The changing immunological paradigm in coeliac disease

Abstract

When coeliac disease is referred to as an inflammatory disorder, this may detract from its true nature. Activation of innate and adaptive immunity takes place in the mucosal lesion, but the tissue reaction is not that of classical inflammation. In fact, coeliac disease contrasts strikingly with typical inflammatory bowel disorders such as ulcerative colitis and Crohn's disease. The coeliac lesion apparently reflects, in the main, immune-driven remodelling of mucosal architecture with only a minor inflammatory component – initially most likely resulting from innate signals. Complement split products might be one of several potential initial hits that lead to activation of lamina propria and epithelial cells with release of mediators such as interleukin-15. This cytokine appears to stimulate potentially pathogenic intraepithelial lymphocytes. In genetically susceptible individuals, such early innate events could turn into persistent pathogenic signalling with subsequent adaptive cellular and humoral immunopathology resulting in a chronic lesion. Nevertheless, mucosal homeostasis is surprisingly well preserved as signified by the remarkable dominance of plasma cells that produce dimeric immunoglobulin A as a basis for enhanced secretory immunity. This shows that the microvascular endothelium in the lesion largely maintains its ‘gatekeeper’ function for mucosal immune cells – in striking contrast to the ‘promiscuous’ situation in inflammatory bowel disease. Altogether, a two-signal model is emerging for the pathogenesis of coeliac disease – signal 1 generated by innate immunity and signal 2 by adaptive immunity. Hence, there is currently an increased focus on immune activation in the epithelial compartment rather than on changes in the microvasculature as a basis for classical inflammation.

Introduction

Gluten-sensitive enteropathy, including coeliac disease and a similar proximal gut affection in dermatitis herpetiformis (DH), is a rather common although variable malabsorption disorder. Coeliac disease is not only an important clinical entity both in children and adults, but it is also an interesting human model for studies of mucosal immunity and immunopathology. The intestinal lesion is by many researchers referred to as a chronic inflammatory disorder. This may detract from the true nature of its pathogenesis which – by comparison with inflammatory bowel disease (IBD) – induces only minor signs of inflammation in the classical sense.

Pathology textbooks give the following definition of inflammation [1]: ‘… what characterizes the inflammatory process in higher forms is the reaction of blood vessels, leading to the accumulation of fluid and leukocytes in extravascular tissues’ and [2]: ‘inflammation is the reaction of a tissue and its microcirculation to a pathogenic insult. It is characterized by the generation of inflammatory mediators and movement of fluid and leukocytes from the blood into extravascular tissues’. Contrary to this, the ‘gatekeeper’ function of the mucosal microvasculature is remarkably well maintained in coeliac disease despite features reflecting strong stimulation of both innate and adaptive immunity. Thus, there is a remarkably well preserved preference for production of homeostatic immunoglobulin A (IgA) in the lamina propria. This is in striking contrast to the situation in IBD lesions – including both ulcerative colitis and Crohn's disease [3], [4].

The gross pathology of coeliac disease is therefore not dominated by chronic inflammation with tissue destruction but, instead, remodelling of mucosal architecture – with, in the extreme, a ‘flat’ duodenal/jejunal lesion – often referred to as villous atrophy. Importantly, this lesion can generally be reverted to normal when wheat gluten and similar proteins of rye and barley are eliminated from the diet.

It is still debated which of two principal pathogenic mechanisms could cause the flat lesion (Fig. 1): (a) negative effects on the surface epithelium that cause cell damage and loss of enterocytes (villous atrophy) followed by compensatory crypt hyperplasia or (b) positive effects on the crypt cells directly inducing proliferation, with villous atrophy being only ‘apparent’ as a result of crypt hyperplasia. There are considerable experimental data to support both these possibilities, and the lesion most likely reflects a ‘joint venture’. The balance of evidence suggests that the coeliac immunopathology involves a complex individualized interplay of many pathophysiological variables on a genetic background [5].