Vasoactive intestinal peptide axis is dysfunctional in patients with Graves’ disease

Abstract

Vasoactive intestinal peptide (VIP) is a neuropeptide with potent immunoregulatory properties. Reduced serum VIP levels and alterations in VIP receptors/signaling on immune cells have been associated with different inflammatory/autoimmune diseases. However, its role in autoimmune thyroid diseases (AITD) remains unknown. This study examined the interrelationship between VIP system, autoimmune background and thyroid hormones in peripheral immune cells in patients with AITD. Only Graves' disease (GD) patients showed significantly lower serum VIP levels when compared to healthy subjects and to Hashimoto's thyroiditis patients. Serum VIP levels were lower at the onset of GD, showing a significant negative correlation with thyroid hormone levels. The expression of VIP receptors, VPAC1 and VPAC2, was significantly upregulated in peripheral blood mononuclear cells (PBMC) from GD patients. There was an impairment of VIP signalling in these patients, probably attributable to a dysfunction of VPAC1 with preservation of VPAC2. The correlation between VPAC1 and thyroid hormone receptor expression in PBMC from healthy subjects was lost in GD patients. In summary, the VIP system is altered in peripheral immune cells of GD patients and this finding is associated with different thyroid hormone receptor patterns, showing a dynamic inter-regulation and a prominent role of VIP in this setting. Experimental data and clinical observations in animal models and humans point to an important role of interactions between neuroendocrine and immune systems for the maintenance of the overall homeostasis 1,2. This bidirectional network is functionally supported by the presence of shared signalling molecules, including hormones, neuropeptides, cytokines, and their respective receptors. Thus, neuropeptides and hormones are able to modulate immune functions, and immune mediators are capable of affecting the endocrine system. Therefore, although the immune system itself has mechanisms of self-regulation, the neuroendocrine system is also involved in its control. Accordingly, impairment of mechanisms mediating such regulatory relationships has been linked with the development of autoimmune diseases 3. Thyroid hormones, triiodothyronine (T3) and thyroxine (T4), are implicated in key physiological processes, including development, differentiation, and regulation of metabolism 4. Besides, accumulating evidence proves the impact of thyroid status on immune responses and inflammation, by directly affecting the functional activity of monocytes, macrophages, lymphocytes and natural killer 3. Biological actions of thyroid hormones are mediated by classical signalling mechanisms initiated through binding to their corresponding nuclear receptors, TRα and TRβ, that directly modulate gene transcription 5. In addition, recent investigations have described that they also act at the plasma membrane via integrin αvβ3, triggering signalling cascades that indirectly contribute to the regulation of gene expression 4. Thyroid autoimmune diseases (AITD) include a broad...

Comparative Study of Senescent Th Biomarkers in Healthy Donors and Early Arthritis Patients. Analysis of VPAC Receptors and Their Influence

“…The changes in VPAC pattern expression in PBMCs from autoimmune diseases are not exclusives of EA patients. In PBMCs from patients with Graves' disease, there is an increased expression of both receptors, however, only VPAC 2 was functional in an adenylate cyclase-dependent signaling pathway [46]. Thus, changes in mRNA expressions of both receptors during different Th cell stages or different stages of an autoimmune disease such as EA suggest a possible dynamic regulation of both, probably acting as a compensatory mechanism.…”

Human CD4+CD45RA+ T Cells Behavior after In Vitro Activation: Modulatory Role of Vasoactive Intestinal Peptide

“…Some studies evince that the balance between VPAC 1 and VPAC 2 receptors, in pathological conditions or when immune system cells are activated, is always in favor of VPAC 2 , suggesting that this receptor could play a key role in these situations [17,19]. This statement further correlates with the fact that the expression of both receptors has been proposed as a biomarker in some autoimmune diseases, such as early arthritis or Graves' disease [53]. VIP actions can be affected not only by changes in VPAC expression in lymphocytes but also changes in cellular location as occurs with other GPCRs or even VPAC 1 in other types of cells [54][55][56][57].…”

The G Protein-Coupled Receptor, VPAC1, Mediates Vasoactive Intestinal Peptide-Dependent Functional Homeostasis of the Gut Microbiota

“…Peripheral blood mononuclear cells (PBMCs) from GD patients with hyperthyroidism consisting of elevated free thyroxine serum levels have defective VPAC1 signaling compared with healthy donors. 51 Serum VIP levels negatively correlated with free thyroxine serum levels, and PBMCs also expressed high levels of the intestinal chemoattractant CCR9, leading the authors to suggest that defective VPAC1 signaling in PBMCs originated within the intestines. Patients with GD also experienced gut microbiota dysbiosis with reduced levels of Firmicutes and elevated levels of Bacteroidetes that has been recently suggested to contribute to this systemic, multiorgan, autoimmune disease.…”