Altered expression of vasoactive intestinal peptide receptors in T lymphocytes and aberrant Th1 immunity in multiple sclerosis

Abstract

Vasoactive intestinal peptide (VIP) has a unique property of regulating T(h)1 and T(h)2 immunity of CD4+ T cells. In this study, we demonstrated, for the first time, that differential expression of VIP receptors and a compensatory mechanism directly affect the responsiveness of CD4+ T cells and their T(h)1 and T(h)2 properties to VIP. The expression of VIP receptor-1 (VPAC1) and VPAC2 in CD4+ T cells changed reciprocally in the context of the activation state. In activated CD4+ T cells of healthy individuals, markedly decreased VPAC1 expression was compensated for by increased expression of VPAC2 induced by T cell activation. In contrast, there was altered expression of VPAC2 in activated CD4+ T cells derived from multiple sclerosis (MS) patients, which rendered CD4+ T cells less responsive to VIP and skewed the system to a predominantly in a T(h)1 direction. Detailed characterization with agonist peptides of VIP showed that residues Met and Ser at positions 17 and 25 of VIP were critical to its regulatory properties through interaction with VAPC2. Furthermore, altered levels of VPAC2 expression in T cells of MS patients were not associated with single-nucleotide polymorphism in the encoding region of the VPAC2 gene but with gene regulation as characterized by a distinct DNA footprinting pattern in the promoter region of the VPAC2 gene in MS as compared with controls. This study has provided new evidence for an intrinsic mechanism associated with an aberrant, pro-inflammatory state of CD4+ T cells in MS.

Genetic association of vasoactive intestinal peptide receptor with rheumatoid arthritis: Altered expression and signal in immune cells

“…This is the first report to describe a genetic association of VIP or of its 2 VIP receptors with any autoimmune disorder. Reduced levels of VIP and altered expression of VPAC 2 in T cells from patients with multiple sclerosis were recently reported (9); however, results of 2 different studies have failed to support the notion of genetic polymorphisms within the VIP and VPAC 2 genes in that disease (8,9).…”

“…Although studies have been undertaken in an effort to correlate altered VIP levels, presence of VIP autoantibodies, or VIP genetic variants with severity and incidence of autoimmunity, no association has been conclusively demonstrated (6)(7)(8)(9). We hypothesized that the exacerbated inflammatory autoimmune response in RA might result directly from altered expression and/or signaling of VIP receptors in immune cells.…”

Vasoactive intestinal peptide loss leads to impaired CNS parenchymal T-cell infiltration and resistance to experimental autoimmune encephalomyelitis

“…For example, it has been reported that patients with multiple sclerosis (MS) have reduced VIP immunoreactivity in the cerebral spinal fluid (12). Moreover, Th cells isolated from patients with MS have an altered profile of VIP receptors, and are resistant to an action of VIP to promote a positive Th2/Th1 balance (13). In contrast, an up-regulation of VIP levels was observed in the serum and joints of mice with collagen-induced arthritis (14) and in the serum and peritoneal suspensions of mice injected with LPS (8).…”

Vasoactive Neuropeptides in Autoimmune Diseases

“…This compromise to VPAC2 in MS patients may also occur at the molecular level where mRNA expression levels of VPACR2 are down regulated. Additionally, the formation of the VIP ligand receptor complex stimulates cAMP/PKA downstream effects which ultimately dampen IFN-and stimulates the generation of GATA3 (Sun et al, 2006). This in effect increases the expression of Th2 immune cells.…”