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Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified—such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function 1 —these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus , and integrated these findings with data from the accompanying Tabula Muris Senis 2 —or ‘Mouse Ageing Cell Atlas’—which follows on from the original Tabula Muris 3 . We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions—including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue—including plasma cells that express immunoglobulin J—which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age. Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis , a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1—infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.

Immunoglobulin A (IgA) is the most abundantly produced antibody in mammals, with its secretory dimeric form playing a central role in maintaining intestinal homeostasis. Although the J chain is known to be essential for IgA transcytosis, its precise role in IgA biosynthesis and secretion is not fully understood. Here, using CRISPR/Cas9-edited J558 plasmacytoma cells, a mouse line that secretes IgA, we demonstrate that MZB1 and the J chain act sequentially to ensure proper IgA assembly. MZB1 stabilizes α-heavy chain-light chain complexes (HL complexes), thereby enabling their efficient association with the J chain, which subsequently drives rapid assembly into IgA dimers and higher-order polymers. Loss of MZB1 reduced the secretion of dimeric IgA, whereas J chain deficiency caused both excessive intracellular accumulation and secretion of HL complexes, while allowing the generation and secretion of limited amounts of monomeric IgA but completely abolishing dimer formation. Combined deficiency reproduced the additive defects of the single knockouts, confirming their cooperative function in a shared assembly pathway. In vivo , loss of MZB1, the J chain, or both altered IgA abundance and form, differentially affected susceptibility to DSS-induced colitis, and reshaped gut microbiota composition. These findings define a cooperative mechanism by which MZB1 and the J chain orchestrate IgA biogenesis, with MZB1 regulating quantity and the J chain determining quality, and reveal how variation in IgA form and abundance contributes to mucosal immune protection.

Breast cancer metastasis is the primary cause of mortality of patients with breast cancer. The present study aimed to explore the role and underlying mechanisms of IGJ in the invasion and metastasis of breast cancer. The Cancer Genome Atlas database was utilized to analyze the differential gene expression profiles in patients with breast cancer with or without metastasis; the target gene, joining chain of multi-meric IgA and IgM (JCHAIN, also known as IGJ, as referred to herein), with significant expression and with prognostic value was screened. The expression levels of IGJ in human breast cancer paired tissues and cell lines were detected using reverse transcription-quantitative PCR and western blot analysis. IGJ differential expression was detected in paired human breast cancer tissues using immunohistochemistry. The role of IGJ in breast cancer was verified using CCK-8, invasion and migration assays, and scratch tests in vivo and in vitro. Further exploration of the role and mechanism of IGJ in breast cancer was conducted through Gene Set Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes analysis, western blot analysis and immunofluorescence experiments. Through the analysis of gene expression profiles, it was found that IGJ was poorly expressed in patients with breast cancer with metastasis compared to patients with non-metastatic breast cancer. The overexpression of IGJ was associated with an improved distant metastasis-free survival and overall survival (OS). COX multivariate regression analysis demonstrated that IGJ was an independent prognostic factor for the OS and relapse-free survival of patients with breast cancer. In comparison to healthy breast cancer adjacent tissues and cell lines, IGJ was poorly expressed in breast cancer tissues and cell lines (P<0.05). Further analyses indicated that the overexpression of IGJ suppressed the proliferation, invasion and metastasis of breast cancer cells in vivo and in vitro by inhibiting the occurrence of epithelial-to-mesenchymal transition (EMT) and suppressing the nuclear translocation of p65. Finally, rescue experiments indicated that IGJ restricted the proliferation and metastasis of breast cancer cells by regulating the NF-κB signaling pathway. On the whole, the present study demonstrates that IGJ suppresses the invasion and metastasis of breast cancer by inhibiting both the occurrence of EMT and the NF-κB signaling pathway. These findings may provide novel biomarkers and potential therapeutic targets for the treatment of metastatic breast cancer.

The prevention of the COVID-19 pandemic is highly complicated by the prevalence of asymptomatic and recurrent infection. Many previous immunological studies have focused on symptomatic and convalescent patients, while the immune responses in asymptomatic patients and re-detectable positive cases remain unclear. Here we comprehensively analyzed the peripheral T-cell receptor (TCR) repertoire of 54 COVID-19 patients in different courses, including asymptomatic, symptomatic, convalescent, and re-detectable positive cases. We identified a set of V–J gene combinations characterizing the upward immune responses through asymptomatic and symptomatic courses. Furthermore, some of these V–J combinations could be awakened in the re-detectable positive cases, which may help predict the risk of recurrent infection. Therefore, TCR repertoire examination has the potential to strengthen the clinical surveillance and the immunotherapy development for COVID-19.

The MC38 (derived from carcinogen-induced colon adenocarcinoma) tumor model is sensitive to anti-programmed cell death-1 (anti-PD-1) treatment. However, there is no comprehensive description of the T and B cell receptor (TCR, BCR) repertoires of the MC38 tumor model following anti-PD-1 treatment, an improved understanding of which is highly important in the development of anti-PD-1 immunotherapy. The present study analyzed the TCR and BCR repertoires of three types of tissue, including tumor, spleen and tumor draining lymph node (DLN) from 20 MC38 syngeneic mice receiving murine anti-PD-1 (mDX400) treatment or mouse immunoglobulin G1 (mIgG1) control treatment. To obtain enough tissues for high-throughput sequencing, samples were collected on day 8 after the start of initial treatment. The usage frequencies of seven TCR β chain (TRB) V genes and one TRBJ gene were significantly different between mDX400- and mIgG1-group tumors. TCR repertoire diversity was significantly lower in mDX400-group tumors compared with mIgG1-group tumors, with the top 10 most frequent TCR clonotypes notably expanded in mDX400-group tumors. In addition, the proportion of high-frequency TCR clonotypes from mDX400-group tumors that were also present both in the DLN and spleen was significantly higher than that in mIgG1-group tumors. Among the highly expanded TCR clonotypes, one TCR clonotype was consistently expanded in >50% of the mDX400-group tumors compared with mIgG1-group tumors. Similarly, one BCR clonal family was highly expanded in >50% of mDX400-group tumor samples. The consistently expanded TCR and BCR clones were co-expanded in 29% of mDX400-group tumors. Moreover, mutation rates of immunoglobulin heavy chain sequences in the spleen within complementarity determining region 2 and framework region 3 were significantly higher in the mDX400 group than in the mIgG1 group. The findings of this study may contribute to an improved understanding of the molecular mechanisms of anti-PD-1 treatment.

