| 1. |
- Klareskog, L., et al.
(författare)
-
The importance of differences : On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis
- 2020
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 287:5, s. 514-533
-
Forskningsöversikt (refereegranskat)abstract
- The current review uses rheumatoid arthritis (RA) as a prominent example for how studies on the interplay between environmental and genetic factors in defined subsets of a disease can be used to formulate aetiological hypotheses that subsequently can be tested for causality using molecular and functional studies. Major discussed findings are that exposures to airways from many different noxious agents including cigarette smoke, silica dust and more interact with major susceptibility genes, mainly HLA-DR genetic variants in triggering antigen-specific immune reactions specific for RA. We also discuss how several other environmental and lifestyle factors, including microbial, neural and metabolic factors, can influence risk for RA in ways that are different in different subsets of RA.The description of these processes in RA provides the best example so far in any immune-mediated disease of how triggering of immunity at one anatomical site in the context of known environmental and genetic factors subsequently can lead to symptoms that precede the classical inflammatory disease symptoms and later contribute also to the classical RA joint inflammation. The findings referred to in the review have led to a change of paradigms for very early therapy and prevention of RA and to efforts towards what we have named 'personalized prevention'. We believe that the progress described here for RA will be of relevance for research and practice also in other immune-mediated diseases.
|
|
| 2. |
- Mahdi, H, et al.
(författare)
-
Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis
- 2009
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:12, s. 1319-1324
-
Tidskriftsartikel (refereegranskat)abstract
- Gene-environment associations are important in rheumatoid arthritis (RA) susceptibility, with an association existing between smoking, HLA- DRB1 'shared epitope' alleles, PTPN22 and antibodies to cyclic citrullinated peptides (CCP). Here, we test the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of these associations. In 1,497 individuals from three RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43-63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22 and smoking showed the strongest association with the anti-CEP-1-positive subset (odds ratio (OR) of 37, compared to an OR of 2 for the corresponding anti-CEP-1-negative, anti-CCP-positive subset). We conclude that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of RA.
|
|
