CGRP Deficiency-Mediated Prolactin Upregulation Via Mag Antibodies Contributes to Painless Pathogenesis in IgG4-Related Disease

Abstract

Abdominal pain is the most common symptom of pancreatitis, but IgG4-related autoimmune pancreatitis is characterized by painless jaundice. This specific pathological phenomenon may be a breakthrough in finding a new pain mechanism. Recently, we found CGRP deficiency, plasma cell neurotropic enrichment, high basal level of prolactin (PRL) expression, and some specific neuro-antibodies in IgG4-related disease (IgG4-RD). MAG (myelin-associated glycoprotein) antibodies were detected in the serum of IgG4-RD patients by immunofluorescence (IFA) using a monkey nerve as a substrate. The specific antibodies were verified and quantified by ELISA. Cytokines were measured in tissues homogenate obtained from CGRP+/- rats by liquid suspension chip technology. A significant increase in the serum PRL level and an imbalanced ratio Th1/Th2 of IgG4-RD were established. Differential proteins in the inflammatory tissues of IgG4-RD were concentrated in the hormone-sensitive pathway. Specifically, the level of the calcitonin gene-related peptide (CGRP) was significantly decreased. Intriguingly, MAG antibodies (IgG, IgG4, and IgM) were detected by IFA and ELISA. In vivo, higher levels of PRL and Th2 cytokines were detected in CGRP+/- rats than in wild-type rats. Similarly, decreasing trends in the concentrations of IgG4-RD, Akt1 (Ser473), and STAT3 (Ser727) phosphorylation were also found in the CGRP+/- rats. Our findings indicate that the presence of CGRP-deficiency-mediated MAG antibodies is a probable molecular basis for the initial events were triggered in painless IgG4-RD via prolactin upregulation. Funding: This work was supported by a grant from the National Natural Science Foundation of China (no.81571613, 81871293 to L.Q.C., and no.81572442 to G.F.). Declaration of Interest: All authors declare that they have no conflicts of interest. Ethical Approval: This research project was approved by the Ethics Committee of the Fujian Medical University, which supervised the study.