The ability to culture and expand B cells in vitro has become a useful tool for studying human immunity. A limitation of current methods for human B cell culture is the capacity to support mature B cell proliferation. We developed a culture method to support the efficient activation and proliferation of naive and memory human B cells. This culture supports extensive B cell proliferation, with ∼10³-fold increases following 8 d in culture and 10⁶-fold increases when cultures are split and cultured for 8 more days. In culture, a significant fraction of naive B cells undergo isotype switching and differentiate into plasmacytes. Culture-derived (CD) B cells are readily cryopreserved and, when recovered, retain their ability to proliferate and differentiate. Significantly, proliferating CD B cells express high levels of MHC class II, CD80, and CD86. CD B cells act as APCs and present alloantigens and microbial Ags to T cells. We are able to activate and expand Ag-specific memory B cells; these cultured cells are highly effective in presenting Ag to T cells. We characterized the TCR repertoire of rare Ag-specific CD4⁺ T cells that proliferated in response to tetanus toxoid (TT) presented by autologous CD B cells. TCR Vβ usage by TT-activated CD4⁺ T cells differs from resting and unspecifically activated CD4⁺ T cells. Moreover, we found that TT-specific TCR Vβ usage by CD4⁺ T cells was substantially different between donors. This culture method provides a platform for studying the BCR and TCR repertoires within a single individual.

Predicting complex disease risks on the basis of individual genomic profiles is an advancing field in human genetics^1,2. However, most genetic studies have focused on populations of European ancestry, creating a global imbalance in precision medicine and underscoring the need for genomic research in non-European groups^3,4. The Taiwan Precision Medicine Initiative recruited more than half a million Taiwanese residents, providing a large dataset of genetic profiles and electronic medical record data for people with Han Chinese ancestry. Using extensive phenotypic data, we conducted comprehensive genomic analyses across the medical phenome with individuals genetically similar to Han Chinese reference populations. These analyses identified population-specific genetic risk variants and new findings for various complex traits. We developed polygenic risk scores, demonstrating strong predictive performance for conditions such as cardiometabolic diseases, autoimmune disorders, cancers and infectious diseases. We observed consistent findings in an independent dataset, Taiwan Biobank, and among people of East Asian ancestry in the UK Biobank and the All of Us Project. The identified genetic risks accounted for up to 10.3% of the overall health variation in the Taiwan Precision Medicine Initiative cohort. Our approach of characterizing the phenome-wide genomic landscape, developing population-specific risk-prediction models, assessing their performance and identifying the genetic effect on health serves as a model for similar studies in other diverse study populations.

Immunological tolerance removes or inactivates self-reactive B cells, including those that also recognize cross-reactive foreign antigens. Whereas a few microbial pathogens exploit these “holes” in the B cell repertoire by mimicking host antigens to evade immune surveillance, the extent to which tolerance reduces the B cell repertoire to foreign antigens is unknown. Here, we use single-cell cultures to determine the repertoires of human B cell antigen receptors (BCRs) before (transitional B cells) and after (mature B cells) the second B cell tolerance checkpoint in both healthy donors and in patients with systemic lupus erythematosus (SLE) . In healthy donors, the majority (~70%) of transitional B cells that recognize foreign antigens also bind human self-antigens (foreign+self), and peripheral tolerance halves the frequency of foreign+self-reactive mature B cells. In contrast, in SLE patients who are defective in the second tolerance checkpoint, frequencies of foreign+self-reactive B cells remain unchanged during maturation of transitional to mature B cells. Patterns of foreign+self-reactivity among mature B cells from healthy donors differ from those of SLE patients. We propose that immune tolerance significantly reduces the scope of the BCR repertoire to microbial pathogens and that cross-reactivity between foreign and self epitopes may be more common than previously appreciated.

Introduction: Awareness of psoriasis-related comorbidities has been established in the current guidelines; however, evidence regarding the association of bone density or bone fragility with psoriatic disease remains inconclusive. Methods: We conducted a systematic review and meta-analysis to assess bone mineral density and the risk of osteoporosis and fractures in patients with psoriatic disease, including those with cutaneous psoriasis and psoriatic arthritis. We searched electronic databases for published observational studies. A meta-analysis was performed using the random-effect model. Pooled estimates and their confidence intervals (CIs) were calculated. Small-study effects were examined using the Doi plot and Luis Furuya–Kanamori index. Results: The analysis of the standardized mean difference in the absolute value of bone mineral density at different measuring sites (lumbar spine, femoral neck, and total hip) revealed no significant difference between patients with psoriatic disease and non-psoriatic controls. The pooled results of the adjusted odds ratios (ORs) demonstrated no increased risk of osteoporosis in patients with psoriatic disease. Notably, patients with psoriatic disease had a higher OR of developing bone fractures (adjusted OR: 1.09; 95% CI: 1.06 to 1.12; I²: 0%). Conclusion: Patients with psoriatic disease may be more likely to develop fractures compared with non-psoriatic controls. This higher risk for fracture may not necessarily be associated with lower bone mineral density nor a higher risk for osteoporosis.

CD27, a member of the TNFR superfamily, is used to identify human memory B cells. Nonetheless, CD27+ B cells are present in patients with HIGM1 syndrome who are unable to generate GCs or memory B cells. CD27+IgD+ fetal B cells are present in umbilical cord blood, and CD27 may also be a marker of the human B1-like B cells. To define the origin of naïve CD27+IgD+ human B cells, we studied B cell development in both fetal and adult tissues. In human FL, most CD19+ cells coexpressed CD10, a marker of human developing B cells. Some CD19+CD10+ B cells expressed CD27, and these fetal CD27+ cells were present in the pro-B, pre-B, and immature/transitional B cell compartments. Lower frequencies of phenotypically identical cells were also identified in adult BM. CD27+ pro-B, pre-B, and immature/transitional B cells expressed recombination activating gene-1, terminal deoxynucleotidyl transferase and Vpre-B mRNA comparably to their CD27− counterparts. CD27+ and CD27− developing B cells showed similar Ig heavy chain gene usage with low levels of mutations, suggesting that CD27+ developing B cells are distinct from mutated memory B cells. Despite these similarities, CD27+ developing B cells differed from CD27− developing B cells by their increased expression of LIN28B, a transcription factor associated with the fetal lymphoid lineages of mice. Furthermore, CD27+ pro-B cells efficiently generated IgM+IgD+ immature/transitional B cells in vitro. Our observations suggest that CD27 expression during B cell development identifies a physiologic state or lineage for human B cell development distinct from the memory B cell compartment.