A study published in the journal of Clinical Immunology demonstrates that the cytokine profiles in generalized anxiety disorder (GAD) individuals show traits of T helper (Th)1 and Th2 deficiencies but are associated with a predominant Th17 phenotype, particularly in the presence of substance P.
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene.
Substance P was discovered in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro. A peptide involved in pain and neurotransmission, its biological target is the neurokinin receptor subtype NK1; and with a huge amount of research in this area, and particularly its role in the peripheral nerves, the spinal cord, and the brain.
Substance P has been shown to stimulate the inflammatory response, contributing to control of infections primarily by enhancing Th1 pathways. In addition, psychological stress leads to increases in SP, and chronically stressed individuals are more vulnerable to infections.
In the journal of Clinical Immunology study, Barros and colleagues drew peripheral blood from unmedicated patients with anxiety and healthy subjects, and measured T cell proliferation and cytokine profiles after polyclonal activation of peripheral blood mononuclear cells cultures with phytohemagglutinin, and following in vitro SP and glucocorticoid (GC) challenges.
Cultures from anxious individuals demonstrated lower T cell proliferation in response to SP as compared to controls, attributable to both lower cell viability and low IL-2 levels, while GC decreased proliferation in controls and had no effect in anxious subjects. In activated cultures from anxious subjects, the production of Th1 cytokines was not altered by SP addition, while this neuropeptide up-regulated the release of IFN-γ in polyclonally activated T cell cultures from healthy subjects.
The SP is known to favor immune protection against infections by enhancing Th1 cytokines production. In this study, this neuropeptide, in fact, up-regulated the release of IFN-γ in polyclonally activated T cell cultures from control group. In activated cultures from anxious subjects, the production of both Th1 cytokines was significantly lower, and was not altered by SP addition. The Th1 phenotype deficiency detected in this study may clearly provide a reason by which anxious individuals have greater susceptibility to infectious diseases and malignancies. Therefore, the classical SP function in enhancing Th1 response seems not to be true for GAD individuals.
On the other hand, activated cell cultures from anxious individuals produced higher amounts of IL-17 and TNF-α, which increased even further after SP addition, but were unchanged when GC was added, compared to decreases in IL-17 upon GC stimulation in healthy subjects. Also, levels of the anti-inflammatory cytokine IL-10 decreased upon GC stimulation in healthy subjects but were unchanged in the anxious ones.
According to the authors, a deficient Th1 pathway in chronically stressed individuals could explain their increased susceptibility to infections.
As Th17 hyperactivity has been extensively linked to the pathogenesis of inflammatory conditions such as systemic lupus erythematosus, multiple sclerosis, and chronic inflammatory bowel disease, excessive Th17 activation in the context of GC insensitivity could hold clues to the association of stress and autoimmune disease exacerbations.
The authors speculate that the ability of SP in enhancing Th17 phenotype, associated to immune resistance to GC, could be a mechanism by which chronic stress has been associated with exacerbations of autoimmune disease, such as psoriasis, multiple sclerosis, and rheumatoid arthritis.