Document Detail

Association of a Toll-like receptor 1 polymorphism with heightened Th1 inflammatory responses and antibiotic-refractory Lyme arthritis.
MedLine Citation:
PMID:  22246581     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Single-nucleotide polymorphisms (SNPs) that alter immune function, inflammatory responses, and disease susceptibility have been identified in several genes encoding Toll-like receptors (TLRs). The TLR SNPs with the best evidence of an effect on immune function are those in TLR1 (1805GG), TLR2 (2258GA), and TLR5 (1174CT). This study was undertaken to assess the frequency and functional outcomes of these polymorphisms in patients with Lyme disease.
METHODS: SNP frequencies and functional outcomes were assessed in 248 patients with Lyme disease. Cytokine and chemokine levels were determined using multiplex assays in the serum of patients with erythema migrans (EM), joint fluid of patients with Lyme arthritis, and supernatants of Borrelia burgdorferi-stimulated peripheral blood mononuclear cells (PBMCs) from patients with Lyme arthritis.
RESULTS: The frequency of the TLR1-1805GG polymorphism was greater in patients with antibiotic-refractory arthritis compared with patients with EM or those with antibiotic-responsive arthritis. Early in the illness, patients with EM carrying 1805GG, primarily those infected with B burgdorferi 16S-23S ribosomal spacer RNA intergenic type 1 (RST1) strains, had higher serum levels of interferon-γ (IFNγ), CXCL9, and CXCL10 and had more severe infection than EM patients carrying the 1805TG/TT polymorphism. These inflammatory responses were amplified in patients with Lyme arthritis, and the highest responses were observed in patients with 1805GG in the antibiotic-refractory group who had been infected with RST1 strains. When PBMCs from patients with Lyme arthritis were stimulated with a B burgdorferi RST1 strain, the 1805GG group had a significantly larger fold increase in the levels of IFNγ, CCL2, CXCL9, and CXCL10 compared to the 1805TG/TT group. In contrast, the TLR2 and TLR5 polymorphisms did not vary in frequency or function among the groups.
CONCLUSION: The TLR1-1805GG polymorphism in B burgdorferi RST1-infected patients was associated with stronger Th1-like inflammatory responses, an environment that may set the stage for antibiotic-refractory arthritis.
Klemen Strle; Junghee J Shin; Lisa J Glickstein; Allen C Steere
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  64     ISSN:  1529-0131     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-27     Completed Date:  2012-07-13     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1497-507     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 by the American College of Rheumatology.
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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MeSH Terms
Anti-Bacterial Agents / therapeutic use*
Biological Markers / blood
Borrelia burgdorferi / classification,  drug effects,  genetics
Cells, Cultured
Chemokine CXCL10 / blood
Chemokine CXCL9 / blood
Drug Resistance, Bacterial / genetics*
Interferon-gamma / blood
Joints / microbiology,  pathology
Leukocytes, Mononuclear
Lyme Disease* / drug therapy,  genetics,  immunology
Middle Aged
Polymorphism, Single Nucleotide*
Synovial Fluid / metabolism,  microbiology
Synovitis* / genetics,  immunology,  pathology
Th1 Cells / immunology*,  pathology
Toll-Like Receptor 1 / genetics*,  metabolism
Young Adult
Grant Support
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Biological Markers; 0/CXCL10 protein, human; 0/CXCL9 protein, human; 0/Chemokine CXCL10; 0/Chemokine CXCL9; 0/Toll-Like Receptor 1; 82115-62-6/Interferon-gamma
Comment In:
Arthritis Rheum. 2012 May;64(5):1311-5   [PMID:  22246662 ]

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