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Intraepithelial lymphocytes and coeliac disease

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The diagnosis of coeliac disease is easy in cases with symptoms and unequivocal small intestinal villous atrophy. However, patients often suffer from only subtle if any symptoms. Borderline villous shortening is common, making the histologic diagnosis difficult. The increase in intraepithelial lymphocytes is typical even in early-stage untreated coeliac disease. Unfortunately, this finding is unspecific. In coeliac disease, the relative density of γδ+ intraepithelial lymphocytes is increased. The presence of IgA class anti-endomysium or anti-tissue transglutaminase antibodies clearly increases the likelihood of the disease. Coeliac disease is closely linked to HLA DQ2 and DQ8, and their absence speaks strongly against the condition, whereas a positive finding is virtually of no diagnostic value. In borderline cases, the gluten-dependency of symptoms or mucosal inflammation should be shown by gluten-free diet or gluten challenge. No single test is efficient enough to distinguish unspecific increase in intraepithelial lymphocytes from early coeliac disease; clinical history, histology, serology and gluten-dependency should be taken into account in the diagnostic work-up.

Section snippets

IELS and diagnosis of CD

The diagnosis of CD is currently based on the description of characteristic small bowel mucosal inflammation and its dependence of gluten ingestion. This inflammation comprises of several components; architectural changes of crypt hyperplasia and villous atrophy; infiltration of the lamina propria with lymphocytes, macrophages and eosinophils and thirdly; expansion of the intraepithelial lymphocytes population.7 Usually, the diagnosis is easy in cases with unequivocal symptoms and total villous

Marsh classification

The spectrum of gluten enteropathy consists of progressive mucosal changes, which have been artificially classified into four stages originally by Michael Marsh.9 Each stage represents a progression up a spectrum of severity. Marsh stage I consists of mucosal inflammation characterised by increased density of intraepithelial lymphocytes (IELs) but with preservation of the villous/crypt structure. The addition of subtle hyperplasia of the crypts to the increased IELS defines Marsh II. When

Dermatitis herpetiformis as a model of early-stage gluten-sensitive enteropathy

Dermatitis herpetiformis (DH) is an extremely itchy blistering skin rash associated with gluten sensitive enteropathy. Originally, dermatitis herpetiformis was not thought to be due to gluten sensitive enteropathy or CD.14 However, the genetic similarity of the two disorders, response of the skin rash to a gluten free diet and recently the reproduction of DH in a HLA transgenic animal model of intestinal gluten sensitivity has confirmed that DH is a part of the spectrum of gluten CO.15 In the

Borderline findings in CD

Diagnostic difficulties arise especially in borderline mucosal findings. The distinction between partial villous atrophy and normal mucosal structure is not always easy. The diagnosis should be made of well-oriented samples. However, in clinical practice the sampling is often compromised, for instance by oblique slicing of the specimens. Even in centres with a high interest in CD, 12% of biopsy specimens were not suitable for interpretation rendering the histological diagnosis impossible.21 In

Immunostaining of IELS

Immunohistochemical staining offers additional value for the specificity and also for the sensitivity to detect genetic CD. The majority of IELs are CD3/CD8+ lymphocytes carrying the αβ+ T-cell receptor, and the minority of γδ+ T-cell receptor bearing lymphocytes. In CD, the relative density of γδ+ IELs is increased.1 This is not a specific phenomenon for CD, as earlier thought. An increased density can be seen in some other conditions, such as cow's milk allergy or post-enteritis syndrome, or

Further investigations

A suspicion of CD should always arise when there is an increased density of IELs in small intestinal mucosa. In the absence of villous atrophy, further evidence should be present in order to make the diagnosis. Family history or CD, and the concomitant occurrence of other autoimmune conditions increase the likelihood of CD. Serum IgA class anti-endomysium and anti-tissue transglutaminase antibodies are highly specific.32, 33 Their sensitivity has not been as good in all studies.34 Even though

HLA and CD

CD is closely linked to HLA DQ haplotypes, and HLA DQ2 is present in 90% of coeliac patients, and most of the rest, 8–9%, have HLA DQ8.37, 38 In the European population, 61 out of 1008 (6%) did not carry the HLA DQ2 or DQ8 heterodimers.38 Of these, 57 encoded half of the DQ2 heterodimer, that is either DQA1*05 or DQB1*02; thus only four were negative. This high specificity indicates that the absence of both DQ2, or its alleles, and DQ8 in patients with a borderline small intestinal finding

Clinical studies

Gluten challenge or gluten-free diet might be useful in showing gluten sensitivity. Wahab et al39 investigated 38 patients with Marsh I lesion and subjected them to gluten challenge. A significant deterioration in mucosal histology was seen in 12 of them together with a symptom relief. HLA DQ2 or DQ8 was not present in all of these patients. As stated earlier, in the study at Mayo Clinic, 4 out of 43 patients with an increased density of IELs but normal villous structure appeared to be gluten

Summary

The recognition that subtle enteropathy can be the result of gluten ingestion in symptomatic patients and those with consequences suggest that the current criteria of ESPGHAN should be revised. The demonstration of gluten sensitive enteropathy in genetically susceptible individuals should not require the presence of overt small intestinal villous atrophy. An increase in small intestinal IELs is helpful in recognising early and borderline CD, but the finding is not specific. The presence of γδ+

Acknowledgements

Supported by a grant from the Medical Research Fund of Tampere University Hospital.

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