RESEARCH - Citrullinated proteins are link between smoking, HLA-DR SE genotype, RA risk

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Citrullinated proteins are link between smoking, HLA-DR SE genotype, RA risk

Rheumawire

Jan 6, 2006

Janis

Stockholm, Sweden - Smoking is the major environmental risk factor for

rheumatoid arthritis (RA). The HLA-DR shared epitope (SE) is a major genetic

risk factor. Dr Lars Klareskog (Karolinska Institute, Stockholm, Sweden)

reports in the January 2006 issue of Arthritis and Rheumatism that the

interaction between these two risk factors is mediated by antibodies

directed against citrulline-modified proteins, a distinctive autoimmune

hallmark of RA [1].

" This is the first time that environmental agents, genes, and immune

reactions have been tied together in a tentative model for the development

of RA, " Klareskog told rheumawire. " This model now offers a number of

possibilities for studying the sequence of events that ultimately lead to

RA. Understanding this sequence, with respect to environment, genes, and

immune reactions, which potentially cause RA, will allow us to design a

number of new intervention strategies both before (prevention) and during

(treatment) the disease. "

RA with and without anti-CCP: Two different diseases?

Klareskog reported a case-control study in which 930 patients with

recent-onset RA (onset within the previous 12 months), drawn from the

Epidemiological Investigation of Rheumatoid Arthritis Study Group, were

matched with 383 healthy controls, drawn from the blood bank of northern

Sweden. Subjects were matched for age, sex, and residential area. All

participants completed questionnaires about their past and present smoking

habits; genotyping profiles were developed and levels of antibodies to

citrulline-containing peptides and of rheumatoid factor (RF) were analyzed.

The researchers also analyzed bronchoalveolar lavage samples from eight

healthy individuals with normal chest radiographs (four current smokers and

four nonsmokers) and four current smokers with pulmonary inflammatory

conditions.

" A dose-dependent relationship was found between the extent of smoking

(counted as pack-years) and the frequency of elevated

anticitrulline-antibody levels at the onset of RA, " Klareskog writes.

Data from the non-RA subjects showed that 16 of 576 smokers and 6 of 435

nonsmokers were anticitrulline-antibody positive (p=0.13).

The investigators next examined the correlation between the frequency of

anticitrullinated peptide antibodies and the presence of no SE genes, a

single SE gene copy, or double-copy SE genes. The number of SE-gene copies

strongly influenced the occurrence of anti-cyclic citrullinated (anti-CCP)

peptides.

Either single or double copies of SE were RA risk factors only for subjects

who also had anticitrulline antibodies. Smoking was a risk factor only for

patients with anticitrulline antibodies.

The interaction of smoking and SE is such that smoking increases the risk of

RA only slightly in SE-negative individuals, but the relative risk of RA for

smokers rises to 6.5 for those with a single SE-gene copy and to 21 for

those with two copes of SE.

Klareskog told rheumawire that, taken together, these findings suggest that

smoking induces a posttranslational modification of autoantigens present in

the lungs; that in individuals carrying HLA-DR SE, the citrullinated

proteins induce an immune response and the production of anticitrulline

antibodies; and that a trigger event in such subjects leads to

undifferentiated arthritis and citrullination of proteins in the synovium.

RF may enter the fray after anticitrulline antibodies form immune complexes

with citrullinated proteins and T cells have been activated against the

antigen in this complex. " This is the classic model for the triggering of

RF, which can now be used for RA, " Klareskog noted.

Klarkeskog also warned that anticitrulline-positive and

anticitrulline-negative RA are two very different conditions when it comes

to the major environmental agent (smoking) and the major genetic risk factor

(HLA-DR SE). " We can postulate that partly different molecular mechanisms

are active in the disease process in these two variants of RA. The

implication for clinical trials is that we should always stratify for

anticitrulline-positive vs anticitrulline-negative RA when performing

therapeutic (as well as other) studies in RA, " he concluded.

Source

1. Klareskog L, Stolt P, Lundberg K, et al. A new model for

an etiology of rheumatoid arthritis. Smoking may trigger HLA-DR (shared

epitope)-restricted immune reactions to autoantigens modified by

citrullination. Arthritis Rheum 2006; 54:38-46.

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