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Recent evidence indicates that immune cells are crucial in modulating the pathogenesis of postherpetic neuralgia (PHN), with significant associations identified between immune responses and the development of PHN. However, the specific dynamic immune profile, the underlying molecular mechanisms, and especially the causal relationship between immune cells and PHN have yet to be comprehensively elucidated. We implemented a comprehensive analytical framework incorporating two-sample Mendelian randomization (MR), multivariable Mendelian randomization(MVMR), and colocalization analyses to elucidate the causal relationships between immune cell phenotypes and PHN. Utilizing publicly available genetic datasets, we explored potential causal associations between 731 immune cell phenotypes and susceptibility to PHN. Comprehensive sensitivity analyses were performed to assess the robustness of the findings, evaluate heterogeneity, and investigate horizontal pleiotropy.The Steiger directionality test was utilized to address and reduce the likelihood of reverse causation. After applying the Bonferroni-adjusted, eight immune cell phenotypes exhibited significant causal associations with PHN. Further MVMR analysis revealed a significant positive causal relationship between CD27 on IgD- CD38dim B cell and the risk of PHN, with an odds ratio (OR) of 1.228 (95% confidence interval [CI]: 1.059-1.566, P = 0.011). Colocalization analysis offered limited evidence supporting a shared genetic architecture. Our findings present compelling genetic evidence that identifies CD27 on IgD- CD38dim B cell as a potential therapeutic target for the prevention and treatment of PHN. This study reinforces the mechanistic connection between immune cell function and the pathogenesis of PHN, highlighting the necessity for further exploration in this area. These insights provide significant guidance for future clinical research and the development of therapeutic strategies.

Double negative (DN) B cells, defined as CD27-IgD- B cells, are increased in older healthy individuals as well as in patients with certain diseases. However, the relationship between DN B cells and Sjögren’s disease (SjD) in newly diagnosed patients remains unclear. Seventy SjD patients and thirty-six healthy controls (HCs) were recruited in this study. Peripheral blood B cell subsets were analyzed using flow cytometry. The percentage and absolute count of DN B cells were significantly lower in SjD patients compared to HCs ( p = 0.000 and p = 0.007, respectively). Patients with medium to high disease activity, defined by an EULAR Sjögren Syndrome Disease Activity Index (ESSDAI) score ≥ 5, exhibited lower DN B cell levels compared to those with low disease activity (ESSDAI score < 5, p = 0.029 and p = 0.000, respectively). Moreover, lower DN B cell percentages were associated with glandular involvement ( p = 0.039) and neutropenia ( p = 0.034). Regression analysis revealed a negative correlation between DN B cells and SjD disease activity (B=-0.240, 95% CI:-0.468 to -0.013, p = 0.039). Additionally, DN B cells showed weak negative correlation with the percentage of total B cells ( r =-0.266, p = 0.026). This study demonstrates that DN B cells are decreased in SjD, particularly in patients with glandular involvement and high disease activity. Moreover, the inverse correlation between DN B cells and total B cells suggested that DN B cells may play a role in the pathogenesis of SjD.

Natural antibodies, particularly natural IgM, are proved to play indispensable roles in the immune defenses against common infections. More recently, the protective roles of these natural IgM were also recognized in autoimmune diseases. They are mainly produced by B-1 and innate-like B cells (ILBs). Human CD19 CD27 IgD B cells, also termed as un-switched memory B cells, were proposed to be a kind of ILBs. However, functional features and characteristics of these cells in rheumatoid arthritis (RA) remained poorly understood. In this study, we found that human CD27 IgD B cells could produce natural antibody-like IgM. Under RA circumstance, the frequencies of these cells were significantly decreased. Moreover, the IgM-producing capacities of these cells were also dampened. Interestingly, the BCR repertoire of these cells was altered in RA, demonstrating decreased diversity with preferential usage alteration from VH3-23D to VH1-8. Single cell sequencing further revealed the proinflammatory biased features of these cells in RA. These CD27 IgD B cells were negatively correlated with RA patient disease activities and clinical manifestations. After effective therapy with disease remission in RA, these cells could be recovered. Taken together, these results have revealed that CD27 IgD B cells were impaired in RA with dysfunctional features, which might contribute to the disease perpetuation.

Glaucoma is a group of retinal neurodegenerative diseases causing irreversible visual impairment. The pathogenesis of this disease is complicated. Studies have shown that the immune system is involved in the neurodegenerative process of glaucoma. There are continuous evidences that autoantibodies play a crucial role in the pathogenesis of glaucoma. However, focuses on B cells, the antibody-producing cells in glaucoma are surprisingly limited. Fresh peripheral blood samples were collected from 44 glaucoma patients (38 with primary angle-closure glaucoma (PACG) and 6 with (primary open-angle glaucoma POAG)) and 36 age-matched healthy donors (HD). Density gradient centrifugation was performed to obtain peripheral blood mononuclear cells (PBMC). Flow cytometry was performed to determine B cell phenotypes. The severity of glaucoma was determined based on the mean deviation (MD) of visual field. In this study, we demonstrated that total B cells was significantly increased in glaucoma patients compared to HD. Next, we checked changes of different B cell subsets in glaucoma. Glaucoma patients were found to have a significant increase in the frequencies of antibody-secreting cells (ASC)/plasmablasts, naïve, and CD19 CD27 IgD double negative (DN) subpopulations, but a decrease in the CD27 IgD unswitched memory compartment. Notably, we found that the increment of CD27 IgD DN B cells was significantly magnified according to the clinical severity. We demonstrate, for the first time, that peripheral B cell subsets are altered and unveil the correlation of a newly identified pro-inflammatory CD27 IgD DN subset with clinical features of glaucoma, suggesting that these B cell subsets could serve as potential biomarkers to monitor the disease progression of glaucoma patients.

