New study unravels role of interferon gamma in autoimmune polyendocrine syndrome type 1: NEJM

The small study showed that APS-1, which is caused by autoimmune regulator (AIRE) deficiency, is characterized by excessive, multiorgan interferon-γ–mediated responses. JAK inhibition with ruxolitinib showed promising results in five patients.

Autoimmune polyendocrine syndrome type 1 is a rare genetic disorder characterized by the dysfunction of multiple endocrine glands, leading to a wide range of clinical manifestations, including hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis. Despite advances in understanding the genetic basis of APS-1, the precise mechanisms driving autoimmune pathology remain elusive.

Michail S. Lionakis, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, and colleagues examined whether APS-1 could be classified as a disease mediated by interferon-γ.

For this purpose, the researchers assessed APS-1 patients participating in a prospective natural history study and evaluated mRNA and protein expression in tissues and blood. Then, they examined the pathogenic role of interferon-γ using Aire−/−Ifng−/− mice and Aire−/− mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. Based on their findings, they used ruxolitinib to treat five patients with APS-1 and assessed transcriptional, immunologic, clinical, histologic, and autoantibody responses.

The study revealed the following findings:

• Patients with APS-1 had enhanced interferon-γ responses in blood, and all examined autoimmunity-affected tissues. Aire−/− mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs.
• Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire−/− mice normalized interferon-γ responses, and averted T-cell infiltration and organ damage.
• Ruxolitinib treatment of five patients with APS-1 led to reduced levels of T–T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, nail dystrophy, oral candidiasis, gastritis, arthritis, enteritis, Sjögren’s-like syndrome, thyroiditis, and urticaria.
• No serious adverse effects from ruxolitinib were identified in these patients.

In conclusion, the study highlights the central role of IFN-γ in autoimmune polyendocrine syndrome type 1, providing new insights into the underlying mechanisms of this rare disorder and offering potential therapeutic targets for future intervention.

"There is a need for further research to examine other JAK inhibitors such as tofacitinib (Xeljanz), as well as the biologic drug emapalumab (Gamifant) that neutralizes interferon-γ directly," the researchers wrote. "Dosing might be further optimized."

Reference:

Oikonomou V, et al "The role of interferon-γ in autoimmune polyendocrine syndrome type 1" N Engl J Med 2024; DOI: 10.1056/NEJMoa2312665.