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Type I and III Interferon in the Gut: Tight Balance between Host Protection and Immunopathology

Johanna Pott and Silvia Stockinger

 

Importance of Type I/III IFN Signaling Under Inflammatory Conditions..

 

Type I IFN and IBD

The IBD, comprising Crohn’s disease (CD), and ulcerative colitis (UC) are chronic debilitating inflammatory disorders of the gastrointestinal tract. IBD affects about 0.2% of Western populations and there is no current cure, typically requiring long-term treatment with immune suppressive agents and, in many cases, surgical intervention. Although the etiology remains unclear, IBD is thought to arise due to aberrant immune responses to components of the commensal bacterial microbiota (117). Recent genome-wide association studies have identified more than 160 genetic susceptibility loci for IBD, with affected genes involved in immunity and in barrier function (118). Many of those single-nucleotide polymorphisms (SNPs) are found in genes associated with pathogenic cytokine circuits, such as the Th17/IL23 circuit, IL-10, and type I IFN-I signaling (119). The majority of signaling mediators are shared between different cytokine signaling cascades and therefore exact determination of the relevant pathways is impossible from the genetic data only. Interestingly, several of the IBD-associated genes are also involved in the type I IFN signaling pathway. The rs2284553 SNP is commonly associated with the IFNGR2 gene but could also affect the IFNAR1 gene (118). JAK2, TYK2, STAT1, and STAT3 genes harbor identified SNPs and are signaling mediators in many cytokine pathways such as IL-22, IL-10, and also type I/III IFN. Furthermore, polymorphisms in the MDA5 or IRF5 gene might alter the production of type I/III IFN (118). Although the type I IFN signaling network is not one of the major players in IBD pathology, slight alterations may contribute to the imbalanced immune response at the lamina propria, as suggested by mouse studies.

Indeed, Giles and colleagues analyzed the responsiveness of T cells from healthy controls and IBD patients to IFN-β and found that IFN-β signaling modulates colonic T cell responses in a context-dependent manner. Human colonic T cells were responsive to exogenous IFN-β and endogenous IFN-β influenced the cytokine profile of ex vivo cultured T cells. T cells from healthy controls produced decreased levels of IL-10 in the absence of IFN-β signaling whereas T cells from IBD patients produced elevated levels of proinflammatory cytokines (120).

Interferons-β has been approved for the treatment of multiple sclerosis (MS); however, a subset of patients does not respond to the treatment. Axtell and colleagues analyzed the effect of IFN-β on different Th subsets and found that IFN-β treatment in a mouse model of EAE attenuates disease development in a Th1-driven pathology, but had no effect or even exacerbates pathology in Th17-driven disease. Furthermore, they could correlate high IL-17-F serum levels in MS patients to non-responsiveness toward IFN-β treatment. These findings confirm the immunomodulatory role of IFN-β but also demonstrate the diverse consequences it has in different context with opposing effects within a Th1 and Th17 setting (121).

Despite the varying results from mouse studies on the role of type I IFN in colitis and the discrepancy between type I IFN effects on suppressing acute colitis and delaying recovery (74, 75), type I IFN have been suggested for the treatment of IBD. Several small studies have evaluated the consequences of IFN-β1a in IBD patients with varying results (122–128). Although small pilot studies suggested a beneficial outcome of type I IFN treatment of IBD patients (123, 124), a placebo-controlled, double-blind study on Crohn’s patients in remission did not find any improvement by IFN-β1a treatment on the maintenance of remission (127). Also two randomized placebo-controlled studies in UC patients with active disease could not show a beneficial effect of IFN-α or IFN-β1 treatment on disease remission (125, 126). A small study analyzing cytokine levels before and after treatment with IFN-β1a found a correlation between responsiveness and reduction of IL-13 levels in UC patients. The unresponsiveness to IFN-β1 treatment correlated with elevated levels of IL-17 in accordance with the findings in MS patients (121, 128).

Taken together, these studies do not support a beneficial outcome of type I IFN treatment during IBD. This conclusion was also drawn in a recent intervention review analyzing all trial data published on the effectiveness of type I IFN treatment on remission in UC patients (129). However, considering the analysis of IFN-β non-responsiveness of patients with MS (121), context-specific responsiveness of T cells toward type I IFN (120), and controversial findings in mouse studies (23, 74, 75), the effect of the treatment might vary between Th profiles of patients and a careful pre-selection of patients would be required. Further studies with sufficient patient numbers and thorough analysis of immunological and disease parameters are required.

