Rheumatoid Rescue?

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Science  04 Apr 2014:
Vol. 344, Issue 6179, pp. 11
DOI: 10.1126/science.344.6179.11-b

MHC class II molecules can rescue endoplasmic reticulum–localized misfolded proteins from protein degradation and transport them to the cell surface intact by associating with the misfolded protein. MHC class II allelic polymorphisms are associated with susceptibility to many autoimmune diseases. Jin et al. have now found that cellular misfolded autoantigens rescued and complexed with MHC class II molecules can become targets for autoantibodies in patients with rheumatoid arthritis (RA). By analyzing sera from some RA patients in which autoantibodies against correctly folded intact proteins were not detectable, autoantibodies specific to misfolded proteins complexed with MHC class II molecules of disease-susceptible alleles but not disease-resistant MHC class II alleles were observed. This suggested that misfolded proteins complexed with MHC class II molecules are natural autoantigens for autoantibodies. Autoantibody binding to misfolded proteins transported by MHC class II molecules was strongly correlated with susceptibility to RA. Thus, misfolded proteins, which normally would not be exposed to the immune system, can be targets for autoantibodies when they avoid protein degradation.

Proc. Natl. Acad. Sci. U.S.A. 111, 3787 (2014).

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