Acute gastrointestinal infection can turn on autoimmune disorders

Autoimmune disorders can be promoted by a variety of factors that must be considered in case management. A fascinating and important paper just published in the journal Science demonstrates how an acute gastrointestinal infection—such as a food-borne illness or viral gastroenteritis—can cause the immune system to lose tolerance for commensal bacteria (the ones that normally live in the intestines) which further induces autoimmune disorders. The authors observe:

"The intestinal microbiome is essential to multiple aspects of host physiology. Recent studies have estimated that the human microbiome contains ~3 × 106 distinct genes each of which may possess multiple antigens. Regulating immune responses to this extraordinarily diverse set of antigens is a formidable task because commensals also express inflammatory pathogen-associated molecular patterns (PAMPs) that could potentially activate the host immune response. To limit contact with the commensal microbiota, the gut is compartmentalized and contains various innate and adaptive mechanisms that prevent adaptive immune responses against food and commensal antigens. Maintaining immune tolerance to commensal–derived antigens in the gastrointestinal (GI) tract is critical because activated CD4 T cells have been strongly associated with inflammatory bowel disease (IBD)."

So this is also a mechanism by which tolerance to foods can be lost. So they set out to investigate what happens with the immune response to commensal bacteria after an infection by Toxoplasma gondii. This is a pathogen known induce intestinal permeability allowing an escape of gut bacteria from the intestines to the lymph nodes, liver and spleen.

"We postulated that immune ignorance of the microbiota may be lost during T. gondii infection as a result of bacterial translocation and impaired immune regulation."

And in fact they found that a very large proportion of CD4 T cells were converted to making the inflammatory cytokine IFN-γ (interferon-gamma) in response to general stimulation:

"Although the gut heals after clearance of T. gondii, the siLP (small intestine lamina propria, 'lining' of the small intestine) harbored a significantly higher frequency of interferon-γ (IFN-γ+) CD4 T cells...As expected, a fraction of these cells (~10% of CD4 T cells) were T. gondii–specific. However, CD4 T cells making IFN-γ in response to nonspecific stimulation far outnumbered those responding to T. gondii–derived antigens (~45% of CD4 T cells), implying that a proportion of these cells may be specific to commensal bacteria."

Then they showed how this breaching of the mucosal 'firewall' can result in loss of tolerance to commensal bacteria antigens in a way that promotes autoimmune disorders such as Crohn's disease:

"To circumvent the high diversity of commensal antigens, we used a T cell receptor (TCR) transgenic mouse specific to a commensal-derived flagellin (CBir1 Tg)...CBir1 is clinically relevant because antibodies to CBir1 flagellin are associated with Crohn’s disease. Because of the segregation imposed by the mucosal firewall, splenic T cells from CBir1 Tg mice remain largely naïve. Upon transfer into T. gondii–infected hosts, CBir1 Tg T cells proliferated extensively, whereas T cells that had been transferred into uninfected hosts remained undivided. Thus, T cells specific to commensal-derived antigens proliferate during a heterologous GI infection."

They further demonstrated that when tolerance to the normal commensal bacteria is lost, T cells react to the commensals like they would to pathogens, and that these responses can be systemic:

"Activated commensal-specific T cells produced IFN-γ in response to ex vivo stimulation and were observed in all tissues examined, indicating that anti-commensal T cell responses are systemic and functional. Taken together, our data show that during GI infection CD4 T cell ignorance of commensal antigens is lost, and microbiota-specific T cells respond in a manner comparable with pathogen-specific T cells."

Of striking importance is the observation that this loss of tolerance that promotes autoimmune disorders can persist a very long time:

"Immunological memory is a cardinal property of the adaptive immune system allowing for long-term protection against reinfection. During acute infections, TH1 T cell responses persist after the clearance of the pathogen but slowly decay over time. Whether microbiota-specific effector T cells persist as memory cells is a critical question. Assessment of CBir1 Tg T cell response revealed that the number of effector (CD44hi) CBir1 Tg T cells expanded ~10-fold from day 6 to the peak of the anti-microbiota response at day 12 after infection in both the spleen and siLP. In accordance with what has been observed for pathogen-specific CD4 T cell responses, CBir1 Tg T cells contracted after day 12 of infection. However, small populations of CD44hi CBir1 Tg T cells can be identified from both the spleen and lamina propria up to 240 days after infection, indicating that microbiota-specific cells generated in the context of heterologous GI infection have the potential for long-term survival...Strikingly commensal-specific T cells largely differentiate to a phenotype consistent with long-lived TH1 memory T cells."

This is but one reason why it is unrealistic to expect an amelioration of autoimmune disorders with regaining of tolerance to occur overnight. The process is more like converting a weedy lot to an organic garden than to paving it with asphalt. Interestingly, 240 days is about how long it takes for anti-gliadin (anti-gluten) antibodies to die down after from gluten avoidance after chronic exposure. And it's not only infection that can induce this predisposition to autoimmune disorders, but also other agents that disrupt the intestinal barrier:

"The majority of CBir1-specific T cells was also activated in mice treated with DSS (chemical disruption of the GI tract by dextran sodium sulfate), highlighting the importance of GI tract integrity in maintenance of CD4 T cell ignorance to commensal antigens. Therefore, commensal-specific T cells activated during GI infection survive long-term and persist in extra-lymphoid tissue in a manner consistent with that of pathogen-specific memory cells."

Not only that, but subsequent infection can arouse the T cells that have become sensitized to commensal bacteria:

"We next tested whether an established commensal-specific T cell population could be reactivated by GI infection. To address this point, we activated naïve CBir1 Tg T cells in vivo with peptide and LPS, waited for the primary immune response to subside, and then infected mice with T. gondii. Secondary infection induced proliferation of a fraction of CBir1 Tg T cells in both the siLP and spleen, as indicated by expression of Ki67 . Thus, activated commensal-specific T cells can proliferate in response to infectious rechallenge."

The 'army' is ready to go should there be another insult to the gut. Since infection and other agents that disrupt the gut 'firewall' can cause the immune system to lose tolerance to commensal bacteria in a way that promotes autoimmune disorders, what other agents can also do this? Could NSAIDs make arthritis worse in the long run? The authors conclude:

"The GI tract represents a major site of exposure to pathogens, and our results propose that these pathogenic exposures lead to long-lived anticommensal immunity...a fraction of the memory CD4 T cell population induced in response to GI infection is likely composed of various commensal-specific clones that together may constitute a substantial population. Further, our results suggest that primary immune responses to GI infections occur in the context of broader secondary responses against commensals. Several genes involved in sustaining the intestinal barrier and CD4 function have been associated with IBD, and in the context of such mutations, regulation of activated commensal-specific T cells could be jeopardized, leading to immunopathology. Indeed, GI barrier dysfunction and infection have been shown to synergize to induce IBD. Because bacteria colonize all pathogen entryways, such as the skin, lung, and GI tract, our findings raise the question of whether immunity and inflammation at barrier sites is generally controlled by responses to commensals."

This extends the reach of commensal mediated autoimmune inflammation to asthma, skin diseases, and much more. Forthcoming posts will report on other factors that promote autoimmunity and interventions that help to regain tolerance.