Although the antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been extensively studied in blood, relatively little is known about the antibody response in saliva and its relationship to systemic antibody levels. Here, we profiled by enzyme-linked immunosorbent assays (ELISAs) immunoglobulin G (IgG), IgA, and IgM responses to the SARS-CoV-2 spike protein (full-length trimer) and its receptor binding domain (RBD) in serum and saliva of acute and convalescent patients with laboratory-diagnosed coronavirus disease 2019 (COVID-19) ranging from 3 to 115 days postsymptom onset (PSO), compared with negative controls. Anti–SARS-CoV-2 antibody responses were readily detected in serum and saliva, with peak IgG levels attained by 16 to 30 days PSO. Longitudinal analysis revealed that anti–SARS-CoV-2 IgA and IgM antibodies rapidly decayed, whereas IgG antibodies remained relatively stable up to 105 days PSO in both biofluids. Last, IgG, IgM, and, to a lesser extent, IgA responses to spike and RBD in the serum positively correlated with matched saliva samples. This study confirms that serum and saliva IgG antibodies to SARS-CoV-2 are maintained in most of the patients with COVID-19 for at least 3 months PSO. IgG responses in saliva may serve as a surrogate measure of systemic immunity to SARS-CoV-2 based on their correlation with serum IgG responses.

While the antibody response to SARS-CoV-2 has been extensively studied in blood, relatively little is known about the mucosal immune response and its relationship to systemic antibody levels. Since SARS-CoV-2 initially replicates in the upper airway, the antibody response in the oral cavity is likely an important parameter that influences the course of infection. We developed enzyme linked immunosorbent assays to detect IgA and IgG antibodies to the SARS-CoV-2 spike protein (full length trimer) and its receptor binding domain (RBD) in serum (n=496) and saliva (n=90) of acute and convalescent patients with laboratory-diagnosed COVID-19 ranging from 3-115 days post-symptom onset (PSO), compared to negative controls. Anti-CoV-2 antibody responses were readily detected in serum and saliva, with peak IgG levels attained by 16-30 days PSO. Whereas anti-CoV-2 IgA antibodies rapidly decayed, IgG antibodies remained relatively stable up to 115 days PSO in both biofluids. Importantly, IgG responses in saliva and serum were correlated, suggesting that antibodies in the saliva may serve as a surrogate measure of systemic immunity.

In the past 15 years, B cells have been rediscovered to be not merely bystanders but rather active participants in autoimmune aetiology. This has been fuelled in part by the clinical success of B cell depletion therapies (BCDTs). Originally conceived as a method of eliminating cancerous B cells, BCDTs such as those targeting CD20, CD19 and BAFF are now used to treat autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis. The use of BCDTs in autoimmune disease has led to some surprises. For example, although antibody-secreting plasma cells are thought to have a negative pathogenic role in autoimmune disease, BCDT, even when it controls the disease, has limited impact on these cells and on antibody levels. In this Review, we update our understanding of B cell biology, review the results of clinical trials using BCDT in autoimmune indications, discuss hypotheses for the mechanism of action of BCDT and speculate on evolving strategies for targeting B cells beyond depletion.

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA+ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota–specific IgA+ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.

The remarkable success of anti‐CD20 B cell depletion therapies in reducing the burden of multiple sclerosis (MS) disease has prompted significant interest in how B cells contribute to neuroinflammation. Most focus has been on identifying pathogenic CD20+ B cells. However, an increasing number of studies have also identified regulatory functions of B lineage cells, particularly the production of IL‐10, as being associated with disease remission in anti‐CD20–treated MS patients. Moreover, IL‐10–producing B cells have been linked to the attenuation of inflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. In addition to IL‐10–producing B cells, antibody‐producing plasma cells (PCs) have also been implicated in suppressing neuroinflammation. This review will examine regulatory roles for B cells and PCs in MS and EAE. In addition, we speculate on the involvement of regulatory PCs and the cytokine BAFF in the context of anti‐CD20 treatment. Lastly, we explore how the microbiota could influence anti‐inflammatory B cell behavior. A better understanding of the contributions of different B cell subsets to the regulation of neuroinflammation, and factors that impact the development, maintenance, and migration of such subsets, will be important for rationalizing next‐generation B cell–directed therapies for the treatment of MS.