Hookworm infection and microchallenge for coeliac disease?

I'm getting rather baffled by some of the literature appearing with the autoimmune condition coeliac (celiac) disease in mind. The paper by Kalliokoski and colleagues [1] started the bafflement ball rolling with their suggestion that: "administration of IgA-deficient celiac disease patient serum or total IgG induces both deterioration of the intestinal mucosa and clinical features of celiac disease in mice". Then came the paper from Namatovu and colleagues [2] who concluded that: "Neighborhood composition influences CD [coeliac disease] risk". Such discussions were based on a condition which science seemed to be getting a handle on in terms of the genetic and biological processes involved... or maybe not.

"Klaatu Barada N... Necktie... Neckturn... Nickel"

Enter also the findings reported by John Croese and colleages [3] observing that: "Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD [coeliac disease] subjects" and the bafflement ball starts to roll away yet faster and further.

A few points from the Croese paper are worth noting:

• This was a year long study looking at a small number of adults with "diet-managed" CD (N=12). In case you might not know, the diet in question is a gluten-free diet.
• Said participants were "inoculated" with 20 hookworm larvae (see here for a picture if you really wish) and subsequently fed increasing doses of gluten - consumed as pasta - ranging from micrograms to grams over the course of some weeks. 
• "Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined".
• Results: Not all the participants went the distance with the gluten challenge; two of which were labelled 'gluten intolerant' (which is a little odd because intolerance of gluten is I presume a hallmark of all CD). That being said, there were some interesting findings observed such as: "the mean IgA-tissue transglutaminase titers declined". I'm not an expert on CD but elevated IgA-tissue transglutaminase is closely associated with CD and I believe levels should fall when a person adopts a gluten-free diet [4]. The fact that levels declined when a gluten challenge (ingesting gluten) was in place was, in the words of the authors, "contrary to the predicted rise".
• Researchers also described how: "Intestinal T cells expressing IFNγ were reduced following hookworm infection". Again with my non-expert hat on, these are some interesting results. The interferons have been previously discussed on this blog with autism in mind (see here) but with CD in focus, are thought to be part of the destructive immune system processes which describe the condition (see here). The suggestion that hookworm infection might be somehow placating such immune processes is intriguing.

Obviously, there is a lot more to do in this area before anyone decides that hookworm infection is a panacea for CD. I've already mentioned the small participant number and attrition rate but given also that CD is usually described as a lifelong condition, one year of experimental study is not nearly enough to discuss any long-term effects. That other studies from the authors have reported less eventful results [5] is also worth mentioning.

But, I'm also minded to discuss another paper from this research group [6] which was covered on a sister blog (see here). On that occasion, authors talked about how hookworm infection seemed to influence production of the TH-17 cytokine, IL-17A too: "Hookworm infection suppressed basal production of the inflammatory cytokines IFN-γ and IL-17A". I've become quite interested in IL-17 over the years, again with the autism research connection in mind (see here) and a possible link with autoimmunity. The fact that IL-17 might also represent one way of distinguishing subgroups with CD [7] is likewise intriguing and offer something in the way of a variable on response to such helminthic therapy...

Music to close. How about some bluegrass... The Grascals and Bugle Call Rag?

And since, I have your attention, here's a link to my latest paper [8] on the potential use of gluten and casein-free diets for autism (shameless self-publicity I know).

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[1] Kalliokoski S. et al. Injection of celiac disease patient sera or immunoglobulins to mice reproduces a condition mimicking early developing celiac disease. J Mol Med (Berl). 2014 Sep 12.

[2] Namatovu F. et al. Neighborhood conditions and celiac disease risk among children in Sweden. Scand J Public Health. 2014 Sep 23. pii: 1403494814550173.

[3] Croese J. et al. Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. J Allergy Clin Immunol. 2014 Aug 29. pii: S0091-6749(14)01010-0.

[4] Dahele AV. et al. Serum IgA tissue transglutaminase antibodies in coeliac disease and other gastrointestinal diseases. QJM. 2001 Apr;94(4):195-205.

[5] Daveson AJ. et al. Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial. PLoS One. 2011 Mar 8;6(3):e17366.

[6] McSorley HJ. et al. Suppression of inflammatory immune responses in celiac disease by experimental hookworm infection. PLoS One. 2011;6(9):e24092.

[7] Sapone A. et al. Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol. 2010;152(1):75-80.

[8] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2014 Oct 14:1-6.

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Croese J, Giacomin P, Navarro S, Clouston A, McCann L, Dougall A, Ferreira I, Susianto A, O'Rourke P, Howlett M, McCarthy J, Engwerda C, Jones D, & Loukas A (2014). Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. The Journal of allergy and clinical immunology PMID: 25248819