This work attempts to explore the genetic and expression profiles of a special set of individuals in the CD domain. Potential Celiac patients, with positive serology and undamaged small intestinal mucosa appear to be differently associated with some genetic risk factors compared to full blown CD patients.
Potential CD bears a load of HLA-related CD risk significantly lighter than that of CD cases, with a mix of high-intermediate-low risk different from that observed in CD cases. No difference in HLA profile was observed between M0 and M1 potential patients, neither between the cases who developed full blow disease and those who remained potential at follow up. Subjects without the classical DQ2 or DQ8 heterodimers were double in potential (23, 18.0%) than in classical celiacs (28, 9.0%), but they produced antibodies against Human Tissue Tranglutaminase, with positive Endomysial antibodies, just as much as the DQ2 positive cases. In addition we could find no discrimination on the outcome between the DQ2/DQ8 carriers and those who carried only half of the heterodimers. This is one of the results of this work and should not produce a selection bias. Three cases were questionable on the basis of having only DQA1*01 /DQB1*0501: but this haplotype was previously described in celiac disease 
. Although they may not represent the typical potential celiac, we did not exclude them, to avoid selection bias. We better accept that only 3/127 cases may not show the full pattern of the majority of the cohort.
We identified six polymorphisms suggestive to be differently distributed between controls and potential CD: KIAA1109, IL-21, LPP, c-REL and CCR. We suppose that these factors are implicated at some stages of CD pathogenesis, and that, as for HLA, there may be a “gene-dosage effect”. Furthermore, c-REL and KIAA1109 are more expressed in M0 potential patients suggesting that they may play a role in the development of adaptive anti-gluten immunity.
The SNP at c-REL gene shows a different distribution of the G allele, as well as of the corresponding genotype, in potential CD versus celiacs and versus controls. Unfortunately we were unable to correlate the G allele of the polymorphic marker of the gene with RNA expression, but we will explore further in more cases. c-REL gene has been recently associated to CD but no significant effect of the rs842647 polymorphism on gene expression was observed 
. In small-intestine tissue from controls and from treated and untreated celiac patients, c-REL gene did not show significant differential expression among the three groups 
. c-REL, a subunit of the NF-kB complex, is crucial for the regulation of this major nuclear factor for the innate and adaptive immunity 
. It's regulation can terminate the NF-kB activation by innate immune stimuli. The integral structure of c-REL is crucial for the activation as well as for the termination of NF-kB induced immunoresponse 
In conclusion, the finding of the different allele and genotype distribution of this gene in the potential CD model does point to the crucial role of NF-kB in the pathogenesis of the innate as well as induced immune response in CD. Sustained activation of NF-kB in intestinal mucosa of CD patients leads to prolonged induction of inflammatory genes expression and thereby perpetuates the chronic inflammatory process. Our group produced consistent evidence of the very early involvement of NF-kB mechanism in the gliadin-induced innate immune response in CD 
. NF-kB is constitutively active in intestinal mucosa of patients with untreated CD and reverts to normal values when gluten is removed from the diet.
The polymorphic markers of the 4q candidate region show significant differences between potential CD and CD cases.
Potential CD show a marked suppression of IL-21, below the level of CD cases, celiacs on GFD and even of normal controls. IL-2 and KIAA1109, on the contrary were both over-expressed in M0 potential CD compared to M1, to celiacs and to controls. M1 cases show an IL-2 and KIAA1109 expression very similar to that of CD.
The finding that the IL-21 gene differentiates potential from controls suggests that it may be implicated also in the adaptive anti-gluten immune responses. This is compatible with findings indicating that IL-21 is produced by follicular helper cells and plays a critical role in B cell differentiation. However IL-21 is also implicated in tissue damage because of its ability to promote NK activity and block regulatory T cells.
In accordance with the role of IL-21 in tissue damage and its down regulation in the mucosa of potential CD patients we found that the IL-21/IL-2 candidate region differentiates potential from CD patients. Conversely, IL-2, which was found to be a critical growth factor for Foxp3+ regulatory T cells, is highly expressed at the transcriptional level in potential CD mucosa. Because Foxp3 regulatory T cells play a critical role in blocking effectors T cell functions, these finding suggests that the level of IL-2 may be a critical factor in the development of tissue damage.
Potential patients have most of the features of CD patients: they have similar genes. produce the same antibodies but they lack the final destructive phase of the gluten induced immunoresponse, the cytotoxic destruction of small intestinal mucosa. No clinical, serological or histological features could distinguish M0 from M1 patients up to now 
, for the first time we can speculate that potential CD are a mixture of two populations, with different non-HLA genetics and significant differential expression of some candidate genes.
Those potential cases who developed full blow mucosal damage on follow up, did not show any of the time 0 serologic markers worse than those who remained potential over a prolonged follow up. Similarly no genetic polymorphism, including HLA, could predict the outcome of these potential cases. We observed the same distribution of the HLA as well as of the non-HLA genes in the cases who eventually become full blown celiacs.
The limit of this study is the relatively short follow up time of this peculiar cohort of Potential CD cases: up to now there has been no possibility to identify any marker (clinical, environmental, serological or genetic) that could help to predict the time of conversion from predisposition to CD to full blown disease. In conclusion we cannot state that the cohort of potential celiacs who have again show an undamaged intestinal mucosa after 4 to 6 years of follow up, will not eventually develop it later in life. We can only observe that this group did not developed the full blown disease after 4–6 years. But the genetic and expression features point to the existence of a peculiar molecular profile, that may help to identify cases who do not have the complete molecular repertoire to develop the disease.
They may indeed be considered a live biological model of CD pathogenesis, where the process is, for some time or even forever, interrupted just before the final destructive phase.