Peripheral sensory neurons widely innervate various tissues to continuously monitor and respond to environmental stimuli. Whether peripheral sensory neurons innervate the spleen and modulate splenic immune response remains poorly defined. Here, we demonstrate that nociceptive sensory nerve fibers extensively innervate the spleen along blood vessels and reach B cell zones. The spleen-innervating nociceptors predominantly originate from left T8-T13 dorsal root ganglia (DRGs), promoting the splenic germinal center (GC) response and humoral immunity. Nociceptors can be activated by antigen-induced accumulation of splenic prostaglandin E2 (PGE2) and then release calcitonin gene-related peptide (CGRP), which further promotes the splenic GC response at the early stage. Mechanistically, CGRP directly acts on B cells through its receptor CALCRL-RAMP1 via the cyclic AMP (cAMP) signaling pathway. Activating nociceptors by ingesting capsaicin enhances the splenic GC response and anti-influenza immunity. Collectively, our study establishes a specific DRG-spleen sensory neural connection that promotes humoral immunity, suggesting a promising approach for improving host defense by targeting the nociceptive nervous system.

Acute viral infections are characterized by rapid increases in viral load, leading to cellular damage and the resulting induction of complex innate and adaptive antiviral immune responses that cause local and systemic inflammation. Successful antiviral immunity requires the activation of many immune cells, including T cells, natural killer cells, and macrophages. B cells play a unique part through their production of antibodies that can both neutralize and clear viral particles before virus entry into a cell. Protective antibodies are produced even before the first exposure of a pathogen, through the regulated secretion of so-called natural antibodies that are generated even in the complete absence of prior microbial exposure. An early wave of rapidly secreted antibodies from extrafollicular (EF) responses draws on the preexisting naive or memory repertoire of B cells to induce a strong protective response that in kinetics tightly follows the clearance of acute infections, such as with influenza virus. Finally, the generation of germinal centers (GCs) provides long-term protection through production of long-lived plasma cells and memory B cells, which shape and broaden the B cell repertoire for more effective responses following repeat exposures. In this study, we review B cell responses to acute viral infections, primarily influenza virus, from the earliest nonspecific B-1 cell to early, antigen-specific EF responses and finally to GC responses. Throughout, we address known factors that lead to distinct B cell response outcomes and discuss how their functions effect viral clearance, highlighting the critical contributions of each response type to the induction of highly protective antiviral humoral immunity.

The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy.
We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC).
We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID.
We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG+ B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria.
Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.