Journal of Clinical Immunology最新文献

Purpose: Pathogenic variants in the T-cell receptor alpha constant (TRAC) gene have been primarily associated with combined immunodeficiency (CID). To date, only five patients from three unrelated families harboring the same TRAC variant with a CID phenotype, and three patients carrying a distinct variant with severe combined immunodeficiency (SCID), have been described. We report a previously unreported homozygous TRAC variant causing a premature stop codon in three siblings with classical SCID phenotype.

Methods: Comprehensive immunological and molecular analyses were performed, including lymphocyte immunophenotyping, proliferation assays, qPCR for T helper (Th) subset-related gene expression, and cytokine secretion profiling. In silico analyses included conservation assessment, structural modeling using ChimeraX, and protein stability prediction via PremPS to evaluate the variant's structural and functional consequences.

Results: All three siblings exhibited recurrent infections, refractory diarrhea, and elevated liver enzymes, accompanied by profound T-cell lymphopenia with preserved B-cell numbers. Whole-exome sequencing revealed a homozygous TRAC variant in the affected siblings and heterozygous carriage in their parents. The variant alters a highly conserved residue, disrupting hydrogen bonding and likely destabilizing the protein structure. Functional assays demonstrated a marked reduction in recent thymic emigrants (RTEs) cell ratio absence of TCRαβ⁺ T cells, skewed Th polarization, and elevated proinflammatory cytokine levelsfindings consistent with a SCID phenotype.

Conclusion: These findings expand the clinical and molecular spectrum of TRAC-related immunodeficiency and support its inclusion among genes primarily associated with SCID. The results further emphasize that specific mutation sites within immune-related genes critically influence disease severity and phenotype variability.

TREC-NBS identifies patients with inborn errors of immunity (IEI) and syndromic features, but uncertainty remains regarding their immunological management. To address this, syndromic patients detected by TREC-NBS in Germany between August 2019 and April 2024 were systematically analyzed, including phenotype, treatment, and outcomes. National registries were screened, and data were completed by the treating centres. A total of 77 syndromic patients were identified, with 22 different gene defects found in 72 individuals (93.5%). Primary thymic deficiency was present in 64% (49/77), most commonly due to 22q11.2 deletion syndrome (62%). Common clinical features included congenital heart disease (57%), facial/skeletal abnormalities (53%), and neurological symptoms (36%). Definitive treatments were provided promptly in eligible patients, including 6 thymus transplants and 6 hematopoietic stem cell transplants (HSCT). A watch-and-wait approach was applied to the remaining patients, with 34% (22/65) receiving prophylactic treatment. Recovery of CD3 + T-cell counts was limited to a minority. Overall survival was 89%, with a median follow-up of 32 months (range 0.5-60). To conclude, this is the first comprehensive study of syndromic IEI patients identified through TREC-NBS. The findings show that the German healthcare system enables both early prophylactic care and timely access to definitive therapies. Moving forward, interdisciplinary collaboration will be key to developing evidence-based management guidelines for this challenging patient group.