Celiac disease (CeD) is an autoimmune disorder triggered by dietary gluten. While HLA-DQ2/8-mediated presentation of gliadin peptides is required for disease, the mechanisms that underlie the loss of oral tolerance to gluten remain incompletely understood. Long-noncoding RNAs (lncRNAs) have been increasingly recognized as regulators of immune function, yet their role in oral tolerance has not been previously explored. Here, using a screen designed to identify lncRNAs responsive to T cell activation and enriched for CeD-associated GWAS variants, we identified lnc13 as a top candidate. In HLA-DQ8 transgenic mice lacking lnc13, unmanipulated gluten ingestion led to molecular signatures resembling human CeD and hallmark features of loss of oral tolerance to gluten: increased IFN-γ lymphocytes, IL-12 myeloid cells, cytotoxic intraepithelial immune cells and crypt hyperplasia in the small intestine. Mechanistically, lnc13 binds specific DNA regulatory regions and limits immune cell responsiveness to proinflammatory signals. In particular, lnc13 restrains IL-15-driven differentiation of CD8 natural killer-like lymphokine-activated killer cells (an IL-15-dependent pathway strongly implicated in CeD). These findings establish lnc13 as a critical noncoding modulator of oral gluten tolerance.

Immunodeficiency-associated primary CNS lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted an international retrospective multi-center study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL, diagnosed at 23 participating sites in 7 countries. Pre-existing immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%), and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab-methotrexate-(RM)-based chemotherapy was associated with highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment HR: 1.05 (95%-CI:1.02-1.07); p < 0.001), Karnofsky Performance status (KPS) < 70 (HR: 3.10 (95%-CI:1.67-5.87); p < 0.001), EBV positivity (HR: 3.26 (95%-CI:1.47-7.33); p = 0.004) as prognostic factors for OS. A prognostic score was developed based on the sum of these adverse variables (age > 60 years, KPS < 70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to one, two and three unfavorable markers (p < 0.0001). It allowed improved prognostic stratification of ID-PCNSL as compared to the well-established MSKCC and IELSG models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiologic features of ID-PCNSL and introduces an easily applicable prognostic system with potential to guide future management.

Truncating and missense mutations of the CREBBP gene are highly prevalent in follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancies. These mutations are acquired early during tumor evolution by a common precursor cell (CPC) and lead to either complete protein loss or single amino-acid substitutions in the acetyltransferase (KAT) domain. As a result, CREBBP is impaired in its ability to acetylate enhancer histones and non-histone proteins implicated in the germinal center (GC) reaction, the structure from which these tumors originate. However, whether truncating and KAT domain missense mutations are functionally equivalent in instructing the CPC remains unexplored. Using a conditional GC-specific knock-in mouse model for the highly frequent CREBBP-R1446H amino-acid change (CrebbpRH), here we show that, compared to complete Crebbp loss, missense mutants impose distinct quantitative and qualitative effects on the GC response. CrebbpRH controls unique transcriptional programs leading to the pre-neoplastic expansion of GCs with abnormal architecture, increased percentage of Tfh cells, and a skewed immune response toward memory B-cell differentiation. Expression of CrebbpRH, but not Crebbp loss, was by itself sufficient to initiate malignant transformation, indicating a stronger tumor-promoting activity. Of note, lymphoma cells with CREBBPRH and CREBBP loss showed distinct sensitivity to CREBBP/p300 small molecule inhibitors. Together with the differential distribution of missense and truncating mutations in FL and DLBCL, these findings have implications for the pathogenesis and therapeutic targeting of these cancers.

Lymph nodes (LN) are key secondary lymphoid organs (SLO) for a coordinated immune response. They have been extensively characterized by numerous investigative techniques chiefly as single cell suspensions because they are composed of vagile yet crowded hematolymphoid elements, unfriendly to spatial tissue organization-saving techniques. We comprehensively classify in situ all cells of 19 human LN free of pathology with a 78-marker antibody panel, an hyperplexed cyclic staining method, MILAN, and an analytical bioinformatic pipeline, BRAQUE. A total of 77 cell types were classified, encompassing T, B, innate immune and stromal cells. CD4 and CD8 T-cells were classified into 27 unique subsets by leveraging the expression profiles of TCF7, the presence of co-inhibitory receptors and the spatial distribution. CD5 and TCF7 expression defined novel B-cell types. CD27 + mature B-cells occupied previously unrecognized nodal spaces non-overlapping with the cortex and the plasma-cell rich medullary cords. Type 2 conventional dendritic cells were located in nodular paracortical aggregates. Statistically controlled pairwise neighborhood analysis showed sparse cell-cell interactions, known and new neighbors, established and novel LN landscape niches. A high-dimensional proteomic interrogation of the normal human LN provides spatial allocation of known cell types, novel interactions and the landscape organization.