Serum cytokine elevations in celiac disease: association with disease presentation.

Celiac disease (CD) is an autoimmune disorder that is triggered by an immune response to gluten in genetically predisposed individuals. Although considered a primary gastrointestinal disease, CD is now known to have widespread systemic manifestations. We attempted to define the nature and role of systemic cytokine levels in the pathophysiology of CD. Multiplex cytokine assays were performed on four different groups of adult patients; patients with active CD (ACD), patients on a gluten-free diet (GFD) with positive TTG IgA antibodies, patients on a GFD with negative antibodies, and those with refractory CD (RCD). The results were compared with values in healthy adult controls. Patients with active CD and those on GFD with positive antibodies had significantly higher levels of proinflammatory cytokines, such as interferon-gamma, interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6 and IL-8, and also T(h)-2 cytokines such as IL-4 and IL-10, compared with normal controls and patients on GFD without antibodies. Interestingly patients on GFD for less than 1 year had significantly higher levels of both proinflammatory cytokines and T(h)2 cytokines compared with the patients on GFD for more than 1 year. In addition, a statistically significant correlation between levels of TTG IgA titers and serum levels of T(h)-2 cytokines IL-4 (p < 0.001), IL-10 (p < 0.001) and inflammatory cytokines such as IL-1alpha (p < 0.001), IL-1beta (p < 0.005), and IL-8 (p < 0.05) was observed.

Overlap between molecular markers expressed by naturally occurring CD4+CD25+ regulatory T cells and antigen specific CD4+CD25+ and CD8+CD28- T suppressor cells.

Alloantigen specific CD8+CD28- T suppressor (TS) cells differ from naturally occurring CD4+CD25+ T-regulatory (natural TR) cells not only by their phenotype but also by their mechanism of action. Natural TR have been extensively studied, leading to the identification of characteristic "molecular markers" such as Forkhead box P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). We have investigated the expression of these genes in alloantigen specific TS and CD4+CD25+ T regulatory (TR) cells and found that they are expressed at levels similar to those observed in natural TR. Furthermore, similar to natural CD4+CD25+ TR, antigen-specific CD8+CD28-CD62L+ TS cells have more suppressive capacity than CD8+CD28-CD62L- TS cells. In spite of these similarities, natural TR are not antigen-specific and inhibit other T cells by T cell-to-T cell interaction, whereas TS are antigen-specific and exert their inhibitory function by interacting with antigen-presenting cells and render them tolerogenic to other T cells. The molecular characterization of TS cells may contribute to a better understanding of mechanisms involved in inhibition of immune responses in autoimmunity, transplantation, and chronic viral infection.