Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the pandemic human respiratory illness COVID-19, is a global health emergency. While severe acute disease has been linked to an expansion of antibody-secreting plasmablasts, we sought to identify B cell responses that correlated with positive clinical outcomes in convalescent patients. We characterized the peripheral blood B cell immunophenotype and plasma antibody responses in 40 recovered non-hospitalized COVID-19 subjects that were enrolled as donors in a convalescent plasma treatment study. We observed a significant negative correlation between the frequency of peripheral blood memory B cells and the duration of symptoms for convalescent subjects. Memory B cell subsets in convalescent subjects were composed of classical CD24+ class-switched memory B cells, but also activated CD24-negative and natural unswitched CD27+ IgD+ IgM+ subsets. Memory B cell frequency was significantly correlated with both IgG1 and IgM responses to the SARS-CoV-2 spike protein receptor binding domain (RBD) in most seropositive subjects. IgM+ memory, but not switched memory, directly correlated with virus-specific antibody responses, and remained stable over 3 months. Our findings suggest that the frequency of memory B cells is a critical indicator of disease resolution, and that IgM+ memory B cells may play an important role in SARS-CoV-2 immunity.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the pandemic human respiratory illness COVID-19, is a global health emergency. While severe acute disease has been linked to an expansion of antibody-secreting plasmablasts, we sought to identify B cell responses that correlated with positive clinical outcomes in convalescent patients. We characterized the peripheral blood B cell immunophenotype and plasma antibody responses in 40 recovered non-hospitalized COVID-19 subjects that were enrolled as donors in a convalescent plasma treatment study. We observed a significant negative correlation between the frequency of peripheral blood memory B cells and the duration of symptoms for convalescent subjects. Memory B cell subsets in convalescent subjects were composed of classical CD24+ class-switched memory B cells, but also activated CD24-negative and natural unswitched CD27+ IgD+ IgM+ subsets. Memory B cell frequency was significantly correlated with both IgG1 and IgM responses to the SARS-CoV-2 spike protein receptor binding domain (RBD). IgM+ memory, but not switched memory, directly correlated with virus-specific antibody responses, and remained stable over time. Our findings suggest that the frequency of memory B cells is a critical indicator of disease resolution, and that IgM+ memory B cells play an important role in SARS-CoV-2 immunity.
CD11c+T-bet+ B cells are recognized as an important component of humoral immunity and autoimmunity. These cells can be distinguished from other B cells by their higher expression of the adenosine receptor 2a. Here we address whether A2A receptor activation can affect CD11c+T-bet+ B cells. We show that administration of the A2A receptor agonist CGS-21680 depletes established CD11c+T-bet+ B cells in ehrlichial-infected mice, in a B cell-intrinsic manner. Agonist treatment similarly depletes CD11c+T-bet+ B cells and CD138+ B cells and reduces anti-nuclear antibodies in lupus-prone mice. Agonist treatment is also associated with reduced kidney pathology and lymphadenopathy. Moreover, A2A receptor stimulation depletes pathogenic lymphocytes and ameliorates disease even after disease onset, highlighting the therapeutic potential of this treatment. This study suggests that targeting the adenosine signaling pathway may provide a method for the treatment of lupus and other autoimmune diseases mediated by T-bet+ B cells.
The MSOE SMART (Students Modeling A Research Topic) Team Program establishes partnerships between students and research mentors and enables teams to explore the nature of select proteins. The Waddell SMART Team researched and designed physical models using 3D printing technology of two proteins involved in cell division regulation, the Epidermal Growth Factor Receptor (EGFR), and Ras. EGFR, a tyrosine kinase receptor, has an extracellular ligand binding domain that leads to activation of the intracellular kinase signaling pathway. Once activated, EGFR phosphorylates a GRB2/SOS complex that binds to Ras, a regulatory transduction trans‐membrane protein. Ras has a phosphate binding loop that binds to GTP, providing energy for the reaction. Once activated, Ras undergoes a conformational change and signals cell division. Cancer results from uncontrolled cell growth. In some forms of breast cancer, EGFR is overexpressed, leading to tumor formation. A new drug, Lapatinib, may inhibit this excessive cell proliferation by blocking the ATP binding domain of the tyrosine kinase. In many types of cancer, Ras has been mutated, preventing hydrolysis of GTP, and the transduction pathway remains active, signaling for continued cell division, which may lead to tumor formation. Understanding the structure and function of these proteins may lead to further drug development. Supported by a grant from NIH‐NCRR‐SEPA.
T-bet+ B cells have emerged as a major B cell subset associated with both protective immunity and immunopathogenesis. T-bet is a transcription factor associated with the type I adaptive immune response to intracellular pathogens, driving an effector program characterized by the production of IFN-γ. Murine infection with the intracellular bacterium, Ehrlichia muris, generates protective extrafollicular T cell–independent T-bet+ IgM-secreting plasmablasts, as well as T-bet+ IgM memory cells. Although T-bet is a signature transcription factor for this subset, it is dispensable for splenic CD11c+ memory B cell development, but not for class switching to IgG2c. In addition to the T-bet+ plasmablasts found in the spleen, we show that Ab-secreting cells can also be found within the mouse peritoneal cavity; these cells, as well as their CD138− counterparts, also expressed T-bet. A large fraction of the T-bet+ peritoneal B cells detected during early infection were highly proliferative and expressed CXCR3 and CD11b, but, unlike in the spleen, they did not express CD11c. T-bet+ CD11b+ memory B cells were the dominant B cell population in the peritoneal cavity at 30 d postinfection, and although they expressed high levels of T-bet, they did not require B cell–intrinsic T-bet expression for their generation. Our data uncover a niche for T-bet+ B cells within the peritoneal cavity during intracellular bacterial infection, and they identify this site as a reservoir for T-bet+ B cell memory.
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