bims-hummad 2025-12-14 papers

Nat Commun. 2025 Dec 11.

Lactate bridges mesangial cells to the differentiation of follicular helper T cells in lupus nephritis.

Mengdi Liu, Huiyan Ji, Jiaxin Lei, Ming Zheng, Lingyi Li, Xingyu Zhai, Hongmin Wang, Ting Liu, Qinghua Cao, Lin Xu, Zhenke Wen.

Lupus nephritis (LN), a serious complication of systemic lupus erythematosus, is characterized by the deposition of IgG immune complexes. The generation of these autoantibodies depends on T follicular helper (Tfh) cells within secondary lymphoid organs. However, the potential contribution of Tfh cells residing within the kidney has remained unexplored. Here, our analysis of a single-cell kidney dataset from LN patients, alongside studies in humanized chimeras and kidney organoids, identifies the accumulation of renal Tfh cells. Mechanistically, self-DNA-stimulated LN-associated mesangial cells (MC) promote Tfh differentiation by inducing CNBP-mediated MPC1 deficiency, leading to increased lactate production. In turn, elevated lactate levels enhance PCAF-catalyzed BCL6 lactylation and subsequent K6- and K29-linked ubiquitination at Lys430, preventing proteasomal degradation of BCL6. Stabilization of BCL6 ultimately reinforces Tfh differentiation, amplifying renal autoimmune responses. Importantly, targeted depletion of Tfh cells mitigates disease progression in humanized chimeras. Thus, our findings reveal a tissue program of Tfh differentiation within the autoimmune kidney microenvironment, identifying a potential therapeutic target for the management of LN.

DOI: https://doi.org/10.1038/s41467-025-67416-x

Curr Protoc. 2025 Dec;5(12): e70263

HLA Transgenic Mice as a Model to Uncover Biomarkers and Therapeutic Strategies for Rheumatoid Arthritis.

David Luckey, Eric Marietta, Veena Taneja.

Rheumatoid arthritis (RA) is a chronic disease involving inflammation of the joints. While the etiology of RA remains unknown, evidence exists for a significant contribution of the major histocompatibility complex (MHC). Environmental factors are also indicated as playing an etiological role. Since it is impossible to define the mechanisms contributing to disease onset and progression in humans, mouse models have been used widely. While many animal models have been generated by immunization with self-proteins to induce arthritis, type II collagen (CII)-induced arthritis is one of the most commonly used models utilized to understand the immunopathology of RA. CII constitutes 80% to 90% of total collagen content of hyaline cartilage found in joints and is a genetically conserved sequestered protein. Immunization with heterologous CII with an adjuvant in mice leads to cellular and humoral responses to heterologous and autoreactive CII-specific responses and collagen-induced arthritis (CIA). Mice immunized with CII develop inflammatory arthritis that shares many similarities in clinical, serological, and radiological features with RA in humans. However, selecting an antigen for inducing arthritis and the mouse strain are important, as not all strains are susceptible to CIA. A critical difference between RA and CIA is that in mice that lack the expression of human MHC II, the development of CIA is linked to the H2A locus, which is the homologue of HLA-DQ, while most human studies have linked RA susceptibility with HLA-DR alleles. Mice expressing HLA-DQ and HLA-DR molecules have been used to understand the role of MHC genes in susceptibility to RA. The protocols for inducing CIA in the HLA expressing transgenic mice described in this article can be used to understand how the different HLA molecules confer susceptibility to RA. © 2025 Wiley Periodicals LLC. Basic Protocol 1: Use of mouse strains and humanized mice for modeling rheumatoid arthritis Basic Protocol 2: Use of humanized mice for therapeutic protocols.

Keywords: collagen‐induced arthritis; gut‐joint axis; microbiome; transgenic mice; type II collagen

DOI: https://doi.org/10.1002/cpz1.70263

Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2507422122

Glomerular endothelial cells eliminate nicotinamide adenine dinucleotide to instruct CD103+ T cells in human lupus nephritis.

Li Jia, Mengdi Liu, Huiyan Ji, Jiaxin Lei, Danhua Su, Lingyi Li, Ting Liu, Fenghong Yuan, Lin Xu, Qinghua Cao, Huimin Zhang, Zhenke Wen.

Lupus nephritis (LN), which is characterized by the accumulation of DNA-containing immune complexes (ICs), is the leading cause of death in patients with systemic lupus erythematosus (SLE). While growing evidence highlights the central role of CD103+ T cells in shaping the immune landscape of regional tissues, mechanisms driving the cell differentiation in LN remain largely unexplored. In this study, we identified an increased frequency of CD4+CD103+ T cells within the kidneys of SLE patients. Importantly, glomerular endothelial cells (ECs) from human LN tissues were found to promote the differentiation of CD4+CD103+ T cells by upregulating B lymphocyte-induced maturation protein 1 (Blimp-1). Genetic knockdown of Blimp-1 in CD4+ T cells resulted in a reduced frequency of renal CD4+CD103+ T cells and alleviated LN in humanized SLE chimeras. Mechanistically, LN-associated ECs, triggered by circulating DNA from SLE patients, exhibited elevated CD38 expression via the cGAS-STING signaling pathway. This facilitated the transfer of CD38 into CD4+ T cells through an exosome-dependent mechanism, leading to the depletion of nicotinamide adenine dinucleotide (NAD+) levels in CD4+ T cells. The resulting NAD+ depletion impaired the PARP1-mediated ADP-ribosylation of early growth response protein 1 (EGR1), which, in turn, enhanced Blimp-1 transcription and promoted CD103+ T cell differentiation. Targeting the cGAS/STING-CD38-EGR1 axis effectively reduced renal CD103+ T cell accumulation and inhibited LN progression in humanized SLE chimeras. Thus, ECs facilitate NAD+ depletion to drive CD103+ T cell differentiation, presenting a cellular mechanism underlying LN pathogenesis and a potential therapeutic target for the clinical management of human LN.

Keywords: CD103+ T cell; Lupus nephritis; endothelial cell

DOI: https://doi.org/10.1073/pnas.2507422122