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Abstract Maturation of the secondary antibody repertoire requires class‐switch recombination (CSR), which switches IgM to other immunoglobulins (Igs), and somatic hypermutation, which promotes the production of high‐affinity antibodies. Following immune response or infection within the body, activation of T cell‐dependent and T cell‐independent antigens triggers the activation of activation‐induced cytidine deaminase, initiating the CSR process. CSR has the capacity to modify the functional properties of antibodies, thereby contributing to the adaptive immune response in the organism. Ig CSR defects, characterized by an abnormal relative frequency of Ig isotypes, represent a rare form of primary immunodeficiency. Elucidating the molecular basis of Ig diversification is essential for a better understanding of diseases related to Ig CSR defects and could provide clues for clinical diagnosis and therapeutic approaches. Here, we review the most recent insights on the diversification of five Ig isotypes and choose several classic diseases, including hyper‐IgM syndrome, Waldenström macroglobulinemia, hyper‐IgD syndrome, selective IgA deficiency, hyper‐IgE syndrome, multiple myeloma, and Burkitt lymphoma, to illustrate the mechanism of Ig CSR deficiency. The investigation into the underlying mechanism of Ig CSR holds significant potential for the advancement of increasingly precise diagnostic and therapeutic approaches.

Abstract Patients with rheumatoid arthritis (RA) can test either positive or negative for circulating anti-citrullinated protein antibodies (ACPA) and are thereby categorized as ACPA-positive (ACPA+) or ACPA-negative (ACPA−), respectively. In this study, we aimed to elucidate a broader range of serological autoantibodies that could further explain immunological differences between patients with ACPA+ RA and ACPA− RA. On serum collected from adult patients with ACPA+ RA (n = 32), ACPA− RA (n = 30), and matched healthy controls (n = 30), we used a highly multiplex autoantibody profiling assay to screen for over 1600 IgG autoantibodies that target full-length, correctly folded, native human proteins. We identified differences in serum autoantibodies between patients with ACPA+ RA and ACPA− RA compared with healthy controls. Specifically, we found 22 and 19 autoantibodies with significantly higher abundances in ACPA+ RA patients and ACPA− RA patients, respectively. Among these two sets of autoantibodies, only one autoantibody (anti-GTF2A2) was common in both comparisons; this provides further evidence of immunological differences between these two RA subgroups despite sharing similar symptoms. On the other hand, we identified 30 and 25 autoantibodies with lower abundances in ACPA+ RA and ACPA− RA, respectively, of which 8 autoantibodies were common in both comparisons; we report for the first time that the depletion of certain autoantibodies may be linked to this autoimmune disease. Functional enrichment analysis of the protein antigens targeted by these autoantibodies showed an over-representation of a range of essential biological processes, including programmed cell death, metabolism, and signal transduction. Lastly, we found that autoantibodies correlate with Clinical Disease Activity Index, but associate differently depending on patients’ ACPA status. In all, we present candidate autoantibody biomarker signatures associated with ACPA status and disease activity in RA, providing a promising avenue for patient stratification and diagnostics.

IntroductionThe longitudinal responses towards multiple doses of COVID-19 mRNA vaccines in patients with systemic autoimmune diseases remain incompletely understood. While observational studies suggested the safety of COVID-19 mRNA vaccines in rheumatic disease patients, laboratory evidence is lacking.MethodsHere we evaluated seroreactivity, clinical manifestions, and multiple disease biomarkers after 2 or 3 doses of COVID-19 mRNA vaccines in a cohort of patients with rheumatic diseases.ResultsMost patients generated high SARS-CoV-2 spike-specific neutralizing antibodies comparable to those in healthy controls after 2 doses of mRNA vaccines. The antibody level declined over time but recovered after the third dose of the vaccine. Patients with systemic lupus erythematosus (SLE) or psoriatic arthritis (PsA) remained without significant flares post-vaccination. The changes in anti-dsDNA antibody concentration and expression of type I interferon (IFN) signature genes were highly variable but did not show consistent or significant increases. Frequency of double negative 2 (DN2) B cells remained largely stable.DiscussionOur data provide experimental evidences indicating the efficacy and safety of repeated COVID-19 mRNA vaccination in rheumatic disease patients.

Raptor, a key component of mTORC1, is required for recruiting substrates to mTORC1 and contributing to its subcellular localization. Raptor has a highly conserved N-terminus domain and seven WD40 repeats, which interact with mTOR and other mTORC1-related proteins. mTORC1 participates in various cellular events and mediates differentiation and metabolism. Directly or indirectly, many factors mediate the differentiation and function of lymphocytes that is essential for immunity. In this review, we summarize the role of Raptor in lymphocytes differentiation and function, whereby Raptor mediates the secretion of cytokines to induce early lymphocyte metabolism, development, proliferation and migration. Additionally, Raptor regulates the function of lymphocytes by regulating their steady-state maintenance and activation.

