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).
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.
