Biology subjects

Kanczkowski, W.

Publications and source records attributed to Kanczkowski, W..

2 recordsLinked to original sources

bioRxiv2025

IFNG-producing self-reactive CD4+ T cells drive autoimmune adrenalitis in a mouse model of Addison's disease

Autoimmune Addisons disease (AD) is a rare but life-threatening disorder caused by immune-mediated destruction of the adrenal cortex, and progress in therapy has been limited by insufficient mechanistic insight. Here, we establish a model of Experimental Autoimmune Adrenalitis (EAA) that recapitulates key features of AD and reveals sex-dependent differences in disease manifestation within the model. Immunization with peptides derived from the adrenal self-antigen CYP11A1 induces corticosterone insufficiency. We show that autoimmune adrenalitis is driven by IFNG produced by self-reactive CD4 T cells, promoting granulomatous inflammation in the adrenal cortex. Together, these findings identify IFNG as a central effector of autoimmune adrenalitis and suggest that targeting the IFNG pathway may represent a potential therapeutic strategy for AD. SignificanceAddisons disease (AD) is a rare autoimmune disorder that destroys the adrenal cortex, yet its underlying mechanisms remain unknown. We developed a mouse model of Experimental Autoimmune Adrenalitis (EAA) that mirrors the hormonal and immunological features of AD. Our study reveals that IFNG-producing CD4 T cells drive adrenal inflammation and dysfunction, identifying IFNG as a key pathogenic factor and a potential therapeutic target.

immunology↗

bioRxiv2022

INFLAMMATION INDUCED DOWNREGULATION OF SUCCINATE DEHYDROGENASE REGULATES ADRENOCORTICAL FUNCTION

The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH) although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH) leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1{beta} reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the SDHB promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1{beta}-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for the adrenal dysfunction in severe inflammation but also a potential target for therapeutic intervention.

immunology↗