Background/Objectives: COVID-19 has been associated with a wide range of immune responses, including the production of autoantibodies, particularly in severe cases. This study investigates the IgG autoantibody responses in patients with varying severities of COVID-19 infection and compares these responses with vaccinated individuals. Methods: We utilized proteomic profiling to analyze autoantibody reactivity against a broad spectrum of proteins expressed in lymphoid and myeloid cell subsets in serum samples from severe and moderate COVID-19 patients, as well as vaccinated individuals who received the inactivated CoronaVac (Sinovac) vaccine. Results: Our findings indicate a marked increase in the diversity and number of IgG autoantibodies targeting intracellular and membrane-associated proteins in severe COVID-19 cases, compared to those with moderate cases of the disease. The autoantibody response in severe cases was found to primarily target proteins involved in immune cell activation, signaling, and differentiation, suggesting potential pathways of immune dysregulation and autoimmunity. In contrast, vaccinated individuals did not exhibit similar autoantibody reactivity, pointing to a more controlled immune response post-vaccination. Notably, no significant autoimmune responses were detected in the vaccinated cohort, suggesting that the inactivated vaccine does not induce autoreactive IgG. These findings align with the established safety profile of COVID-19 vaccines, especially in comparison to the heightened immune dysregulation observed in severe COVID-19 patients. The absence of a significant autoantibody response in vaccinated individuals supports the notion that vaccines, while inducing robust immune activation, do not typically trigger autoimmunity in healthy individuals. Conclusions: Our study underscores the importance of distinguishing between the immune responses triggered by infection and vaccination and highlights the need for the continued monitoring of autoimmune responses in severe COVID-19 cases. Future research should focus on the long-term persistence and clinical relevance of these autoantibodies, particularly in individuals with pre-existing autoimmune conditions or genetic predispositions.

Santander L, et al. Clin Exp Vaccine Res. 2024 Jan;13(1):1-9. https://doi.org/10.7774/cevr.2024.13.1.1

Human T-lymphotropic virus type 1 (HTLV-1) infection is associated with a spectrum of clinical outcomes, ranging from lifelong asymptomatic carriage to severe conditions such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Although antibody responses are known to shape immune regulation, the functional relevance of IgG idiotype repertoires in HTLV-1 pathogenesis remains poorly understood. This study investigated the immunomodulatory effects of IgG from individuals with distinct HTLV-1 clinical outcomes. IgG was purified from pooled serum samples of asymptomatic carriers (ACs), HAM/TSP, and ATLL patients and used to stimulate peripheral blood mononuclear cells (PBMCs) from healthy donors. Cytokine production in CD4⁺, CD8⁺, and γδ T cells was assessed by flow cytometry. Additionally, proteome-wide IgG reactivity was evaluated using a human protein microarray encompassing over 21,000 proteins, and bioinformatic analyses were conducted to identify protein–protein interaction networks and tissue-specific autoreactivity. HAM/TSP-derived IgG selectively enhanced IFN-γ production in all T-cell subsets and suppressed IL-4 in CD4⁺ T cells. ATLL-derived IgG induced IL-9 and IL-13 production in CD4⁺ T cells, and both HAM/TSP and ATLL IgG elevated IL-13 levels in CD8⁺ T cells. Microarray data revealed distinct autoreactive IgG profiles across clinical groups, targeting immune-related proteins, apoptotic regulators, and proteins expressed in T cells, monocytes, and non-immune tissues such as brain and testis. Notably, no functional or structural clustering was observed in protein–protein interaction networks, suggesting these reactivities reflect complex, idiotype-specific immune alterations rather than compensatory responses. The present findings suggest that HTLV-1 infection may be associated with the development of distinct IgG repertoires that potentially modulate cytokine responses and exhibit broad reactivity toward human proteins. Such patterns could contribute to immune dysregulation and may partially explain the divergent clinical trajectories observed in HAM/TSP and ATLL. Further investigations are warranted to validate these observations at the individual level and to clarify their mechanistic relevance in disease progression.

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.

Immunoglobulin G (IgG) is a central component of humoral immunity in coronavirus disease 2019 (COVID-19); however, increasing evidence suggests that infection-induced IgG repertoires exert immunomodulatory effects beyond classical antiviral functions. In this study, we investigated whether IgG from patients with moderate or severe COVID-19 directly modulates human peripheral γδ T cells and whether these effects are associated with disease severity-dependent IgG idiotype profiles. Purified IgG from non-exposed healthy controls, moderate COVID-19 patients, or severe COVID-19 patients was incubat-ed with peripheral blood mononuclear cells from healthy donors. γδ T cell phenotype, subset distribution, homing markers, and cytokine production were assessed by flow cytometry, while direct IgG–cell interactions were evaluated using fluorescent IgG binding assays. In parallel, proteomic profiling using human proteome microarrays was performed to identify γδ T cell-expressed protein targets recognized by COVID-19-induced IgG. IgG from SARS-CoV-2-infected individuals selectively reduced Vγ9⁺Vδ2⁺ γδ T cells, altered memory differentiation, downregulated CCR5, CCR6, and CD161 expression, and reshaped cytokine production in a severity-dependent manner. COVID-19 IgG bound directly to the γδ T cell membrane without inducing apoptosis, indicating a non-cytotoxic mechanism of modulation. Proteomic analysis revealed a marked expansion and diversification of γδ T cell-associated IgG targets in COVID-19, particularly in severe disease, with enrichment of pathways related to immune signaling and inflammation. Collectively, these findings identify γδ T cells as direct functional targets of SARS-CoV-2-induced IgG repertoires and demonstrate that disease severity shapes IgG idiotype networks with distinct immunomodulatory capacities. This work highlights a previously underappreciated antibody-mediated mechanism contributing to immune dysregulation in COVID-19.