Potential celiac patients: a model of celiac disease pathogenesis

Background and Aim

Potential celiacs have the ‘celiac type’ HLA, positive anti-transglutaminase antibodies but no damage at small intestinal mucosa. Only a minority of them develops mucosal lesion. More than 40 genes were associated to Celiac Disease (CD) but we still do not know how those pathways transform a genetically predisposed individual into an affected person. The aim of the study is to explore the genetic features of Potential CD individuals.

Methods

127 ‘potential’ CD patients entered the study because of positive anti-tissue transglutaminase and no mucosal lesions; about 30% of those followed for four years become frankly celiac. They were genotyped for 13 polymorphisms of ‘candidate genes’ and compared to controls and celiacs. Moreover, 60 biopsy specimens were used for expression studies.

Results

Potential CD bear a lighter HLA-related risk, compared to celiac (χ² = 48.42; p value = 1×10⁻⁸). They share most of the polymorphisms of the celiacs, but the frequency of c-REL* G allele was suggestive for a difference compared to celiac (χ² = 5.42; p value = 0.02). One marker of the KIAA1109/IL-2/IL-21 candidate region differentiated potentials from celiac (rs4374642: χ2 = 7.17, p value = 0.01). The expression of IL-21 was completely suppressed in potentials compared to celiacs (p value = 0.02) and to controls (p value = 0.02), in contrast IL-2, KIAA1109 and c-REL expression were over-expressed.

Conclusions

Potential CD show genetic features slightly different from celiacs. Genetic and expression markers help to differentiate this condition. Potential CD is a precious biological model of the pathways leading to the small intestinal mucosal damage in genetically predisposed individuals.     

Ultrastructure of celiac plexus nodes in the dog

A normal structure of the celiac plexus nodes has been studied in 12 mature dogs. As demonstrate the results of the investigation, gangliocytes of the celiac plexus are characterized with a well developed granular cytoplasmic reticulum and a large number of Golgi complexes. In perikaryon of the gangliocytes, an essential number of mitochondria, microtubules, free ribosomes and polysomes, lysosomes, multivesicular bodies, agranular and granular vesicles and neurofilaments are found. The gangliocyte has one nucleus which occupies about 1/3 of the whole area of the cell. The nucleus is rich in chromatin. The nucleolus makes about 1/5 of the whole area of the nucleus and is intensively rich in heterochromatin. In the celiac plexus nodes amyelinated neural fibers predominate. Dendrites in the gangliocytes differ from axons by a higher electron density of their matrix and contain the same organells that does the perikaryon of the gangliocyte. Rather complex glyoneuronal interrelations are observed in the canine celiac plexus nodes. Synapses are revealed in all ganglionar zones. The axodendritic synaptic contacts predominate over the axosomatic ones.     

Neuronal organization of the left celiac ganglion in the cat

Unit responses of the isolated left celiac ganglion to stimulation of various nerves of the solar plexus were studied by intracellular microelectrode recording in cats before and after degeneration of the preganglionic fibers. The resting potential of the ganglionic neurons was ?62.2±2.9 mV and the amplitude of the spike potential 72.4±3.2 mV. The spike was followed by after-hyperpolarization with a mean amplitude of 24% of the spike amplitude and a duration of between 25 and 180 msec. A characteristic feature of the ganglion was the presence of orthodromic unit responses to stimulation of peripheral nerve fibers of the solar plexus. The higher threshold of activation of the neurons by peripheral fibers than by preganglionic fibers and the preservation of orthodromic unit responses to stimulation of peripheral nerves after degeneration of the preganglionic fibers are evidence that the peripheral reflex arc is closed in this ganglion. Neurons of the left celiac ganglion are divided into three groups. Only preganglionic fibers of the splanchnic nerve with different properties converge on the neurons of the first group (the most numerous); only afferent fibers of peripheral nerves converge on the neurons of the third group (the least numerous); both types of fibers terminate on neurons of the second group. This convergence may lie at the basis of the mechanism of the centrifugal and peripheral reflex interaction in the ganglion for coordinated visceral activity.     

Synaptoarchitectonics of the ganglia of the celiac plexus in white rats

In 50 intact white rats at the age of 6, 15, 23 and 30 months synapsoarchitectonics of the celiac plexus nodes was studied by an electron microscopy method. Peculiarities in synapsoarchitectonics are stipulated by pericaryon processes in neurons, some of them have no contacts with the axonal terminals, while others have contacts with the axonal terminals. The former include small (about 0.5 mkm) drop-like and large (up to 1.5 mkm) polymorphous processes within the limits of perisomatic membrane, as well as processes penetrating the neuronal capsule. All of them contain, in different combinations, vesicles, ribosomas, fibrillae, and the largest processes--small cisterns of granular cytoplasmatic network and single mitochondria. The processes of the first group are considered as original stages for the development of the second group processes. The latter are represented by different in size (about 1.0--2.0 mkm) in form (digital, cone-, pin-, goblet-shaped, cylindrical, branching) and in content formations. There is, as a rule, one contact on the processes of an uncomplicated form, while on the branching processes there can be up to three and more contacting axonal terminals. Peculiar features in the composition of the processes taken as a whole (specific forms, absence of dendritic tubes, sometimes numerous contacts with axonal terminals in spite of small size) distinguish them from newly forming dendritic processes and these formations are considered as independent specialized receptor apparatus in the pericaryon of neurons of the celiac plexus.     

