RESEARCH - A new model for the etiology of RA: smoking may trigger HLA-DR-restricted immune reactions

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Arthritis Rheum. 2006 Jan;54(1):38-46.

A new model for an etiology of rheumatoid arthritis: smoking may trigger

HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified

by citrullination.

Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J,

Ronnelid J, HE, Ulfgren AK, Rantapaa-Dahlqvist S, Eklund A, Padyukov

L, Alfredsson L.

Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska

University Hospital, 171 76 Stockholm, Sweden. lars.klareskog@...

OBJECTIVE: To investigate whether smoking and HLA-DR shared epitope (SE)

genes may interact in triggering immune reactions to citrulline-modified

proteins. METHODS: In a case-control study involving patients with

recent-onset rheumatoid arthritis (RA), we studied interactions between a

major environmental risk factor (smoking), major susceptibility genes

included in the SE of HLA-DR, and the presence of the most specific

autoimmunity known for RA (i.e., antibodies to proteins modified by

citrullination). Immunostaining for citrullinated proteins in cells from

bronchoalveolar lavage fluid was used to investigate whether smoking is

associated with citrullination in the lungs. RESULTS: Previous smoking was

dose-dependently associated with occurrence of anticitrulline antibodies in

RA patients. The presence of SE genes was a risk factor only for

anticitrulline-positive RA, and not for anticitrulline-negative RA. A major

gene-environment interaction between smoking and HLA-DR SE genes was evident

for anticitrulline-positive RA, but not for anticitrulline-negative RA, and

the combination of smoking history and the presence of double copies of

HLA-DR SE genes increased the risk for RA 21-fold compared with the risk

among nonsmokers carrying no SE genes. Positive immunostaining for

citrullinated proteins was recorded in bronchoalveolar lavage cells from

smokers but not in those from nonsmokers.

CONCLUSION: We identified an environmental factor, smoking, that in the

context of HLA-DR SE genes may trigger RA-specific immune reactions to

citrullinated proteins. These data thus suggest an etiology involving a

specific genotype, an environmental provocation, and the induction of

specific autoimmunity, all restricted to a distinct subset of RA.

PMID: 16385494

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=16385494

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