Understanding the molecular basis of celiac disease: What genetic studies reveal

Figures & data

Figure 1 Overview of the path taken by gluten. a) Gluten enters the lumen of the small intestine and is cleaved by several enzymes. b) It subsequently passes through the enterocytes in the intestinal barrier, which is impaired in celiac disease (CD) patients; myosin IXB (MYO9B) might play a role here by affecting the tight junctions. Enterocytes express the MICA ligand that binds to the NKG2D receptor on the intraepithelial lymphocytes (IEL). Besides this, enterocytes also produce IL‐15 capable of stimulating IELs and T cells. c) Both the innate and the adaptive immune system play a role. 1) Adaptive immune response: gluten is deamidated by tissue transglutaminase (tTG) in the lamina propria and elicits an immune response in genetically susceptible individuals who are also HLA‐DQ2.5 and/or ‐DQ8 positive. 2) Innate immune response: gluten induces the antigen‐presenting cell (APC) to produce Il‐15, which stimulates the production and interaction of the MICA ligand and the NKG2D receptor. IL‐15 also stimulates the adaptive immune response.

Table

Marsh stage	Intraepithelial lymphocytes (IEL) >30 per 100 epithelial cells	Crypt hyperplasia	Villous atrophy ^a
0 ^b	−	−	−
I	+	−	−
II	+	+	−
IIIA	+	+	partial
IIIB	+	+	subtotal
IIIC	+	+	total

^a Broadening and disappearing villi, with a crypt/villous ratio >1.

^b Biopsies taken from celiac disease (CD) patients who are on a gluten‐free diet and who returned to a normalized histology. The histology should basically be the same as in healthy controls.

Table

Locus name	Location	λs ^e	Expected role in CD	Gene
CELIAC1	6p21.3	4,6	major	HLA‐DQA1 and ‐DQB1
CELIAC2	5q31–q33	ND	minor
CELIAC3	2q33	ND	minor	CTLA‐4
MYO9B, previously CELIAC4	19p13.1	2,6	intermediate	MYO9B^d
ND	15q11–q13	ND	minor ^a
ND	9p21–p13	ND	minor ^b
ND	6q21–22	2,3	minor ^c

^a This locus was found using large pedigrees in which a different inheritance pattern is observed than in the general population.

^b This locus was found in a large pedigree with a dominant inheritance, and in two other studies it showed some evidence for linkage.

^c This locus was only found once in a celiac disease (CD) population, with suggestive evidence, but is also found in several other immune‐related disorders.

^d Relative risk of this gene, allele frequency = 1.5, heterozygous AG = 1.66 and homozygous AA = 2.27.

^e λs as calculated by Van Belzen et al. 104.

ND = not determined

Van Belzen M. J., Meijer J. W., Sandkuijl L. A., Bardoel A. F., Mulder C. J., Pearson P. L., et al. A major non‐HLA locus in celiac disease maps to chromosome 19. Gastroenterology 2003; 125: 1032–41

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