In mammals, interactions between the bone marrow (BM) stroma and hematopoietic progenitors contribute to bone-BM homeostasis. Perinatal bone growth and ossification provide a microenvironment for the transition to definitive hematopoiesis; however, mechanisms and interactions orchestrating the development of skeletal and hematopoietic systems remain largely unknown. Here, we establish intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) modification as a posttranslational switch that dictates the differentiation fate and niche function of early BM stromal cells (BMSCs). By modifying and activating RUNX2, O-GlcNAcylation promotes osteogenic differentiation of BMSCs and stromal IL-7 expression to support lymphopoiesis. In contrast, C/EBPβ-dependent marrow adipogenesis and expression of myelopoietic stem cell factor (SCF) is inhibited by O-GlcNAcylation. Ablating O-GlcNAc transferase (OGT) in BMSCs leads to impaired bone formation, increased marrow adiposity, as well as defective B-cell lymphopoiesis and myeloid overproduction in mice. Thus, the balance of osteogenic and adipogenic differentiation of BMSCs is determined by reciprocal O-GlcNAc regulation of transcription factors, which simultaneously shapes the hematopoietic niche.

Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues and found 5hmC shows tissue-specific patterns.

hNEIL1 (human endonuclease VIII-like 1) is a broadly specific DNA glycosylase for base excision repair. Here, the authors show that hNEIL1 can assume activated or triage conformations: the structural basis for the mechanism that enables broad specificity and reduces futile repair of normal bases.

Background The clumping bamboo Bambusa oldhamii Munro, known as “green bamboo”, is famous for its edible bamboo shoots and fast-growing timber. The green and yellow striped-culm B. oldhamii variety, named B. oldhamii f. revoluta W.T. Lin & J. Y. Lin, is an attractive system for researching the culm color variation of B. oldhamii. Methods Millions of clean reads were generated and assembled into 604,900 transcripts, and 383,278 unigenes were acquired with RNA-seq technology. The quantification of ABA, IAA, JA, GA1, GA3, GA4, and GA7 was performed using HPLC–MS/MS platforms. Results Differential expression analysis showed that 449 unigenes were differentially expressed genes (DEGs), among which 190 DEGs were downregulated and 259 DEGs were upregulated in B. oldhamii f. revoluta. Phytohormone contents, especially GA1 and GA7, were higher in B. oldhamii. Approximately 21 transcription factors (TFs) were differentially expressed between the two groups: the bZIP, MYB, and NF-YA transcription factor families had the most DEGs, indicating that those TFs play important roles in B. oldhamii culm color variation. RNA-seq data were confirmed by quantitative RT-PCR analysis of the selected genes; moreover, phytohormone contents, especially those of ABA, GA1 and GA7, were differentially accumulated between the groups. Our study provides a basal gene expression and phytohormone analysis of B. oldhamii culm color variation, which could provide a solid fundamental theory for investigating bamboo culm color variation.

Humoral vaccine responses are known to be suboptimal in patients receiving B-cell targeted therapy, and little is known about vaccine induced T-cell immunity in these patients. In this study, we characterized humoral and cellular antigen-specific anti-SARS-CoV2 responses following COVID-19 vaccination in patients with ANCA-associated vasculitis (AAV) receiving anti-CD20 therapy, who were either B-cell depleted, or B-cell recovered at the time of vaccination and in normal control subjects. SARS-CoV-2 anti-spike (S) and anti-nucleocapsid (NC) antibodies were measured using electrochemiluminescence immunoassays, while SARS-CoV-2 specific T-cell responses to S glycoprotein subunits 1 (S1) and 2 (S2) and receptor binding domain peptide pools were measured using interferon-gamma enzyme-linked immunosorbent spot (ELISPOT) assays. In total, 26 recently vaccinated subjects were studied. Despite the lack of a measurable humoral immune response, B-cell depleted patients mounted a similar vaccine induced antigen-specific T-cell response compared to B-cell recovered patients and normal controls. Our data indicate that to assure a humoral response in patients receiving anti-CD20 therapy, SARS-CoV-2 vaccination should ideally be delayed until B-cell recovery (CD-20 positive B-cells > 10/μl). Nevertheless, SARS-CoV-2 vaccination elicits robust, potentially protective cellular immune responses in these subjects. Further research to characterize the durability and protective effect of vaccine-induced anti-SARS-CoV-2 specific T-cell immunity are needed.

After antigenic activation, quiescent naive CD4+ T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4+ T cells. HDAC3-deficient CD4+ T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4+ T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4+ T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4+ T-cell activation to repress cholesterol efflux.

The authors previously showed that mTOR controls the function of regulatory T cells. Here they show how this mTOR signaling orchestrates homeostasis of Treg-cell subsets and prevents fatal autoimmunity.