Prevalence of celiac disease in multiple sclerosis

Background  

Celiac disease (CD) is a common systemic disease related to a permanent intolerance to gluten and is often associated with different autoimmune and neurological diseases. Its mean prevalence in the general population is 1-2% worldwide. Our aim was to study the prevalence of celiac disease in a prospective series of Multiple Sclerosis (MS) patients and their first-degree relatives.     

Genome search in celiac disease.

Celiac disease (CD), a malabsorption disorder of the small intestine, results from ingestion of gluten. The HLA risk factors involved in CD are well known but do not explain the entire genetic susceptibility. To determine the localization of other genetic risk factors, a systematic screening of the genome has been undertaken. The typing information of 281 markers on 110 affected sib pairs and their parents was used to test linkage. Systematic linkage analysis was first performed on 39 pairs in which both sibs had a symptomatic form of CD. Replication of the regions of interest was then carried out on 71 pairs in which one sib had a symptomatic form and the other a silent form of CD. In addition to the HLA loci, our study suggests that a risk factor in 5qter is involved in both forms of CD (symptomatic and silent). Furthermore, a factor on 11qter possibly differentiates the two forms. In contrast, none of the regions recently published was confirmed by the present screening.     

Plasma motilin in untreated celiac disease

Celiac disease (CD) is characterized by mucosal villous atrophy mostly confined to the proximal small intestine. Upper-gut motor abnormalities have been reported. Motilin, localized in cells in the proximal small intestine, is a trigger factor for the migrating motor complex. Plasma levels of motilin were studied in 16 untreated CD patients and in an age-matched control group of 18 healthy subjects by radioimmunoassay and by high-performance liquid chromatography (HPLC). The fasting levels of motilin and postprandial levels were significantly higher in CD patients compared to controls (P<0.01) and HPLC revealed a divergent individual pattern of the motilin fragments.     

Improving the estimation of celiac disease sibling risk by non-HLA genes

Celiac Disease (CD) is a polygenic trait, and HLA genes explain less than half of the genetic variation. Through large GWAs more than 40 associated non-HLA genes were identified, but they give a small contribution to the heritability of the disease. The aim of this study is to improve the estimate of the CD risk in siblings, by adding to HLA a small set of non-HLA genes. One-hundred fifty-seven Italian families with a confirmed CD case and at least one other sib and both parents were recruited. Among 249 sibs, 29 developed CD in a 6 year follow-up period. All individuals were typed for HLA and 10 SNPs in non-HLA genes: CCR1/CCR3 (rs6441961), IL12A/SCHIP1 and IL12A (rs17810546 and rs9811792), TAGAP (rs1738074), RGS1 (rs2816316), LPP (rs1464510), OLIG3 (rs2327832), REL (rs842647), IL2/IL21 (rs6822844), SH2B3 (rs3184504). Three associated SNPs (in LPP, REL, and RGS1 genes) were identified through the Transmission Disequilibrium Test and a Bayesian approach was used to assign a score (BS) to each detected HLA+SNPs genotype combination. We then classified CD sibs as at low or at high risk if their BS was respectively < or ≥ median BS value within each HLA risk group. A larger number (72%) of CD sibs showed a BS ≥ the median value and had a more than two fold higher OR than CD sibs with a BS value < the median (O.R = 2.53, p = 0.047). Our HLA+SNPs genotype classification, showed both a higher predictive negative value (95% vs 91%) and diagnostic sensitivity (79% vs 45%) than the HLA only. In conclusion, the estimate of the CD risk by HLA+SNPs approach, even if not applicable to prevention, could be a precious tool to improve the prediction of the disease in a cohort of first degree relatives, particularly in the low HLA risk groups.     

Cytophotometric study of catecholamines and energy metabolism enzymes in rat celiac plexus neurons under cold and emotional stress

Catecholamine concentration and energy metabolism enzymes were investigated using histochemical and computer analysis techniques in celiac ganglia neurons under cold and emotional stress. Acute short-term cooling was found to lead to intensified catecholamine fluorescence as well as succinate and lactate dehydrogenase activity in celiac ganglia neurons, whereas short-lasting emotional stress produced no changes on fluorescence or energy metabolism enzymes.Institute of Physiology, Academy of Sciences of the Belorussian SSR, Minsk. Translated from Neirofiziologiya, Vol. 20, No. 6, pp. 743–749, November–December, 1988.     

Lateralization of the connections of the ovary to the celiac ganglia in juvenile rats

During the development of the female rat, a maturing process of the factors that regulate the functioning of the ovaries takes place, resulting in different responses according to the age of the animal. Studies show that peripheral innervation is one relevant factor involved.