Cytokine Profiles In Peripheral Blood Of IBD Patients

Cytokine Profiles In Peripheral Blood Of IBD Patients; Correlation With Genotypes And Clinical Phenotypes
N.W. Duijvis1, F.H. van Dooren1, D. Oudejans1, S.C. Wolfkamp1, E.W. Vogels1, F.W. Vergouwe1, P.C. Stokkers2, A.A. te Velde*1
Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, the Netherlands
2Sint Lucas Andreas Ziekenhuis, Amsterdam, the Netherlands
Introduction: Inflammatory bowel disease (IBD) is comprised of two major disorders: ulcerative colitis (UC) and
Crohn's disease (CD). However, it is now commonly recognized that the disease marked as IBD is rather a group
of diseases with several distinct pathogenetic pathways with a variable range of cytokines involved, each
pathway likely benefitting from different therapeutic approaches. These cytokines are key signals in the immune
system, and are known to participate in the disruption of the normal state of controlled inflammation in the gut.
During the last few years, enormous progress has been made by genome-wide association studies (GWAS)
identifying several new susceptibility loci on the genome for IBD and other types of diseases. By assessing the
immunological phenotype of IBD patients with their pathogenic pathways, a genotype-phenotype relation can be
studied. We aim to assess functional differences in the immune response of IBD patients and correlate these with
the known disease-associated genotypes and clinical phenotypes.
Methods: Whole blood of 168 individuals, both IBD patients and healthy controls, has been stimulated with
antiCD3/antiCD28 antibodies and LPS/MDP to mimic the adaptive and innate response, respectively. Twentyeight different cytokines were determined with a multiplex cytokine assay (Merck Millipore). Genotyping was
performed in IBD patients using a customized Illumina GWAS chip (Immunochip) containing ≈200.000 single
nucleotide polymorphisms (SNPs), including the SNPs from recently performed GWAS meta-analyses of UC
and CD by the International IBD Genetics Consortium (IBDGC). The clinical phenotype of patients was
determined using the Montreal classification.
Results: As expected, pro-inflammatory cytokines and chemokines involved in different pathways are
significantly up- or downregulated in IBD patients compared to healthy controls, such as IL-10, IL-12p70, and
CXCL5. Furthermore, we found many interesting correlations between the presence of IBD-associated SNPs and
cytokine levels (i.e. TNFa, IL-10, IL-17) after stimulation. Independent of the cytokine profile, certain SNPs also
seem to be directly associated with the clinical phenotype of patients.
Discussion: Our aim is to link genetic variation to a clinical phenotype by elucidating the causal, biological
pathways involved. This is a pivotal step in unravelling the heterogeneous background of IBD, and supports the
theory that patient-specific therapies can be provided based on a patient-specific genetic and immunological
profile in the near future.