Schjerven et al. compare mouse and human models of pre–B ALL to define conserved target genes and pathways of the tumor suppressor Ikaros, revealing CTNND1 and the early hematopoietic cell-surface receptors SPN (CD43) and CD34 as novel Ikaros targets that each confer oncogenic growth advantage.

Disease-specific plasma cells (PCs) reactive with transglutaminase 2 (TG2) or deamidated gluten peptides (DGP) are abundant in celiac disease (CeD) gut lesions. Their contribution toward CeD pathogenesis is unclear. We assessed expression of markers associated with PC longevity in 15 untreated and 26 treated CeD patients in addition to 13 non-CeD controls, and performed RNAsequencing with clonal inference and transcriptomic analysis of 3251 single PCs. We observed antigen-dependent V-gene selection and stereotypic antibodies. Generation of recombinant DGPspecific antibodies revealed a key role of a heavy-chain residue that displays polymorphism, suggesting that immunoglobulin gene polymorphisms may influence CeD-specific antibody responses.We identified transcriptional differences between CeD-specific vs non-disease-specific PCs and between short-lived vs long-lived PCs. The short-lived CD19 + CD45 + phenotype dominated in untreated and short-term-treated CeD, in particular among disease-specific PCs but also in the general PC population. Thus, the disease lesion of untreated CeD is characterized by massive accumulation of short-lived PCs that are not only directed against disease-specific antigens.

Disease-specific plasma cells (PCs) reactive with transglutaminase 2 (TG2) or deamidated gluten peptides (DGPs) are abundant in celiac disease (CeD) gut lesions. Their contribution toward CeD pathogenesis is unclear. We assessed expression of markers associated with PC longevity in 15 untreated and 26 treated CeD patients in addition to 13 non-CeD controls and performed RNA sequencing with clonal inference and transcriptomic analysis of 3,251 single PCs. We observed antigen-dependent V-gene selection and stereotypic antibodies. Generation of recombinant DGP-specific antibodies revealed a key role of a heavy chain residue that displays polymorphism, suggesting that immunoglobulin gene polymorphisms may influence CeD-specific antibody responses. We identified transcriptional differences between CeD-specific and non–disease-specific PCs and between short-lived and long-lived PCs. The short-lived CD19+CD45+ phenotype dominated in untreated and short-term–treated CeD, in particular among disease-specific PCs but also in the general PC population. Thus, the disease lesion of untreated CeD is characterized by massive accumulation of short-lived PCs that are not only directed against disease-specific antigens.

Paper IIGluten-specific CD4 + T cells express a distinct set of markers after gluten challenge that correlate well on the transcriptomic and phenotypic level

A hallmark of celiac disease (CeD), a chronic condition driven by cereal gluten exposure, is increase of gut intraepithelial γδ T cells. This may indicate pathogenic involvement of γδ T cells and existence of disease-specific γδ T-cell receptors (TCRs) recognizing defined antigen(s). We performed high-throughput and paired γδ TCR sequencing of single intraepithelial γδ T cells of untreated CeD patients (n=8; 1821 cells), CeD patients treated with a gluten-free diet (n=5; 436 cells) and controls (n=7; 1068 cells). We found that CeD patients, both untreated and treated, had larger and more diverse γδ TCR repertoires, more frequent usage of TRDV1 and TRDV3 and different patterns of TCRγ/TCRδ-pairing compared to controls. While we observed no public CDR3δ sequences, there were several public CDR3γ sequencesmany of which were shared by the CeD patients, but also by the controls. These public CDR3s were characterized by few N/P nucleotide insertions with germline and near-germline configuration, hence being easy to generate. Previous findings of CeD-specific CDR3 motifs were not replicated. Thus, being unable to raise evidence for CeD-specific γδ TCRs in this first large, paired γδ TCR single-cell sequencing study, we project challenges for identification of CeD-relevant γδ TCR ligands.

Chronic inflammation of the small intestine in celiac disease is driven by activation of CD4+ T cells that recognize gluten peptides presented by disease-associated HLA-DQ molecules. We have performed direct cell cloning of duodenal biopsies from five untreated and one refractory celiac disease patients, and three non-celiac disease control subjects in order to assess, in an unbiased fashion, the frequency of gluten-reactive T cells in the disease-affected tissue as well as the antigen fine specificity of the responding T cells. From the biopsies of active disease lesions of five patients, 19 T-cell clones were found to be gluten-reactive out of total 1,379 clones tested. This gave an average of 1.4% (range 0.7% - 1.9%) of gluten-reactive T cells in lamina propria of active celiac lesions. Interestingly, also the patient with refractory celiac disease had gluten-reactive T cell clones in the lamina propria (5/273; 1.8%). In comparison, we found no gluten-reactive T cells in any of the total 984 T-cell clones screened from biopsies from three disease control donors. Around two thirds of the gluten-reactive clones were reactive to a panel of peptides representing known gluten T-cell epitopes, of which two thirds were reactive to the immunodominant DQ2.5-glia-α1/DQ2.5-glia-α2 and DQ2.5-glia-ω1/DQ2.5-glia-ω2 epitopes. This study shows that gluten-reactive T cells in the inflamed duodenal tissue are prevalent in the active disease lesion, and that many of these T cells are reactive to T-cell epitopes that are not yet characterized. Knowledge of the prevalence and epitope specificity of gluten-specific T cells is a prerequisite for therapeutic efforts that target disease-specific T cells in celiac disease.

Background For many people public transport is the only mode of travel, and it can be challenging to keep the necessary distances in such a restricted space. The exact role of public transportation and risk of SARS-CoV-2 transmission is not known. Methods Participants (n = 121,374) were untested adult Norwegian residents recruited through social media who in the spring of 2020 completed a baseline questionnaire on demographics and the use of public transport. Incident cases (n = 1069) had a positive SARS-CoV-2 polymerase chain reaction test registered at the Norwegian Messaging System for Infectious Diseases by January 27, 2021. We investigated the association between the use of public transport and SARS-CoV-2 using logistic regression. Odds ratios (ORs) with 95% confidence intervals (CIs) adjusted for age, calendar time, gender, municipality, smoking, income level, fitness and underlying medical conditions were estimated. Frequency of the use of public transport was reported for 2 week-periods. Results Before lockdown, those who tested positive on SARS-CoV-2 were more likely to have used public transport 1–3 times (OR = 1.28, CI 1.09–1.51), 4–10 times (OR = 1.49, CI 1.26–1.77) and ≥ 11 times (OR = 1.50, CI 1.27–1.78, p for trend < 0.0001) than those who had not tested positive. Conclusion The use of public transport was positively associated with contracting SARS-CoV-2 both before and after lockdown.

We compared the αβ T‐cell receptor repertoires of CD8+ αβ intraepithelial lymphocytes from celiac disease patients and healthy subjects by single‐cell sequencing. We demonstrate that the repertoires of untreated celiac disease patients were more polyclonal and more diverse than what was observed in both treated patients and healthy subjects.