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Clonal landscape of autoantibody-secreting plasmablasts in COVID-19 patients

ABSTRACT: Although severe COVID-19 is often associated with elevated autoantibody titers, the underlying mechanism has been unclear. Here, we investigated repertoires and reactivities of immunoglobulins derived from blood plasmablasts (PBs) in COVID-19 patients. This uncovered robust clonal expansion of PBs secreting cardiolipin (CL)-reactive autoantibodies in humoral response to SARS-CoV-2. About half of the expanded CL-reactive clones were also reactive to SARS-CoV-2 antigens and derived from SARS-CoV-2-specific primary responses as well as seasonal coronavirus-reactive memory responses. One such clone, CoV1804, was reactive to both CL and viral nucleocapsid (N), and exhibited anti-nucleolar activity in human cells. Repertoire analysis identified antibodies sharing genetic features with CoV1804 in COVID-19 patient-derived immunoglobulins from our and other cohorts, thereby constituting a novel public antibody. These public autoantibodies had numerous mutations that enhanced anti-N reactivity. On the other hand, anti-CL reactivity fluctuated through somatic hypermutation, which instead resulted in the acquisition of additional self-reactivities, including anti-nucleolar activity in the progeny. Thus, potentially CL-reactive precursors may have developed multiple reactivities to different self-antigens through clonal expansion driven by viral antigens. Our results unraveled a unique process of autoantibody production during COVID-19 and provide novel insights into the origin of virus-induced autoantibodies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233522 | GEO | 2024/09/11

REPOSITORIES: GEO

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Project description:In the last two years, the coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a scientific and social challenge worldwide. Vaccines have been the most effective intervention for reducing virus transmission and disease severity. However, virus genetic variants are still circulating among vaccinated individuals with different symptomatology disease cases. Understanding the protective or disease associated mechanisms in vaccinated individuals is relevant to advance in vaccine development and implementation. To address this objective, serum protein profiles were characterized by quantitative proteomics and data analysis algorithms in four cohorts of vaccinated individuals uninfected and SARS-CoV-2 infected with asymptomatic, nonsevere and severe disease symptomatology. The results showed that immunoglobulins were the most overrepresented proteins in infected cohorts when compared to PCR-negative individuals. The immunoglobulin profile varied between different infected cohorts and correlated with protective or disease associated capacity. Overrepresented immunoglobulins in PCR-positive individuals correlated with protective response against SARS-CoV-2, other viruses, and thrombosis in asymptomatic cases. In nonsevere cases, correlates of protection against SARS-CoV-2 and HBV together with risk of myasthenia gravis and allergy and autoantibodies were observed. Patients with severe symptoms presented risk for allergy, chronic idiopathic thrombocytopenic purpura, and autoantibodies. The analysis of underrepresented immunoglobulins in PCR-positive compared to PCR-negative individuals identified vaccine-induced protective epitopes in various coronavirus proteins including the Spike receptor-binding domain RBD. Non-immunoglobulin proteins were associated with COVID-19 symptoms and biological processes. These results evidence host-associated differences in response to vaccination and the possibility of improving vaccine efficacy against SARS-CoV-2.

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Clonal landscape of autoantibody-secreting plasmablasts in COVID-19 patients

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