Type I IFN and Celiac Disease

Celiac disease is a small-intestinal enteropathy characterized by an aberrant T cell-mediated immune response of susceptible individuals to dietary gluten. The pathogenic adaptive immune response is initiated by the interplay between gluten and the MHC class II molecules HLA-DQ2 and DQ8 and is characterized by a potent Th1 response. The excessive tissue destruction is further driven by a severe IEL hyperplasia targeting IECs. Histologically, celiac disease is characterized by villous flattening, crypt hyperplasia, and IEL infiltration. Affected individuals can present with very variable symptoms ranging from asymptomatic to severe symptoms ascribed to impaired absorption of nutrients (130).

The strongest genetic factor for the disease is HLA-DQ2 and DQ8; however, it is now recognized that further immune-regulatory or activating factors are required for disease establishment. Several celiac disease susceptibility loci in genes associated with innate immune responses have been identified, suggesting a role for innate immunity in the development of the disease (131).

An influence of type I IFN on the development of celiac disease has been widely discussed. Indeed, a number of case studies reported on the development of diarrhea and the onset of celiac disease during treatment with IFN-α for chronic hepatitis C patients (132–137). A retrospective study of 534 hepatitis C patients with or without symptoms of celiac disease showed an activation of silent celiac disease in the majority of patients positive for transglutaminase antibodies while on IFN therapy (138). The immunomodulatory properties of type I IFN might worsen underlying autoimmune disorders and monitoring of hepatitis C patients for celiac disease before starting an IFN therapy has been suggested.

A potential role of cotreatment with ribavirin, which promotes a Th1-mediated immune response while suppressing Th2 responses, has also been discussed (133).

The high prevalence of celiac disease in HCV patients treated with IFN-α was investigated in a study including 210 chronic hepatitis C patients. This study failed to detect a significant association of celiac disease and HCV infection and in addition came to the conclusion that IFN-α therapy per se does not trigger celiac disease in patients negative for endomysium (EMA) and tissue transglutaminase (139). It does not however rule out that IFN-α treatment might trigger the development of celiac disease in susceptible individuals.

To investigate the underlying mechanisms, explant cultures of human fetal gut were analyzed after activation of T cells with anti-CD3 and IFN-α. While single treatment with either anti-CD3 or IFN-α alone did not trigger any profound changes, the combination of both resulted in enhanced Th1 responses and crypt cell hyperplasia associated with enhanced STAT1, STAT3, and FYN phosphorylation. IFN-α treatment might thus facilitate activation of Th1-reactive cells and trigger immunopathology (135, 140).

Onset of celiac disease-like symptoms have also been observed in a case of chronic myeloid leukemia treated with IFN-α again suggesting a role of type I IFN in promoting Th1 responses to gluten (135). Also, IFN-α protein was detected in duodenal tissue of celiac disease patients but not in control samples (135).

Further studies are required to determine whether a direct link exists between type I IFN signaling and celiac disease.

Concluding Remarks

Although important progress has been made in recent years, additional studies are required to deepen our understanding of the role of type I IFN and type III IFN in the gut. Type I IFN signaling in enteric viral infections is mostly protective, whereas it can be detrimental in certain enteric bacterial infections. The clinical data using type I IFN for colitis treatment are partly contradictory and a larger number of patients are required to obtain conclusive results.

With the exception of some viral infection and colitis models, where type III IFN signaling is mostly protective, the data on illuminating the role of type III IFN signaling in the gut are generally scarce. It is now well established that epithelial cells are especially responsive to type III IFN, which enforces the mucosal barrier and prevents viral entry and infection. Less clear is the non-responsiveness of the epithelium to type I IFN observed under several conditions (Figure 1). What benefit do epithelial cells gain from the decreased responsiveness? Can receptor expression levels and localization fully explain reduced type I IFN responsiveness in the epithelium?

The narrow range of cells responding to type III IFN makes it an attractive target for future clinical studies with increased specificity and fewer side effects than type I IFN.