization of targeted antigens, particularly nuclear and cytoskeletal proteins, underscores the role of cell death and antigen exposure in the amplification of autoantibody responses. Furthermore, the detection of functional autoantibodies that interfere with type I interferon signaling, IL-6 activity, or vascular homeostasis provides a mechanistic explanation for many of the clinical features observed in severe COVID-19. In neurological and neuropsychiatric complications, growing evidence supports a role for brain-reactive autoantibodies, further expanding the clinical relevance of humoral autoreactivity.

Importantly, the immunological impact of SARS-CoV-2 extends into unique physiological contexts such as pregnancy, where the transplacental transfer of maternal autoantibodies may have implications for fetal development and neonatal immunity. Additionally, the observed parallels with other viral infections—such as EBV, HTLV-1, or HCV—reinforce the broader concept that infections can serve as potent triggers for autoreactivity in genetically or immunologically susceptible hosts.

Despite these advances, several critical questions remain. The durability of SARS-CoV-2-induced autoantibodies, their functional relevance in long-COVID, and the thresholds at which they become pathogenic rather than epiphenomenal are all areas that require further investigation. Equally, the interplay between pre-existing autoimmunity and COVID-19 outcomes, as well as the potential for vaccination to modulate autoantibody profiles, merits rigorous longitudinal study.

Clinically, the integration of autoantibody testing into COVID-19 management protocols may allow for earlier risk stratification, identification of patients predisposed to severe or prolonged illness, and tailored immunomodulatory therapies. Therapeutic strategies, including intravenous immunoglobulin (IVIG), anti-cytokine biologics, B-cell depletion, and plasmapheresis, are under active investigation and may offer benefit in selected cases.

Ultimately, the SARS-CoV-2 pandemic has exposed a complex and multi-faceted interface between viral infection and autoimmunity. As the global scientific community continues to elucidate these pathways, the insights gained will not only improve our response to COVID-19 and its complications but will also deepen our understanding of fundamental autoimmune mechanisms. Such knowledge holds the promise of transforming our approach to immune-mediated diseases in both infectious and non-infectious settings. An overview of Autoantibody-Mediated Mechanisms in COVID-19 Pathogenesis and Long-Term Sequelae are summarized in Figure 1.