Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease characterized by the presence of autoantibodies, including those targeting O-phosphoseryl-tRNA:selenocysteine-tRNA synthase (SepSecS), also known as soluble liver antigen (SLA). Anti-SepSecS antibodies have been associated with a more severe phenotype, suggesting a key role for the SepSecS autoantigen in AIH. To analyze the immune response to SepSecS in patients with AIH at the clonal level, we combined sensitive high-throughput screening assays with the isolation of monoclonal antibodies (mAbs) and T cell clones. The anti-SepSecS mAbs isolated were primarily IgG1, affinity-matured compared with their germline versions, and recognized at least 3 nonoverlapping epitopes. SepSecS-specific CD4+ T cell clones were found in patients with AIH who were anti-SLA-positive and anti-SLA-negative,and, to a lesser extent, in patients with non-AIH liver diseases and in healthy individuals. SepSecS-specific T cell clones from patients with AIH produced IFN-γ, IL-4, and IL-10, targeted multiple SepSecS epitopes, and, in one patient, were clonally expanded in both blood and liver biopsy. Finally, SepSecS-specific B cell clones, but not those of unrelated specificities, were able to present soluble SepSecS to specific T cells. Collectively, our study provides the first detailed analysis of B and T cell repertoires targeting SepSecS in patients with AIH, offering a rationale for improved targeted therapies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, receptor molecular mimicry, and interactions with RBM backbone atoms. Consequently, VIR-7229 features a high barrier for selection of escape mutants, which are rare and associated with reduced viral fitness, underscoring its potential to be resilient to future viral evolution. VIR-7229 is a strong candidate to become a next-generation medicine.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL) are blood cancers that affect lymphocytes and can be diagnosed by flow cytometry. Flow cytometry is a laboratory technique that analyzes cell properties, including cell surface markers such as cluster of differentiation 19 (CD19).
The main objective of this study was to explore the correlation of the number of CD19-positive cells with other CD antigens in patients with CLL and ALL.
After receiving ethical approval (Approval No. 5S/401), blood was collected from participants who had been diagnosed by a physician. Then the collected blood was prepared for flow cytometry analysis according to the protocol by staining with fluorescent antibodies.
The results of the current study showed that sex and different age groups had no statistical influence on the number of CD19-positive cells in the patients evaluated. The generated models did not reveal an association with the number of CD19-positive cells in patients with CLL and ALL. In patients with CLL, the number of cells expressing CD5, CD20, CD23, and CD200 was significantly and positively related with the number of CD19-positive cells. In patients with ALL, the number of cells expressing CD79 and CD99 was significantly and positively correlated with the number of CD19-positive cells. This comparison study also found that in patients with CLL, the number of CD19-positive cells was significantly higher than the number of cells expressing CD20, CD23, and CD200. In patents with ALL, there was a significantly higher number of CD19-positive cells than CD34-positive and CD79-positive cells.
In patients with CLL, there was a strong positive correlation between the number of CD19-positive cells and the number of cells expressing CD5, CD20, CD23, and CD200. Additionally, in patients with ALL, there was a positive correlation of CD79 and CD99 with the number of CD19-positive cells.
© 2024 The Authors.

Myasthenia gravis (MG) can in rare cases be an autoimmune phenomenon associated with hematologic malignancies such as chronic lymphocytic leukemia (CLL). It is unclear whether in patients with MG and CLL, the leukemic B cells are the ones directly driving the autoimmune response against neuromuscular endplates.
We identified patients with acetylcholine receptor antibody-positive (AChR+) MG and CLL or monoclonal B-cell lymphocytosis (MBL), a precursor to CLL, and described their clinical features, including treatment responses. We generated recombinant monoclonal antibodies (mAbs) corresponding to the B-cell receptors of the CLL phenotype B cells and screened them for autoantigen binding.
A computational immune cell screen revealed a subgroup of 5/38 patients with MG and 0/21 healthy controls who displayed a CLL-like B-cell phenotype. In follow-up hematologic flow cytometry, 2 of these 5 patients were diagnosed with an MBL. An additional patient with AChR+ MG as a complication of manifest CLL presented at our neuromuscular clinic and was successfully treated with the anti-CD20 therapy obinutuzumab plus chlorambucil. We investigated the specificities of expanding CLL-like B-cell clones to assess a direct causal link between the 2 diseases. However, we observed no reactivity of the clones against the AChR, antigens at the neuromuscular junction, or other common autoantigens.
Our study suggests that AChR autoantibodies are produced by nonmalignant, polyclonal B cells The new anti-CD20 treatment obinutuzumab might be considered in effectively treating AChR+ MG.
This is a single case study and provides Class IV evidence that obinutuzumab is safe to use in patients with MG.
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

IL-35 is a potent immunosuppressive and anti-inflammatory cytokine, consisting of a p35 subunit and an Epstein-Barr virus-induced gene 3 (EBI3) subunit, which suppresses CD4+ effector T cell proliferation and promotes regulatory T cell (Treg) expansion. However, the effects of IL-35 on regulatory B cells (Bregs) in ankylosing spondylitis (AS) have not been explored. The present study aimed (i) to measure serum IL-35 levels and the percentages of Bregs in the peripheral blood of patients with AS and (ii) to explore their relationships in the pathogenesis of AS.
A total of 77 patients with AS (AS group), including 47 inactive AS and 30 active AS cases, and 59 healthy controls (HCs) were enrolled into this study. The serum levels of IL-35 and IL-10 were detected by ELISA, and the mRNA levels of p35 and EBI3 were measured by RT-qPCR. The percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs and IL-35 receptor (IL-12Rβ2, IL-27Rα and gp130), IL-10, p-STAT1, p-STAT3, and p-STAT4 in CD19+ B cells were detected by flow cytometry. The correlations between IL-35 levels and percentages of Bregs were analyzed by determining Pearson's correlation coefficient. The effect of IL-35 on Bregs was determined by mix-culture of recombinant (r) IL-35 with peripheral blood mononuclear cells (PBMCs).
The serum IL-35 and IL-10 levels, p35 and EBI3 mRNA levels, and the percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs were significantly lower in AS patients than those in HCs. In addition, the percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs in active AS patients were significantly lower than those in inactive AS patients. The serum IL-35 levels were positively correlated with the percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs in AS patients. IL-12Rβ2 and IL-27Rα, but not gp130 subunit, were expressed in CD19+ B cells in AS patients. RIL-35 could effectively promote CD19+CD24hiCD38hi Breg expansion and IL-10 production. Meanwhile, rIL-35 also promoted the expression of IL-12Rβ2 and IL-27Rα and the phosphorylation of STAT1 and STAT3 in CD19+ B cells.
These results demonstrated that reduced IL-35 production may be associated with Bregs defects in AS patients. RIL-35 induced the proliferation of CD19+CD24hiCD38hi Bregs and IL-10 production, suggesting that IL-35 may serve as a reference for further investigation to develop novel treatments for AS. Key Points • Our study investigated the effects of IL-35 on Bregs in AS patients. • We found the serum IL-35, IL-10 levels, and the percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs were significantly lower in AS patients. • The serum IL-35 levels were positively correlated with the percentages of CD19+CD24hiCD38hi and CD19+CD24hiCD27+ Bregs in AS patients. • Recombinant IL-35 could effectively promote CD19+CD24hiCD38hi Breg expansion and IL-10 production.
© 2022. The Author(s).