This answer explains why a durable celiac disease reversal is presently out of reach.
- Gluten plus celiac genetic risk factors are necessary but not sufficient for overt disease.
- Celiac environmental risk factors other than gluten are also necessary but their identities remain largely unknown.
An autoimmune disease with a strong genetic predisposition that is yet triggered by dietary factors makes celiac eminently reversible in theory because despite similar dietary exposure, only a handful, not all, of the genetically predisposed develop overt disease. Clearly, some additional environmental factors are crucial for disease. Coming up with a surefire approach to reverse celiac requires figuring those out.
Presently, to keep celiac disease at bay patients try to maintain a strict gluten-free diet, a far from satisfactory state of affairs since this is easier said than done.
Gluten plus celiac genetic risk factors are necessary but not sufficient for overt disease
In general, only ~1% of the general population develops celiac, with a 2:1 female:male ratio (1).
Comparing rates in twins helps situate the relative roles of genetic and environmental factors in an autoimmune disease. Celiac disease risk is ~80% in monozygotic twin pairs (2, 3) but only ~20% in dizygotic twins, meaning major role for genetic risk factors. Main celiac genetic risk factors are HLA-DQ2 and -DQ8 (2, 3, 4).
- Antigen processing machinery in cells process antigens and the Human leukocyte antigen – Wikipedia molecules present the resulting antigenic peptides within their grooves to T cells – class I molecules present to CD8 cytotoxic killer T cells and class II to CD4 helper T cells.
- DQ2 and DQ8 are HLA class II molecules which means CD4 helper T cells are key celiac disease-driving agents. Specifically, celiac disease process is initiated and sustained by CD4 helper T cells that respond to specific peptides derived from gluten and related cereal-derived proteins such as gliadins, glutenins, hordeins, secalins.
- We each carry a mix of HLA molecules that we inherit from our parents – this is each person’s HLA haplotype – what gets tested when trying to match donors and recipients during transplants for example.
- Such tight linkage of DQ2 and DQ8 to celiac disease implies that these HLA class II molecules are able to present unique gluten-derived peptides that aren’t presented by other HLA molecules – akin to a needle in a haystack considering there are >5900 HLA class II alleles and new ones continue to be discovered.
However, though ~95% of celiac disease patients are DQ2 or DQ8, having these HLA molecules doesn’t confer a slam dunk certainty for overt celiac disease.
- As many as 20 to 30% of healthy people are DQ2 and/or DQ8 as well (4).
- Risk in siblings with identical HLAs (have HLA-DQ2 and/or -DQ8 but differ in other genes) is only 30 to 40% (1, 2, 5).
Ergo, despite very strong linkage to precisely identified genetic risk factors and well-known immediate trigger, overt celiac disease requires confluence with other genetic and environmental factors, the latter of which remain largely a black box.
Celiac environmental risk factors other than gluten are also necessary but their identities remain largely unknown
Longstanding and overwhelming research focus on gluten has consumed all the oxygen leaving little room to uncover other environmental factors crucial for converting a genetic predisposition into a full-blown autoimmune disease. Developing a more durable reversal among those already diagnosed with celiac and maybe even preventing it outright in those genetically predisposed to it requires uncovering such factors.
Whatever those may be, no surprise that gut microbiota have emerged as key players, the notion being that gut microbiota composition change is the crucial trigger that sets off the celiac disease cascade (below from 1). In that respect, processes such as elective C-sections and recurrent neonatal infections, especially with rotavirus, that change gut microbiota, are now some known risk factors for celiac.
Twin studies may again come in handy here since gut microbiota differences between monozygotic twins where only one in a pair has the disease would help zoom in on crucial differences that help drive the disease process. The project could then turn to restoring specific members of healthy gut microbiota in celiac disease patients.
- Problem is modern molecular biology techniques, exquisitely sensitive though they may be, also bring along the collateral cost of tremendous noise. Separating signal from noise has become such an issue that there is as yet no consensus from multiple studies as to whether monozygotic twins even have similar or dissimilar microbiota composition. Comparing microbiota composition between twins in specific diseases such as celiac depends on first getting a categorical answer to that basic question in healthy twin pairs.
- Another major problem is conceptual. For ~30 years, immunologists have framed the core issue in inflammatory disorders as a choice between more damaging (chronic inflammation) and more benign immune responses even though this approach has yielded few fruitful results in any disease. Immunology is at a theoretical level impasse even as overwhelming research dollars are poured into fruitless efforts driven by this outmoded concept#.
- While this assumption was the basis for interventions such as hookworms as well (6), now focus is instead on how they help reshape gut microbiota composition. Same basis applies to testing prebiotics and probiotics. Such efforts are today at their earliest shot in the dark stages, that is to try this or that pre- or probiotic mix and see if it works in reversing celiac. Understandably, results are also hit or miss.
- A conceptual leap is required here – a need to go back to a focus on specific antigens – ‘it’s the antigens, stupid‘, specific microbiota-derived antigens that is*.
# for the more immunologically inclined reader, that’s a combination of Danger or PAMP (Pathogen-Associated Molecular Patterns) models plus the Th1-Th2-ThX models.
* development of a novel conceptual platform for predictive discovery of disease-associated antigens is precisely my research focus.
Bibliography
1. Dieli-Crimi, Romina, M. Carmen Cénit, and Concepcion Nunez. “The genetics of celiac disease: A comprehensive review of clinical implications.” Journal of autoimmunity 64 (2015): 26-41.
2. Greco, L., et al. “The first large population based twin study of coeliac disease.” Gut 50.5 (2002): 624-628. https://gut.bmj.com/content/50/5…
3. Nisticò, Lorenza, et al. “Concordance, disease progression, and heritability of coeliac disease in Italian twins.” Gut 55.6 (2006): 803-808. Concordance, disease progression, and heritability of coeliac disease in Italian twins
4. Sollid, Ludvig M., et al. “Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer.” Journal of Experimental Medicine 169.1 (1989): 345-350. http://jem.rupress.org/content/j…
5. Louka, A. S., and L. M. Sollid. “HLA in coeliac disease: unravelling the complex genetics of a complex disorder.” Tissue antigens 61.2 (2003): 105-117.
6. Tirumalai Kamala’s answer to Would you consider hookworms to treat your celiac disease?
https://www.quora.com/Can-celiac-disease-be-reversed/answer/Tirumalai-Kamala