Genetic polymorphisms of toll-like receptor 9 influence the immune response to CpG and contribute to hyper-IgM in primary biliary cirrhosis

Kentaro Kikuchi, Zhe Xiong Lian, Yasuhiko Kimura, Carlo Selmi, Guo Xiang Yang, Stuart C. Gordon, Pietro Invernizzi, Mauro Podda, Ross L. Coppel, Aftab A. Ansari, Susumu Ikehara, Hiroshi Miyakawa, M. Eric Gershwin

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Abstract

The serum hallmark of primary biliary cirrhosis (PBC) is the presence of anti-mitochondrial antibodies (AMA), found in 95% of patients. However, nearly every patient with PBC, including those who are AMA-negative, has an elevation in serum IgM. This hyper-IgM is neither representative of other Ig isoforms, nor is due to the levels of AMA. In fact, we have recently reported that the hyper-IgM is an innate immune response and can be induced with CpG-B with concurrent up-regulation of toll-like receptor 9 (TLR9). Based on these observations, we performed a two-tier study. First, we quantitated TLR9 genotypes in patients with PBC and controls and correlated these data with the B cell response to CpG-B. Second, based on these data, we performed an extensive TLR9 genotyping in a large cohort of patients and controls. We report herein that the 2848 AA TLR9 genotype is associated with enhanced gene expression and higher frequency of intracellular IgM+ B cells following CpG stimulation. Interestingly, however, despite the functional association, there is no difference in the distribution of TLR9 genotypes between patients and controls. Our data emphasize the importance of dissecting the innate immune response in PBC.

Original languageEnglish (US)
Pages (from-to)347-352
Number of pages6
JournalJournal of Autoimmunity
Volume24
Issue number4
DOIs
StatePublished - Jun 2005

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Keywords

  • Bacterial motifs
  • Genetic polymorphisms
  • Innate immunity
  • Primary biliary cirrhosis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Kikuchi, K., Lian, Z. X., Kimura, Y., Selmi, C., Yang, G. X., Gordon, S. C., Invernizzi, P., Podda, M., Coppel, R. L., Ansari, A. A., Ikehara, S., Miyakawa, H., & Gershwin, M. E. (2005). Genetic polymorphisms of toll-like receptor 9 influence the immune response to CpG and contribute to hyper-IgM in primary biliary cirrhosis. Journal of Autoimmunity, 24(4), 347-352. https://doi.org/10.1016/j.jaut.2005.03.002