Biology subjects

Basavarajappa, S. C.

Publications and source records attributed to Basavarajappa, S. C..

5 recordsLinked to original sources

bioRxiv2026

MicroRNA-146a Deficiency Protects NOD Mice from Autoimmune Diabetes by Enhancing c-Rel-Dependent Regulatory T Cell Function

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T-cell mediated destruction of pancreatic islet {beta}-cells with genetic, environmental, and molecular triggers involved in disease pathogenesis. Patients with T1D have elevated serum levels of microRNA146a (miR146a). Polymorphisms in the miR146a gene that result in reduced expression of miR146a are associated with protection from T1D. We studied physiological regulators of miR146a expression and found that both hyperglycemia and elevated O-GlcNAcylation increased miR146a expression in T cells. Peripheral blood mononuclear cells (PBMCs) from T1D patients showed increased miR146a and O-GlcNAc transferase (OGT) expression, suggesting increased O-GlcNAcylation may promote miR146a expression in T1D patients. To determine the genetic and developmental role of miR146a in T1D, we generated miR146a-knockout (KO) non-obese diabetic (NOD) mice and found that absence of miR146a significantly protected NOD mice from spontaneous autoimmune diabetes. While we found no impact of miR146a knockout on general hematopoietic parameters and immune cell populations, remarkably, immune cell infiltration into the pancreas was significantly attenuated. Protection from autoimmune diabetes in miR146a-KO NOD mice was associated with increased regulatory T (Treg) cells in the spleen and pancreatic lymph node. Mechanistically, absence of miR146a increased NF-{kappa}B c-Rel expression in Treg cells and enhanced c-Rel binding at the Forkhead box protein P3 (FOXP3) promoter, which positively regulated Treg cell development and suppressor function, offering protection from T1D in miR146a-KO NOD mice. Our findings reveal miR146a as a key regulator of Treg cell-mediated immune tolerance through controlling NF-{kappa}B c-Rel-dependent FOXP3 expression and suggest targeting miR146a as a potential strategy to restore peripheral tolerance in T1D.

immunology↗

bioRxiv2026

Deficiency of IL-36 receptor antagonist (DITRA) is associated with decreased homoeostatic CCL27 expression leading to heightened dermal inflammation.

Deficiency of the Interleukin-36 Receptor antagonist (DITRA) is a rare autoinflammatory condition which commonly manifests as severe, recurrent episodes of Generalized Pustular Psoriasis (GPP). Loss-of-function mutations in the IL36RN gene result in unopposed IL-36 cytokine signalling leading to severe psoriatic inflammation, which can be successfully treated with Anti-IL-36 receptor (IL-36R) monoclonal antibodies. Despite such advances, there remain some key questions concerning how loss of a functional IL-36R antagonist predisposes to GPP, including identifying the potential impacts of IL36RN mutations on skin homeostasis. To address this question, we investigated the consequences of IL-36Ra deficiency using Il36rn-/- mice, which recapitulate the severe psoriatic inflammation observed in DITRA patients. Here, we demonstrate, that in overtly healthy Il36rn-/- mice, prior to disease onset, there is disrupted dermal immune homeostasis, characterised by decreased expression of the chemokine CCL27. Altered skin homeostasis occurred in association with dysbiosis of the skin microbiome, characterised by a significant outgrowth of the commensal bacteria, Cutibacterium acnes. Importantly, intradermal administration of recombinant CCL27, prior to disease induction, significantly reduced the enhanced severity of psoriasiform inflammation, demonstrating a central role for this chemokine in regulating predisposition to increased severity. Transcriptomic analysis of GPP patients skin also revealed decreased CCL27 expression in non-lesional, as well as lesional, compared to healthy skin, indicating that this chemokine may also play a key instructive role among DITRA patients. Together, these data identify a novel mechanism through which IL-36Ra deficiency alters dermal homeostasis and predisposes to increased severity of psoriatic disease observed in DITRA patients.

immunology↗

bioRxiv2026

Targeting redox imbalance through Nrf2 activation in the inflamed coeliac duodenum.