IL-7R activation drives early B cell development, but the signalling is unclear. Here the authors show PLCγ is involved in IL-7R-induced mTOR activation via a DAG/PKC-dependent pathway, and that double deficiency of the two PLCγ isoforms arrests B cell development at the pre-pro-B stage in mice.

Hematopoiesis is dynamically regulated by metabolic cues in homeostatic and stressed conditions; however, the cellular and molecular mechanisms mediating the metabolic sensing and regulation remain largely obscure. Bone marrow adipose tissue remodels in various metabolic conditions and has been recently proposed as a niche for hematopoietic stem cells after irradiation. Here, we investigated the role of marrow adipose tissue-derived hematopoietic cytokine stem cell factor in unperturbed hematopoiesis by selectively ablating the Kitl gene from adipocytes and bone marrow stroma cells using Adipoq-Cre and Osx1-Cre, respectively. We found that both Adipoq-Kitl knockout (KO) and Osx1-Kitl KO mice diminished hematopoietic stem and progenitor cells and myeloid progenitors in the bone marrow and developed macrocytic anemia at the steady-state. The composition and differentiation of hematopoietic progenitor cells in the bone marrow dynamically responded to metabolic challenges including high fat diet, β3-adrenergic activation, thermoneutrality, and aging. However, such responses, particularly within the myeloid compartment, were largely impaired in Adipoq-Kitl KO mice. Our data demonstrate that marrow adipose tissue provides stem cell factor essentially for hematopoiesis both at the steady state and upon metabolic stresses.

Multi-year El Niño events induce severe and persistent floods and droughts worldwide, with significant socioeconomic impacts, but the causes of their long-lasting behaviors are still not fully understood. Here we present a two-way feedback mechanism between the tropics and extratropics to argue that extratropical atmospheric variability associated with the North Pacific Oscillation (NPO) is a key source of multi-year El Niño events. The NPO during boreal winter can trigger a Central Pacific El Niño during the subsequent winter, which excites atmospheric teleconnections to the extratropics that re-energize the NPO variability, then re-triggers another El Niño event in the following winter, finally resulting in persistent El Niño-like states. Model experiments, with the NPO forcing assimilated to constrain atmospheric circulation, reproduce the observed connection between NPO forcing and the occurrence of multi-year El Niño events. Future projections of Coupled Model Intercomparison Project phases 5 and 6 models demonstrate that with enhanced NPO variability under future anthropogenic forcing, more frequent multi-year El Niño events should be expected. We conclude that properly accounting for the effects of the NPO on the evolution of El Niño events may improve multi-year El Niño prediction and projection.

In light of a warming climate, the complexity of the El Niño/Southern Oscillation (ENSO) makes its prediction a challenge. In addition to various flavors of ENSO, oceanic warming in the central and eastern tropical Pacific is not always accompanied by corresponding atmospheric anomalies; that is, the atmosphere and ocean remain uncoupled. Such uncoupled warm events as happened in 1979, 2004, 2014, and 2018 are rare and represent an unusual form of ENSO diversity. A weaker zonal sea surface temperature anomaly gradient across the tropical Pacific compared to a conventional El Niño may partially account for the decoupling. Also, the uncoupled warm events typically start late in the calendar year, which raises the possible influence of seasonality in background conditions for the lack of coupling. Without coupling, the impact of the warming in the central and eastern tropical Pacific on extratropical climate is different from that of its coupled counterpart.

Following the interdecadal shift of El Niño-Southern Oscillation (ENSO) properties that occurred in 1976/77, another regime shift happened in 1999/2000 that featured a decrease of variability and an increase in ENSO frequency. Specifically, the frequency spectrum of Niño-3.4 sea surface temperature shifted from dominant variations at quasi-quadrennial (∼4 yr) periods during 1979-99 to weaker fluctuations at quasi-biennial (∼2 yr) periods during 2000-18. Also, the spectrum of warm water volume (WWV)index had almost no peak in 2000-18, implying a nearly white noise process. The regime shift was associated with an enhanced zonal gradient of the mean state, awestward shift in the atmosphere-ocean coupling in the tropical Pacific, and an increase in the static stability of the troposphere. This shift had several important implications. The whitening of the subsurface ocean temperature led to a breakdown of the relationship between WWV and ENSO, reducing the efficacy of WWV as a key predictor for ENSO and thus leading to a decrease in ENSO prediction skill. Another consequence of the higher ENSO frequency after 1999/2000 was that the forecasted peak of sea surface temperature anomaly often lagged that observed by several months, and the lag increased with the lead time. The ENSO regime shift may have altered ENSO influences on extratropical climate. Thus, the regime shift of ENSO in 1999/2000 as well as the model default may account for the higher false alarm and lower skill in predicting ENSO since 1999/2000.