Cyclic citrullinated MBP87–99 peptide stimulates T cell responses:

Implications in triggering disease

The immunogenicity of linear-Cit and cyclic-Cit peptides in mice is a first report, which gives insights into the triggers of the disease.

Cyclic-Cit peptide conjugated to reduced mannan induced strong IFN-c and IL-4 cytokine responses and no IL-10. Furthermore, strong T cell proliferative responses were observed. Interestingly, mice immunized with linear-Cit peptide conjugated to reduced mannan did not stimulate T cells in T proliferation assays but induced weak IL-4 with no IFN-c and IL-10 responses.

These studies demonstrate that cyclic-Cit peptide induces strong T cell responses which secrete IFN-c and IL-4. From a structural point of view, this may be assumed from an altered TCR interacting interface of the cyclic-Cit compared to the linear-Cit peptide.

This finding may open new avenues in drug design of new substances that inhibit PAD enzymes (citrullination) as a therapeutic strategy for the disease. Indeed, small molecule inhibitors of PAD enzymes have been identified using in silico screening of commercial libraries which reduce CD3+ T cells in mice.