Prolactin Increases the Frequency of Follicular T Helper Cells with Enhanced IL21 Secretion and OX40 Expression in Lupus-Prone MRL/lpr Mice

Yolanda P Alemán-García,Rocio Flores-Fernández,Alberto Pizaña-Venegas,Patricia Gorocica-Rosete,Luis Chávez-Sanchéz,Ezequiel M Fuentes-Pananá,María V Legorreta-Haquet,Francico Blanco-Favela,Ricardo M Vaquero-García,Adriana K Chávez-Rueda,Carlo Perricone

doi:10.1155/2021/6630715

Abstract

Systemic lupus erythematosus is characterized by high levels of IgG class autoantibodies that contribute to the pathophysiology of the disease. The formation of these autoantibodies occurs in the germinal centers, where there is cooperation between follicular T helper cells (TFH) and autoreactive B cells. Prolactin has been reported to exacerbate the clinical manifestations of lupus by increasing autoantibody concentrations. The objective of this study was to characterize the participation of prolactin in the differentiation and activation of TFH cells, by performing in vivo and in vitro tests with lupus-prone mice, using flow cytometry and real-time PCR. We found that TFH cells express the long isoform of the prolactin receptor and promoted STAT3 phosphorylation. Receptor expression was higher in MRL/lpr mice and correlative with the manifestations of the disease. Although prolactin does not intervene in the differentiation of TFH cells, it does favor their activation by increasing the percentage of TFH OX40+ and TFH IL21+ cells, as well as leading to high serum concentrations of IL21. These results support a mechanism in which prolactin participates in the emergence of lupus by inducing overactive TFH cells and perhaps promoting dysfunctional germinal centers.

Highlights

The neuroendocrine and immune systems are closely interrelated, as the secretory products of the neuroendocrine system can act on the immune system and vice versa [1]
Seeking for an explanation for this observation and given that the increased germinal centers (GCs) formation correlates with prodromal systemic lupus erythematosus (SLE) features, we measured the percentage of TFH cells in splenocytes of 9- and 18-week-old mice, in which the disease activity was determined by measuring the concentration of anti-dsDNA antibodies (IgG) and proteinuria
We found that PRL induced phosphorylation of STAT3 only in TFH cells derived from MRL/lpr mice and confirmed this PRL activity with an inhibitor of STAT3 (Stattic)

Summary

Introduction

The neuroendocrine and immune systems are closely interrelated, as the secretory products of the neuroendocrine system can act on the immune system and vice versa [1]. PRL favors the differentiation of thymocytes [10], increasing the expression of CD69 and CD25 in activated CD8+ T cells [11]. Hyperprolactinemia has been detected in many patients with different autoimmune diseases [13,14,15], including systemic lupus erythematosus (SLE), where it has been associated with disease activity [16, 17], with the concentration of anti-dsDNA antibodies [18], Journal of Immunology Research anemia, and all types of serositis [19]. Raising serum PRL levels in this strain, we demonstrated that the concentration of IgG isotype anti-dsDNA autoantibodies increased, resulting in earlier and more severe manifestations of the disease [23, 24]

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