Granuloma formation in the different phenotypes of Crohn’s disease

Our immunological and molecular knowledge base¹ in idiopathic chronic inflammatory bowel disease (IBD) has seen a tremendous increase over the past few years. Laboratory application of sophisticated new methodologies has revealed a plethora of agonistic and antagonistic factors involved in the pathogenesis of both ulcerative colitis and Crohn’s disease. Proinflammatory and Th2 derived anti-inflammatory cytokines are secreted by and act on various different cell types by forming a complex network of interdigitating molecular pathways with profound effects on epithelial cells, lymphocytes, endothelial cells, and monocytes. This multilayered interplay of humoral factors and various cells at different stages of differentiation appears similar to a symphony where the end result is perfect yet the role of various single instruments remains obscure to the casual listener.

Some of the newly discovered pathways have been utilised to develop new therapeutic strategies² and molecular genetic studies in particular have provided fascinating new insights into the problems of genetic host susceptibility. Polymorphisms or mutations in the NOD2 gene^3,4 are coding for proteins involved in the recognition of different pathogen associated molecular patterns and different bacteria, ultimately resulting in the activation of nuclear factor κB. Other members of the innate immune system such as Toll-like receptors appear to be involved in Crohn’s disease.^5,6

Histopathological features of IBD are well defined and little if any changes have occurred during the past few years. Any modern textbook on the subject of IBD will certainly contain a single chapter on histopathology but only the diagnostic role of histopathology in IBD is emphasised. While this remains especially true for the differential diagnosis of Crohn’s disease versus ulcerative colitis, the problem of dysplasia, and issues of inter- and intraobserver variability, attempts to correlate morphology with molecular and immunological mechanisms are rarely found. Granulomas for example are seen as diagnostic tools but their potential role in disease biology is neglected. This is contrasted by numerous basic research publications on IBD in which the authors do not mention granulomas at all and where it remains doubtful whether they have ever seen such lesions.

There have been only a few recent reports on the frequency of granulomas in endoscopic and surgical specimens of patients with Crohn’s disease and prospective population based studies are lacking. The article of Heresbach and colleagues⁷ in this issue of Gut carefully defines the histomorphological features of epithelioid cell granulomas, microgranulomas, and isolated giant cells (see page 215). Correlating the morphological findings with treatment data and clinical outcome revealed that epithelioid cell granulomas might indicate a more aggressive clinical course. The article by Pierik and colleagues,⁸ also in this issue of Gut, compares the occurrence of epithelioid cell granulomas with some of the most important genetic variants of the innate immune system (CARD15/NOD2 and Toll-like receptor 4) in a well defined cohort of patients with Crohn’s disease (see page 223). The lack of significant correlations between the prevalence of epithelioid cell granulomas and immune system variants is disappointing but other findings, such as a higher frequency of granulomas in distal portions of the intestine and in younger patients, are of interest.

Sampling error may have influenced the detection rate of epithelioid cell granulomas in both studies but the morphological and molecular data are well presented and prospectively correlated. This is especially important as most of the basic science in IBD research generates functional data from in vitro experiments or laboratory animal models.

Epithelioid granulomas seen in Crohn’s disease show a specific geographic arrangement with multinuclear giant cells and T lymphocytes, similar to granulomas observed in many infectious diseases. Specific disease phenotypes may provide insights towards answering the question of whether a phenomenon is causative in Crohn’s disease or ulcerative colitis, or simply reflects secondary inflammatory reactions.

Both articles contribute to this question by stressing the significance of epithelioid cell granulomas in the biology and clinical course of the disease. Tremendous progress in the understanding of complex immunological networks and genetic susceptibility provides a new stimulus to re-evaluate certain morphological features of disease. Granulomas may in fact contain previously unsuspected biological information that goes beyond their established role as a diagnostic tool.