Dysregulation of TLR Signaling-Associated Gene Expression in X-linked Agammaglobulinemia: Implications for Correlations Genotype-Phenotype and Disease Expression

Introduction In X-linked agammaglobulinemia (XLA), the diversity of BTK variants complicates the study of genotype-phenotype correlations. Since BTK negatively regulates toll-like receptors (TLRs), we investigated if distinct BTK mutation types selectively modulate TLR pathways, affecting disease expression. Methods Using RT-qPCR, we quantified ten TLR signaling-related genes in XLA patients with missense (n=3) and nonsense (n=5) BTK mutations and healthy controls (n=17). Results BTK, IRAK2, PIK3R4, REL, TFRC, and UBE2N were predominantly downregulated, while RIPK2, TLR3, TLR10, and TLR6 showed variable regulation. The missense XLA group exhibited significant downregulation of IRAK2, PIK3R4, REL, and TFRC, and upregulation of TLR3 and/or TLR6. Conclusion Hypo-expression of TLR3, TLR6, and TLR10 may increase susceptibility to infections, while hyper-expression might contribute to chronic inflammatory conditions like arthritis or inflammatory bowel disease. Our findings shed light on the important inflammatory component characteristic of some XLA patients, even under optimal therapeutic conditions.