Macroprolactin primarily comprises a complex of prolactin (PRL) and IgG molecules, particularly anti-PRL autoantibodies. However, it is unknown why autoantibodies against PRL develop in certain subjects. This study aimed to elucidate post-translational modifications in the PRL molecule that may be involved in the pathogenesis of macroprolactinaemia.
Macroprolactinaemia was screened with a polyethylene glycol method in 238 patients with rheumatoid arthritis (RA) and 302 control subjects and confirmed by gel chromatography. We examined the relationship between macroprolactinaemia and several RA-related laboratory tests including matrix metalloproteinase-3 (MMP-3) and anti-cyclic citrullinated peptide (CCP) antibody titres. The effect of MMP-3 on the PRL molecule was examined by western blotting.
Patients with RA exhibited a significantly higher prevalence of macroprolactinaemia (15/238; 6.3%) than the young control subjects (5/219 subjects; 2.3%), but the prevalence was not different from that observed in the elderly control subjects (5/83 subjects; 6.0%). The prevalence of macroprolactinaemia in patients with elevated MMP-3 levels (9.68%) was significantly higher than that in those with normal MMP-3 levels (2.63%). Digestion of PRL with MMP-3 produced vasoinhibins with several molecular species. Serum total and free PRL levels in RA patients were higher than those in the age- and gender-matched control subjects. The levels of macroprolactin were not significantly correlated with those of RA-specific anti-CCP antibody.
We speculate that elevated MMP-3 levels may lead to the formation of new epitopes on the PRL molecule that might trigger an immune response to produce anti-PRL autoantibodies in some patients with RA. Such post-translational modifications may possibly contribute to the increased prevalence of macroprolactinaemia in elderly subjects.