Development of atopy by severe paramyxoviral infection in a mouse model.

BACKGROUND: Atopic diseases have been increasing in prevalence, yet the initial inciting events that lead to atopy are not understood. Paramyxoviral infections have been suggested to play a role; however, much of these data are correlative. OBJECTIVE: To determine whether exposure to a nonviral antigen during a paramyxoviral infection is sufficient to drive IgE production against the bystander antigen and whether clinical disease against this antigen would result. METHODS: Wild-type C57BL6 mice or mice deficient in FcεRIα (FcεRIα(-/-)) or IgE (IgE(-/-)) were inoculated with Sendai virus (SeV) or UV-inactivated SeV (UV-SeV) and subsequently exposed to ovalbumin (OVA) intranasally. Mice were further challenged 3 times with intranasal OVA on days 20 to 22 after inoculation with SeV, and airway hyperreactivity and mucous cell metaplasia were determined. RESULTS: Exposure to OVA during SeV infection led to significant OVA specific IgE production (median, 548 vs 0 ng/mL; P = .03; SeV vs UV-SeV). This induction of OVA specific IgE production depended on FcεRI because FcεRIα(-/-) mice produced significantly less IgE (112 ng/mL; P = .03; vs wild-type mice). Furthermore, in wild-type mice OVA exposure and challenge significantly enhanced SeV-induced airway hyperreactivity and mucous cell metaplasia, but this failed to occur in either FcεRIα(-/-) or IgE(-/-) mice. CONCLUSION: A single exposure to a bystander allergen during a paramyxoviral infection is sufficient to drive allergen specific IgE production in a partial FcεRI-dependent mechanism. These data begin to provide mechanistic insight into how viral infections might drive development of atopic disease.

Cutting edge: CD49d+ neutrophils induce FcepsilonRI expression on lung dendritic cells in a mouse model of postviral asthma.

The increasing prevalence of atopy and asthma remains unexplained but may be due to infection with respiratory viruses. In support of this hypothesis, we showed that experimental asthma after viral infection in mice depended on type I IFN-driven upregulation of FcεRI on conventional dendritic cells (cDCs) in the lung. In this article, we demonstrate that FcεRI expression on lung cDCs depends on an unexpected activity of a CD49d(+) subset of polymorphonuclear neutrophils (PMNs) that are found in the lungs of wild-type C57BL6 but not mice deficient in type I IFNR. Expression of FcεRI depends in part on a CD11b-dependent interaction between PMNs and cDCs. This study demonstrates a PMN-cDC interaction in the lung that is necessary for the ability of viral infection to induce atopic disease.

Inducible regulatory T cells (iTregs) from recent-onset type 1 diabetes subjects show increased in vitro suppression and higher ITCH levels compared with controls.

CD4+CD25+(high) regulatory T cells (Tregs) play a pivotal role in the control of the immune response. A growing body of evidence suggests the reduced function of these cells in autoimmune diseases, including type 1 diabetes (T1D). Restoration of their function can potentially delay further disease development. In the present study, we have converted conventional effector T cells into induced Tregs (iTregs) in recent-onset (RO) T1D (n=9) and compared them with the same cells generated in controls (n=12) and in long-standing (LS) T1D subjects (n=9). The functional potential of in-vitro-generated Tregs was measured by using an in vitro proliferation assay. We noted that the suppressive potential of iTregs exceeded that of natural regulatory T cells (nTregs) only in the RO T1D subjects. We showed that iTregs from RO T1D subjects had increased expression of Foxp3, E3 ubiquitin ligase (ITCH) and TGF-beta-inducible early gene 1 (TIEG1) compared with control and LS T1D subjects. We also expanded natural, thymically derived Tregs (nTregs) and compared the functional ability of these cells between subject groups. Expanded cells from all three subject groups were suppressive. RO T1D subjects were the only group in which both iTregs and expanded Tregs were functional, suggesting that the inflammatory milieu impacts in vitro Treg generation. Future longitudinal studies should delineate the actual contribution of the stage of disease to the quality of in-vitro-generated Tregs.

Apoptosis of CD4+ CD25(high) T cells in type 1 diabetes may be partially mediated by IL-2 deprivation.

BACKGROUND: Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease targeting the insulin-producing pancreatic beta cells. Naturally occurring FOXP3(+)CD4(+)CD25(high) regulatory T cells (T(regs)) play an important role in dominant tolerance, suppressing autoreactive CD4(+) effector T cell activity. Previously, in both recent-onset T1D patients and beta cell antibody-positive at-risk individuals, we observed increased apoptosis and decreased function of polyclonal T(regs) in the periphery. Our objective here was to elucidate the genes and signaling pathways triggering apoptosis in T(regs) from T1D subjects. PRINCIPAL FINDINGS: Gene expression profiles of unstimulated T(regs) from recent-onset T1D (n = 12) and healthy control subjects (n = 15) were generated. Statistical analysis was performed using a Bayesian approach that is highly efficient in determining differentially expressed genes with low number of replicate samples in each of the two phenotypic groups. Microarray analysis showed that several cytokine/chemokine receptor genes, HLA genes, GIMAP family genes and cell adhesion genes were downregulated in T(regs) from T1D subjects, relative to control subjects. Several downstream target genes of the AKT and p53 pathways were also upregulated in T1D subjects, relative to controls. Further, expression signatures and increased apoptosis in T(regs) from T1D subjects partially mirrored the response of healthy T(regs) under conditions of IL-2 deprivation. CD4(+) effector T-cells from T1D subjects showed a marked reduction in IL-2 secretion. This could indicate that prior to and during the onset of disease, T(regs) in T1D may be caught up in a relatively deficient cytokine milieu. CONCLUSIONS: In summary, expression signatures in T(regs) from T1D subjects reflect a cellular response that leads to increased sensitivity to apoptosis, partially due to cytokine deprivation. Further characterization of these signaling cascades should enable the detection of genes that can be targeted for restoring T(reg) function in subjects predisposed to T1D.