Background B-Acute lymphoblastic leukemia (B-ALL) represents a hematologic malignancy with poor clinical outcome and low survival rates in adult patients. Remission rates in Hispanic population are almost 30 % lower and Overall Survival (OS) nearly two years inferior than those reported in other ethnic groups. Only 61 % of Colombian adult patients with ALL achieve complete remission (CR), median overall survival is 11.3 months and event-free survival (EFS) is 7.34 months. Identification of prognostic factors is crucial for the application of proper treatment strategies and subsequently for successful outcome. Our goal was to identify a gene expression signature that might correlate with response to therapy and evaluate the utility of these as prognostic tool in hispanic patients. Methods We included 43 adult patients newly diagnosed with B-ALL. We used microarray analysis in order to identify genes that distinguish poor from good response to treatment using differential gene expression analysis. The expression profile was validated by real-time PCR (RT-PCT). Results We identified 442 differentially expressed genes between responders and non-responders to induction treatment. Hierarchical analysis according to the expression of a 7-gene signature revealed 2 subsets of patients that differed in their clinical characteristics and outcome. Conclusions Our study suggests that response to induction treatment and clinical outcome of Hispanic patients can be predicted from the onset of the disease and that gene expression profiles can be used to stratify patient risk adequately and accurately. The present study represents the first that shows the gene expression profiling of B-ALL Colombian adults and its relevance for stratification in the early course of disease.

Background Survival of adults with B-Acute Lymphoblastic Leukemia requires accurate risk stratification of patients in order to provide the appropriate therapy. Contemporary techniques, using clinical and cytogenetic variables are incomplete for prognosis prediction. Methods To improve the classification of adult patients diagnosed with B-ALL into prognosis groups, two strategies were examined and combined: the expression of the ID1/ID3/IGJ gene signature by RT-PCR and the immunophenotypic profile of 19 markers proposed in the EuroFlow protocol by Flow Cytometry in bone marrow samples. Results Both techniques were correlated to stratify patients into prognostic groups. An inverse relationship between survival and expression of the three-genes signature was observed and an immunophenotypic profile associated with clinical outcome was identified. Markers CD10 and CD20 were correlated with simultaneous overexpression of ID1, ID3 and IGJ. Patients with simultaneous expression of the poor prognosis gene signature and overexpression of CD10 or CD20, had worse Event Free Survival and Overall Survival than patients who had either the poor prognosis gene expression signature or only CD20 or CD10 overexpressed. Conclusion By utilizing the combined evaluation of these two immunophenotypic markers along with the poor prognosis gene expression signature, the risk stratification can be significantly strengthened. Further studies including a large number of patients are needed to confirm these findings.

Previous studies have suggested a geographical pattern of immunoglobulin rearrangement in chronic lymphocytic leukaemia (CLL), which could be as a result of a genetic background or an environmental antigen. However, the characteristics of Ig rearrangements in the population from the South of France have not yet been established. Here, we studied CLL B‐cell repertoire and mutational pattern in a Southern French cohort of patients using an in‐house protocol for whole sequencing of the rearranged immunoglobulin heavy‐chain genes. Described biased usage of variable, diversity and joining genes between the mutated and unmutated groups was found in our population. However, variable gene frequencies are more in accordance with those observed in the Mediterranean patients. We found that the third complementary‐determining region (CDR) length was higher in unmutated sequences, because of bias in the diversity and joining genes usage and not due to the N diversity. Mutations found in CLL followed the features of canonical somatic hypermutation mechanism: preference of targeting for activation‐induced cytidine deaminase and polymerase motifs, base change bias for transitions and more replacement mutations occurring in CDRs than in framework regions. Surprisingly, localization of activation‐induced cytidine deaminase motifs onto the variable gene showed a preference for framework regions. The study of the characteristics at the age of diagnosis showed no difference in clinical outcome, but suggested a tendency of increased replacement and transition‐over‐transversion mutations and a longer third CDR length in older patients.

As in other mammals, immunoglobulin A (IgA) in the horse has a key role in immune defense. To better dissect equine IgA function, we isolated complementary DNA (cDNA) clones for equine J chain and polymeric Ig receptor (pIgR). When coexpressed with equine IgA, equine J chain promoted efficient IgA polymerization. A truncated version of equine pIgR, equivalent to secretory component, bound with nanomolar affinity to recombinant equine and human dimeric IgA but not with monomeric IgA from either species. Searches of the equine genome localized equine J chain and pIgR to chromosomes 3 and 5, respectively, with J chain and pIgR coding sequence distributed across 4 and 11 exons, respectively. Comparisons of transcriptional regulatory sequences suggest that horse and human pIgR expression is controlled through common regulatory mechanisms that are less conserved in rodents. These studies pave the way for full dissection of equine IgA function and open up possibilities for immune-based treatment of equine diseases.