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"... People with psoriasis have overactive immune systems that cause them to develop red, scaly, and itchy patches across their body. More than 4.6 million people were living with psoriasis globally in 2019.
This world first discovery also identified what drives the skin-only disease to occasionally progress to a skin and joint disease known as psoriatic arthritis. ...
They found that mice with a single copy of the mutated IKBKB gene developed a skin disease with characteristics of psoriasis. While those with two copies of the mutation resulted in psoriatic arthritis. ..."
The mutation in the IKBKB gene is what’s known as a gain-of-function mutation.
From the abstract:
"Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3 + CD25+ Tregs of which a subset express IL-17. These modified Tregs are enriched in both inflamed tissues, blood and spleen, and their transfer is sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs reveal expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-κB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation."
IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model (open access)
Fig. 1: Overactive IKK2 leads to psoriasis.
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