{Reference Type}: Clinical Study
{Title}: The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.
{Author}: Oikonomou V;Smith G;Constantine GM;Schmitt MM;Ferré EMN;Alejo JC;Riley D;Kumar D;Dos Santos Dias L;Pechacek J;Hadjiyannis Y;Webb T;Seifert BA;Ghosh R;Walkiewicz M;Martin D;Besnard M;Snarr BD;Deljookorani S;Lee CR;DiMaggio T;Barber P;Rosen LB;Cheng A;Rastegar A;de Jesus AA;Stoddard J;Kuehn HS;Break TJ;Kong HH;Castelo-Soccio L;Colton B;Warner BM;Kleiner DE;Quezado MM;Davis JL;Fennelly KP;Olivier KN;Rosenzweig SD;Suffredini AF;Anderson MS;Swidergall M;Guillonneau C;Notarangelo LD;Goldbach-Mansky R;Neth O;Monserrat-Garcia MT;Valverde-Fernandez J;Lucena JM;Gomez-Gila AL;Garcia Rojas A;Seppänen MRJ;Lohi J;Hero M;Laakso S;Klemetti P;Lundberg V;Ekwall O;Olbrich P;Winer KK;Afzali B;Moutsopoulos NM;Holland SM;Heller T;Pittaluga S;Lionakis MS;
{Journal}: N Engl J Med
{Volume}: 390
{Issue}: 20
{Year}: 2024 May 30
{Factor}: 176.079
{DOI}: 10.1056/NEJMoa2312665
{Abstract}: <B>BACKGROUND: </B>Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.<BR><B>METHODS: </B>We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses.<BR><B>RESULTS: </B>Patients with APS-1 had enhanced interferon-γ responses in blood and in 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 damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients.<BR><B>CONCLUSIONS: </B>Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).