Unraveling the Immunogenetics of STAT Proteins:Clinical Perspectives on Gain-of-Function and Loss-of-Function Variants

Signal Transducer and Activator of Transcription (STAT) proteins play pivotal roles in immune regulation. The dysregulation of these proteins, attributed to both gain-of-function (GOF) and loss-of-function (LOF) variants, has emerged as a substantial and intricate area of research. This comprehensive review delves into the intricate details of the diverse clinical spectrum associated with STAT variants and the immunological findings linked to these genetic alterations. Although this review does not encompass the treatment of each individual disease, we discuss investigative approaches ranging from immunophenotyping assessment to evaluation of STAT protein activity. These investigations play a crucial role in identifying affected patients and understanding the complexities of STAT.</p

Endoscopic colorectal cancer screening: a cost-saving analysis

BACKGROUND: Comprehensive analyses have shown that screening for cancer usually induces net costs. In this study, the possible costs and savings of endoscopic colorectal cancer screening are explored to investigate whether the induced savings may compensate for the costs of screening. METHODS: A simulation model for evaluation of colorectal cancer screening, MISCAN-COLON, is used to predict costs and savings for the U.S. population, assuming that screening is performed during a period of 30 years. Plausible baseline parameter values of epidemiology, natural history, screening test characteristics, and unit costs are based on available data and expert opinion. Important parameters are varied to extreme but plausible values. RESULTS: Given the expert opinion-based assumptions, a program based on every 5-year sigmoidoscopy screenings could result in a net savings of direct health care costs due to prevention of cancer treatment costs that compensate for the costs of screening, diagnostic follow-up, and surveillance. This result persists when costs and health effects are discounted at 3%. The "break-even" point, the time required before savings exceed costs, is 35 years for a screening program that terminates after 30 years and 44 years for a screening program that continues on indefinitely. However, net savings increase or turn into net costs when alternative assumptions about natural history of colorectal cancer, costs of screening, surveillance, and diagnostics are considered. CONCLUSIONS: Given the present, limited knowledge of the disease process of colorectal cancer, test characteristics, and costs, it may well be that the induced savings by endoscopic colorectal cancer screening completely compensate for the costs

No Evidence for Circulating Retina Specific Autoreactive T-cells in Latent Tuberculosis-associated Uveitis and Sarcoid Uveitis

Purpose: To detect circulating retina-specific autoreactive CD4+ T-cells and antiretinal antibodies (ARA) in latent tuberculosis (TB)-associated uveitis or sarcoid uveitis patients. Methods: The presence of crude retinal extract (RE) autoreactive CD4+ T-cells was determined by a highly sensitive flowcytometric-based technique examining co-expression of CD25 and CD134 (OX40) on RE stimulated PBMC. The presence of ARA in available matched serum samples was assessed by indirect immunofluorescence. Results: No autoreactive CD4+ T-cells against RE could be detected in either latent TB-associated uveitis or sarcoid uveitis patients, while ARA were detected in the serum of the majority (5/6) of latent TB-associated uveitis and all (3/3) sarcoid uveitis patients. Conclusion: Even with the use of this highly sensitive flowcytometric technique circulating retina-specific autoreactive CD4+ T-cells could not be detected. In contrast, ARA were detected in the majority of patients indicating an adaptive humoral immune response toward retinal antigens had occurred

A novel heterozygous mutation in the STAT1 SH2 domain causes chronic mucocutaneous candidiasis, atypically diverse infections, autoimmunity, and impaired cytokine regulation

Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency characterized by persistent or recurrent skin and mucosal surface infections with Candida species. Different gene mutations leading to CMC have been identified. These include various heterozygous gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) that are not only associated with infections but also with autoimmune manifestations. Recently, two STAT1 GOF mutations involving the Src homology 2 (SH2) domain have been reported, while so far, over 50 mutations have been described mainly in the coiled coil and the DNA-binding domains. Here, we present two members of a Dutch family with a novel STAT1 mutation located in the SH2 domain. T lymphocytes of these patients revealed STAT1 hyperphosphorylation and higher expression of STAT1 target genes. The clinical picture of CMC in our patients could be explained by diminished production of interleukin (IL)-17 and IL-22, cytokines important in the protection against fungal infections