介绍在X连锁无丙种球蛋白血症(XLA)中,BTK变异的多样性使基因型-表型相关性研究复杂化.由于BTK负调节toll样受体(TLRs),我们调查了不同的BTK突变类型是否选择性调节TLR途径,影响疾病表达。方法采用RT-qPCR,我们在有错义(n=3)和无义(n=5)BTK突变的XLA患者和健康对照(n=17)中定量了10个TLR信号相关基因.结果BTK,IRAK2,PIK3R4,REL,TFRC,UBE2N主要被下调,而RIPK2,TLR3,TLR10和TLR6显示可变调节。错义XLA组表现出IRAK2、PIK3R4、REL、和TFRC,和上调TLR3和/或TLR6。结论TLR3、TLR6、TLR10低表达可能增加感染的易感性。而高表达可能会导致慢性炎症,如关节炎或炎症性肠病。我们的发现揭示了一些XLA患者的重要炎症成分特征,即使在最佳治疗条件下。
BACKGROUND: 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 reverse transcription-quantitative polymerase chain reaction, 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.
CONCLUSIONS: 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.