A hallmark of T cell dependent (TD) humoral immune responses is the generation of long–lived memory B cells. The generation of these cells occurs primarily in the germinal center (GC) reaction, where antigen–activated B cells undergo affinity maturation as a major consequence of the combined processes of proliferation, somatic hypermutation of their immunoglobulin V (IgV) region genes, and selection for improved affinity of their B–cell antigen receptors. As many B cells also undergo class–switching to IgG or IgA in these TD responses, there was traditionally a focus on class–switched memory B cells in both murine and human studies on memory B cells. However, it has become clear that there is also a large subset of IgM–expressing memory B cells, which have important phenotypic and functional similarities but also differences to class–switched memory B cells. There is an ongoing discussion about the origin of distinct subsets of human IgM + B cells with somatically mutated IgV genes. We argue here that the vast majority of human IgM–expressing B cells with somatically mutated IgV genes in adults is indeed derived from GC reactions, even though a generation of some mostly lowly mutated IgM + B cells from other differentiation pathways, mainly in early life, may exist.

BackgroundActivated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD . The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM.ObjectiveTo explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS.MethodsClinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27-IgD- double-negative B (DNB) cells.ResultsThe patients had increased B cell sizes and higher proportions of IgM+ DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient’s DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes.ConclusionsThe present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels.

The diversity of B cell subsets and their contribution to vaccine-induced immunity in humans are not well elucidated but hold important implications for rational vaccine design. Prior studies demonstrate that B cell subsets distinguished by immunoglobulin (Ig) isotype expression exhibit divergent activation-induced fates. Here, the antigen-specific B cell response to tetanus toxoid (TTd) booster vaccination was examined in healthy adults, using a dual-TTd tetramer staining flow cytometry protocol. Unsupervised analyses of the data revealed that prior to vaccination, IgM-expressing CD27 + B cells accounted for the majority of TTd-binding B cells. 7 days following vaccination, there was an acute expansion of TTd-binding plasmablasts (PB) predominantly expressing IgG, and a minority expressing IgA or IgM. Frequencies of all PB subsets returned to baseline at days 14 and 21. TTd-binding IgG + and IgA + memory B cells (MBC) exhibited a steady and delayed maximal expansion compared to PB, peaking in frequencies at day 14. In contrast, the number of TTd-binding IgM + IgD + CD27 + B cells and IgM-only CD27 + B cells remain unchanged following vaccination. To examine TTd-binding capacity of IgG + MBC and IgM + IgD + CD27 + B cells, surface TTd-tetramer was normalised to expression of the B cell receptor-associated CD79b subunit. CD79b-normalised TTd binding increased in IgG + MBC, but remained unchanged in IgM + IgD + CD27 + B cells, and correlated with the functional affinity index of plasma TTd-specific IgG antibodies, following vaccination. Finally, frequencies of activated (PD-1 + ICOS + ) circulating follicular helper T cells (cT FH ), particularly of the CXCR3 - CCR6 - cT FH 2 cell phenotype, at their peak expansion, strongly predicted antigen-binding capacity of IgG + MBC. These data highlight the phenotypic and functional diversity of the B cell memory compartment, in their temporal kinetics, antigen-binding capacities and association with cT FH cells, and are important parameters for consideration in assessing vaccine-induced immune responses.

Common variable immunodeficiency (CVID) is the most frequent form of primary hypogammaglobulinemia in adults. In addition to recurrent infections and respiratory manifestations, CVID patients may present several non-infection complications such as autoimmune diseases. The mechanisms that lead to immune dysregulation in CVID are not completely understood. Given the role of IgD on naïve B cells in the maintenance of tolerance and secreted IgD in the respiratory mucosa, we evaluated the frequency of IgD+ naïve and IgD+ memory B cells in CVID patients. Here, no differences were observed in the percentages and proliferative responses of anergic IgD+IgM−CD27− B cells between CVID patients, with or without autoimmune disease, and the control group. Interestingly, in the compartment of memory B cells, the percentage of IgD+IgM− cells was higher only in CVID patients with allergic rhinitis/allergic asthma. Our results may indicate that anergic IgD+IgM−CD27− B cells may not be compromised in our CVID cohort. However, IgD+IgM− memory B cells may play a role in the immunopathogenesis of allergic rhinitis/allergic asthma in CVID patients. Further studies are needed to better understand the participation of IgD+IgM− memory B cells in the immunopathogenesis of allergic rhinitis/allergic asthma in CVID patients.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by a greatly increased susceptibility to severe fungal and bacterial infections caused by defects in NADPH oxidase of phagocytic cells. We aimed to investigate immunophenotype alterations of naïve and memory B cells and B1a cells in peripheral whole blood from Iranian patients with CGD. Flow cytometric analysis was performed on peripheral blood samples from 31 CGD patients and 23 healthy controls (HC) to study naïve (IgD+/CD27-), memory (CD27+) B and B1a (CD5+) cells. Soluble CD27 (sCD27) and immunoglobulins were also measured by ELISA and the nephelometric method, respectively. We found significantly higher levels of naïve B cells and B1a cells but lower levels of memory B cells in CGD patients compared to HC.. There was no significant difference in soluble CD27 (sCD27) alteration between CGD patients and HC. Our findings suggested a role for NADPH oxidase in process of B cell differentiation and impairing conversion of naïve B cells to memory B cells and altered B1a cells in CGD patients. Increased susceptibility of CGD patients to opportunistic infections and autoimmune disorders could be partly explained by the altered phenotype of B lymphocytes in these patients.