Mycobacteria in Crohn’s disease: how innate immune deficiency may result in chronic inflammation

Abstract

Crohn’s disease (CD) is often considered to be an autoimmune condition or, alternatively, an autoinflammatory condition, based on the observation of host-directed inflammatory processes. However, the underlying basis of this deleterious inflammatory response remains elusive. Recent findings from genetic and genomic studies have altered the perspective on the pathogenesis of CD, hinting at defects in innate immune sensing of intracellular bacteria and the handling of these organisms through autophagy. These findings are consistent with emerging data from immunological studies that point to a systemic immune deficiency in CD patients. Both sets of data (genetic predisposition and immunodeficiency) are consistent with the longstanding hypothesis that mycobacteria might be involved in the etiology of CD. In this article, we discuss the convergence of these three lines of investigation and highlight important knowledge gaps required in order to address the mycobacterial hypothesis with greater clarity. In the coming years, clinical immunological investigations should focus on defining the specificity of functional immune defects with regards to microbes and their associated ligands. Should CD result from a dysfunctional host–pathogen interaction, elucidation of the microbes that can exploit such defects to induce a chronic inflammatory disease is critical for the development of subsequent diagnostic assays and clinical interventions.

Keywords::

• autophagy
• Crohn’s disease
• immune deficiency
• Mycobacterium avium paratuberculosis
• NOD2

Financial & competing interests disclosure

Jean-Daniel Lalande is supported by a studentship award from the Canadian Institutes for Health Research (CIHR). Marcel A Behr is supported by a Chercheur Boursier Senior award from the Fonds de Recherche en Santé du Québec and a William Dawson Scholar award from McGill University. Work in our laboratory is supported by operating grants from the CIHR. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.