Coeliac Disease (CeD) is a chronic gastrointestinal inflammatory disease initiated by dietary gluten in genetically predisposed individuals. While the inflammatory processes which drive tissue destruction in the coeliac duodenum have been extensively characterised, an increased oxidative stress (OS) response has also been suggested to contribute to CeD pathogenesis. However, the precise mechanisms which regulate OS in the coeliac mucosa and whether they impact inflammation remain ill defined. The master anti-oxidant transcriptional regulator Nuclear factor erythroid 2-related factor 2 (Nrf2), and its inhibitor, Kelch like ECH-associated protein 1 (Keap1) have been implicated in chronic gastrointestinal inflammatory diseases, such as ulcerative colitis but have been largely unexplored in the context of CeD. To investigate redox balance in the CeD duodenum, we utilised single cell transcriptomics to assess overall OS and cytoprotective Nrf2 activation across cell subsets in duodenal biopsies from CeD patients. OS induced gene expression was broadly increased across multiple cell subsets in the CeD mucosa. Simultaneously, specific markers of Nrf2 activation were decreased in cell subtypes central to pathogenesis of CeD, including activated CD4+ T cells and intraepithelial T lymphocytes, indicating a distinct redox imbalance in these cells. Furthermore, pharmacological activation of Nrf2 significantly decreased gliadin induced IFNG expression in CeD duodenal biopsies. Taken together, our findings demonstrate that redox imbalance represents a therapeutic opportunity for the modulation of proinflammatory responses that drive the pathogenesis of CeD.

immunology↗

bioRxiv2025

Immune signaling mediates stromal changes to support epithelial reprogramming in Celiac duodenum

Coeliac Disease (CeD) is a chronic autoimmune disorder affecting 0.5-1% of the general population with a wide geographical distribution. Despite recent efforts to deeply phenotype gluten-specific immune activation at the single cell level, recent clinical studies targeting gluten degradation and other immune tolerance mechanisms have been unsuccessful. To this end, a deeper understanding of immune and non-immune cellular dynamics and interactions are required to characterize tissue-specific mechanisms responsible for CeD pathogenesis, repair, and resolution. Here, we assembled the most comprehensive scRNAseq dataset in Coeliac Disease to date, including 203,555 cells across 21 active CeD and 11 control duodenal samples. Compared to control duodenum, CeD was characterized by single cell differential changes in abundance, gene expression and cell-cell interactions across cellular compartments. In the immune compartments, CeD samples showed expected increases in plasma cell abundance and shifts toward type 1 effector biology (e.g., increase in cycling CD8pos, {gamma}{delta} T cells and IFNG transcriptional shifts) and Tfh-related biology (e.g., increases in IL21 signaling to effector T cells). In addition, activated myeloid subsets, including DC2 and monocytes, were increased in disease and were characterized by increased pro-inflammatory pathway expression, including IL-1{beta}. Non-immune compartments showed increased stem/crypt and secretory enterocytes in CeD samples with a decrease in absorptive enterocytes, reflecting the villus atrophy and crypt hyperplasia hallmarks of CeD epithelial dysfunction. Accompanying the epithelial changes, distinct changes in stromal populations were identified, particularly with increases in abundance and transcriptional activity of NRG1 and SMOC2 fibroblasts. Cell-cell interaction analysis across multiple cellular compartments proposed a distinct increased role of fibroblasts to support the epithelial reprogramming of the increased stem/crypt epithelial fraction in CeD, mediated by myeloid derived IL-1{beta} signal and lymphoid-derived IFN-{gamma}. This dataset reveals a previously unknown role for T-myeloid-stromal-epithelial cell communication in CeD, highlighting key mechanisms of the tissue-level cellular dynamics in response to gluten ingestion.

immunology↗

bioRxiv2021

Molecular dynamics simulations and functional studies reveal that hBD-2 binds SARS-CoV-2 spike RBD and blocks viral entry into ACE2 expressing cells

New approaches to complement vaccination are needed to combat the spread of SARS-CoV-2 and stop COVID-19 related deaths and long-term medical complications. Human beta defensin 2 (hBD-2) is a naturally occurring epithelial cell derived host defense peptide that has antiviral properties. Our comprehensive in-silico studies demonstrate that hBD-2 binds the site on the CoV-2-RBD that docks with the ACE2 receptor. Biophysical and biochemical assays confirm that hBD-2 indeed binds to the CoV-2-receptor binding domain (RBD) (KD [~] 300 nM), preventing it from binding to ACE2 expressing cells. Importantly, hBD-2 shows specificity by blocking CoV-2/spike pseudoviral infection, but not VSV-G mediated infection, of ACE2 expressing human cells with an IC50 of 2.4{+/-} 0.1 M. These promising findings offer opportunities to develop hBD-2 and/or its derivatives and mimetics to safely and effectively use as novel agents to prevent SARS-CoV-2 infection.

biochemistry↗