Decoding the Effects of Gain-of-Function Mutations in STAT1 and STAT3: A Literature Review on Immune Dysregulation and Treatment Strategies

Abstract

Inborn errors of immunity (IEIs) are genetic conditions that disrupt the immune system, leading to susceptibility to infections, autoimmunity, inflammation, and other immune dysregulations. Under normal circumstances, the JAK-STAT pathway transduces signals from the cytokine receptors to the nucleus, where it regulates immune cell responses. Gain-of-function (GOF) mutations in the STAT1 and STAT3 genes are examples of IEIs that disrupt the JAK-STAT signaling pathway. STAT1 GOF mutations often result in chronic mucocutaneous candidiasis (CMC), recurrent infections, and autoimmune diseases, while STAT3 GOF mutations are associated with severe bacterial infections, systemic autoimmunity, and multi-organ effects, such as diabetes and enteropathy. Both STAT syndromes show significant heterogeneity in clinical manifestations and responses to treatments. This heterogeneity impacts the diagnosis and treatment strategies for STAT1 or STAT3 GOF diseases. Current therapies, such as JAK inhibitors, are not effective in all patients. Some STAT3 GOF patients benefit from combination therapies, while STAT1 GOF patients often respond to JAK inhibitors alone. Novel research strategies, such as patient-derived stem cells are being used to better understand the disease and improve treatment strategies. Further research is needed to investigate the molecular mechanisms underlying STAT GOF mutations and develop patient-specific therapeutic strategies. Insights from these STAT GOF syndromes may also help in understanding and treating other immune-related diseases such as cancer and autoimmune disorders.