Abstract
Crohn’s disease is a chronic inflammatory condition most commonly affecting the ileum and colon. The aetiology of Crohn’s disease is complex and may include defects in peptidoglycan recognition, and/or failures in the establishment of intestinal tolerance. We have recently described a novel constitutive endogenous delivery system for the translocation of nanomineral-antigen-peptidoglycan (NAP) conjugates to antigen presenting cells (APCs) in intestinal lymphoid patches. In mice NAP conjugate delivery to APCs results in high surface expression of the immuno-modulatory molecule programmed death receptor ligand 1 (PD-L1). Here we report that NAP conjugate positive APCs in human ileal tissues from individuals with ulcerative colitis and intestinal carcinomas, also have high expression of PD-L1. However, NAP-conjugate positive APCs in intestinal tissue from patients with Crohn’s disease show selective failure in PD-L1 expression. Therefore, in Crohn’s disease intestinal antigen taken up by lymphoid patch APCs will be presented without PD-L1 induced tolerogenic signalling, perhaps initiating disease.
Highlights
Ensure that luminally-derived antigen is presented in a tolerogenic context to minimise intestinal inflammation
We have previously shown that peptidoglycan can upregulate PD-L1 expression[7] and that mice deficient in Nod[1] and Nod[2] display defective PD-L1 expression in their intestinal APCs6
We hypothesised that defects in the delivery or recognition of peptidoglycan to APCs in the intestinal tract would result in aberrant PD-L1 expression and underpin the development of Crohn’s disease
Summary
M cells have recently been shown to be critical for the translocation of NAP-conjugates to underlying APCs6 This pathway remains functional in Crohn’s disease, as peptidoglycan co-localised with nanomineral positive cells (identified by calcein staining) are present in both control and Crohn’s disease tissues (Fig. 2B). Aureus the levels of surface PD-L1 and PD-L2 increased significantly in both control and Crohn’s disease cohorts (Fig. 4B) These observations fit with our previous work showing that PBMCs from Crohn’s disease patients homozygous for NOD2 L1007fsincC do not induce PD-L1 upon exposure to muramyl dipeptide, but they do so when stimulated with crude peptidoglycan in a manner presumed to be mediated by a receptor other than NOD2. Restoring PD-L1 signalling in the NAP pathway would present an interesting therapeutic option for the treatment of Crohn’s disease
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