Biology subjects

Korn, T.

Publications and source records attributed to Korn, T..

3 recordsLinked to original sources

bioRxiv2026

Targeting soluble immunoglobulins ameliorates idiopathic multicentric Castleman disease in a mouse model

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder that affects lymph nodes at multiple sites and can progress to life-threatening organ dysfunction. While curative therapies remain unavailable, largely due to a critical gap in understanding the diseases underlying etiology, the cytokine interleukin-6 (IL-6) is recognized as a major pathogenic driver, particularly in iMCD patients with plasmacytic lymphadenopathy. Here, we demonstrate the presence of Foxp3-expressing cells alongside plasma cells within germinal centers of lymph nodes from such iMCD patients. Based on this observation, we directed IL-6 overexpression specifically to Foxp3+ Treg cells and established a novel preclinical mouse model of iMCD. This targeted approach successfully recapitulated the key characteristics of iMCD in mice, including multifocal lymphadenopathy, splenomegaly, anemia, thrombocytopenia, marked plasmacytosis, and mortality in young adults. Advanced disease was characterized by renal pathology, including proteinuria and elevated creatinine levels. In this model, IL-6 directly promoted plasmacytosis, resulting in profound IgG1 hyperimmunoglobulinemia. Genetic ablation of soluble immunoglobulin production ameliorated iMCD symptoms, prevented renal dysfunction, and significantly extended survival. Our findings identify IL-6-driven IgG1 plasmacytosis as a critical pathogenic factor in iMCD, shedding light on the mechanisms underlying its development. Key pointsO_LITransgenic IL-6 expression in Foxp3+ cells models iMCD in mice and drives lethal IgG1 plasmacytosis C_LIO_LILoss of soluble immunoglobulins prevented renal impairment and prolonged survival in iMCD-like mice C_LI

immunology↗

bioRxiv2022

Rapamycin rescues loss-of-function in blood-brain barrier-interacting regulatory T cells

In many autoimmune diseases, FOXP3+ regulatory T cells (Tregs) skew towards a pro-inflammatory and non-suppressive phenotype and are therefore unable to control the exaggerated autoimmune response. This may largely impact the success of autologous Treg therapy which is currently under investigation for treatment of autoimmune diseases, including multiple sclerosis (MS). Thus, there is a need to ensure in vivo stability of Tregs before successful Treg therapy can be applied. Using a murine genetic fate-mapping model, we demonstrate that inflammatory exFOXP3 T cells accumulate in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). In a human in vitro BBB model, we discovered that interaction with inflamed blood-brain barrier (BBB)-endothelial cells induces loss of suppressive function in Tregs. Transcriptome analysis further revealed that Tregs which migrated across inflamed BBB-endothelial cells in vitro have a pro-inflammatory Th1/17 signature and upregulate the mTORC1 signaling pathway compared to non-migrated Tregs. These findings suggest that interaction with BBB-endothelial cells is sufficient to affect Treg function, and that transmigration triggers an additive pro-inflammatory phenotype switch, which was also seen in CNS-derived exFOXP3 T cells of EAE mice. In vitro treatment of migrated human Tregs with the clinically-approved mTORC1 inhibitor rapamycin completely restored the loss of suppressive function. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less suppressive CD49d+ Tregs in the cerebrospinal fluid of MS patients, thereby underscoring the relevance of our findings for human disease. In sum, our findings provide firm evidence that the inflamed BBB affects human Treg stability, which can be restored using a mTORC1 inhibitor. These insights can help in significantly improving the efficacy of autologous Treg therapy of MS.

immunology↗

bioRxiv2018

Profound functional and molecular diversity of mitochondria revealed by cell type-specific profiling in vivo

Mitochondria vary in morphology and function in different tissues, however little is known about their molecular diversity among cell types. To investigate mitochondrial diversity in vivo, we developed an efficient protocol to isolate cell type-specific mitochondria based on a new MitoTag mouse. We profiled the mitochondrial proteome of three major neural cell types in cerebellum and identified a substantial number of differential mitochondrial markers for these cell types in mice and humans. Based on predictions from these proteomes, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neurons. Moreover, we identified Rmdn3 as a major determinant of ER-mitochondria proximity in Purkinje cells. Our novel approach enables exploring mitochondrial diversity on the functional and molecular level in many in vivo contexts.

cell biology↗