Genetic polymorphisms of toll-like receptor 9 influence the immune response to CpG and contribute to hyper-IgM in primary biliary cirrhosis.
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.
Kikuchi
Kentaro
K
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility, 451 E Health Sciences Drive, suite 6510, Davis, CA 95616, USA.
Lian
Zhe-Xiong
ZX
Kimura
Yasuhiko
Y
Selmi
Carlo
C
Yang
Guo-Xiang
GX
Gordon
Stuart C
SC
Invernizzi
Pietro
P
Podda
Mauro
M
Coppel
Ross L
RL
Ansari
Aftab A
AA
Ikehara
Susumu
S
Miyakawa
Hiroshi
H
Gershwin
M Eric
ME
D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D020862:GC Rich Sequence / Q000276:immunology; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D008928:Mitochondria / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D001323:Autoantibodies; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors