Dysregulation of Toll-Like Receptor Signaling-Associated Gene Expression in X-Linked Agammaglobulinemia: Implications for Correlations Genotype-Phenotype and Disease Expression

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. Usi...

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Bibliographic Details
Published in:Journal of innate immunity 2024-01, Vol.16 (1), p.425-439
Main Authors: Teocchi, Marcelo, de Andrade Eugênio, Thaís, Furlaneto Marega, Lia, Quinti, Isabella, Dos Santos Vilela, Maria Marluce
Format: Article
Language:English
Subjects:
Adolescent
Adult
Agammaglobulinaemia Tyrosine Kinase - genetics
Agammaglobulinemia - genetics
Agammaglobulinemia - immunology
b-lymphocytes
Brief Report
bruton’s tyrosine kinase
Child
Child, Preschool
Female
gene expression profiling
Gene Expression Regulation
Genetic Association Studies
Genetic Diseases, X-Linked - genetics
Genetic Diseases, X-Linked - immunology
Humans
Male
Mutation
nf-kappab
Signal Transduction - genetics
toll-like receptor
Toll-Like Receptors - genetics
Toll-Like Receptors - metabolism
x-linked agammaglobulinemia
Young Adult
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Summary: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. 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). 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. 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.
ISSN:1662-8128
1662-811X
1662-8128
DOI:10.1159/000540082