Protective humoral memory forms in secondary lymphoid organs where B cells undergo affinity maturation and differentiation into memory or plasma cells. Here, we provide a comprehensive roadmap of human B cell maturation with single-cell transcriptomics matched with bulk and single-cell antibody repertoires to define gene expression, antibody repertoires, and clonal sharing of B cell states at single-cell resolution, including memory B cell heterogeneity that reflects diverse functional and signaling states. We reconstruct gene expression dynamics during B cell activation to reveal a pre–germinal center state primed to undergo class switch recombination and dissect how antibody class–dependent gene expression in germinal center and memory B cells is linked with a distinct transcriptional wiring with potential to influence their fate and function. Our analyses reveal the dynamic cellular states that shape human B cell–mediated immunity and highlight how antibody isotype may play a role during their antibody-based selection.
BackgroundChronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is characterized by eosinophilia, IgE production, and TH2 cytokine expression. Type 2 innate lymphoid cells from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33, although the relevance of this axis to local mucosal T-cell responses is unknown.ObjectiveWe sought to investigate the role of the IL-25/IL-33 axis in local mucosal T-cell responses in patients with CRSwNP.MethodsPolyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsy specimens and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T-cell surface phenotype/intracellular cytokines were assessed by means of flow cytometry. T-cell receptor variable β-chain analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis.ResultsIL-25 receptor (IL-17RB)–expressing TH2 effector cells were identified in nasal polyp tissue but not the healthy nasal mucosa or periphery. IL-17RB+CD4+ polyp–derived TH2 cells coexpressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB+CD4+ T cells, several identical T-cell receptor variable β-chain complementarity-determining region 3 sequences were identified in different subjects, suggesting clonal expansion driven by a common antigen. Abundant IL-17–producing T cells were observed in both healthy nasal mucosal and polyp populations, with TH17-related genes the most overexpressed compared with peripheral blood T cells.ConclusionIL-25 and IL-33 can interact locally with IL-17RB+ST2+ polyp T cells to augment TH2 responses in patients with CRSwNP. A local TH17 response might be important in healthy nasal mucosal immune homeostasis.
Background: Pregnancy-induced rhinitis (PIR) is often misclassified and under-diagnosed. There is currently no cure or optimum symptomatic treatment. Objective: To summarize current knowledge of PIR and assess evidence supporting treatment options. Type of review: Structured literature search. SEARCH STRATEGY AND EVALUATION METHOD: Review of English-language articles addressing evidence for aetiology, classification, differential diagnosis or treatment options for PIR. Comparisons to management of other types of rhinitis in pregnancy are also considered. Results: Incidence and prevalence of PIR vary widely between studies. Hormonal changes have a presumed aetiological role, although present evidence is scanty. Smoking appears to be the only agreed identifiable risk factor. Distinction between PIR and other types of rhinitis in pregnancy, especially allergic rhinitis, is important as effective treatments differ. Management of PIR focuses on minimal intervention required for symptom relief. Conclusions: Although PIR is temporary, its impact on patients` quality of life can be profound. Advice and conservative treatment provide the mainstay of clinical management. None of the currently available medical options offer an ideal solution. Any potential benefit gained should be balanced against risks to the foetus. Clarifying the definition of this separate category of rhinitis will lead to better recognition, with prompt and appropriate treatment.
SummaryBackground: Pregnancy-induced rhinitis (PIR) is often misclassified and under-diagnosed. There is currently no cure or optimum symptomatic treatment.Objective: To summarize current knowledge of PIR and assess evidence supporting treatment options.
Conclusions:Although PIR is temporary, its impact on patients' quality of life can be profound. Advice and conservative treatment provide the mainstay of clinical management. None of the currently available medical options offer an ideal solution. Any potential benefit gained should be balanced against risks to the foetus. Clarifying the definition of this separate category of rhinitis will lead to better recognition, with prompt and appropriate treatment.
15In response to antigen challenge, B cells clonally expand, undergo selection and differentiate to produce 16 mature B cell subsets and high affinity antibodies. However, the interplay between dynamic B cell states 17 and their antibody-based selection is challenging to decipher in primary human tissue. We have applied 18 an integrated analysis of bulk and single-cell antibody repertoires paired with single-cell transcriptomics 19 of human B cells undergoing affinity maturation. We define unique gene expression and antibody 20 repertoires of known and novel B cell states, including a pre-germinal centre state primed to undergo 21 class switch recombination. We dissect antibody class-dependent gene expression of germinal centre 22 and memory B cells to find that class switching prior to germinal centre entry dictates the capacity of B 23 cells to undergo antibody-based selection and differentiate. Together, our analyses provide 24 unprecedented resolution into the gene expression and selection dynamics that shape B cell-mediated 25 immunity. 26 27 121 122 157 sampling of IgH sequences from bulk repertoires to enhance genotype correction, identification of 158
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