Paul Pavli

Analysis of Australian Crohn's disease pedigrees refines the localization for susceptibility to inflammatory bowel disease on chromosome 16.

A number of localizations for the putative susceptibility gene(s) have been identified for both Crohns disease and ulcerative colitis. In a genome wide scan, Hugot et al. (1996) identified a region on chromosome 16 which appeared to be responsible for the inheritance of inflammatory bowel disease in a small proportion of families. Subsequent work has suggested that this localization is important for susceptibility to Crohns disease rather than ulcerative colitis (Ohmen et al. 1996; Parkes et al. 1996). We investigated the contribution of this localization to the inheritance of inflammatory bowel disease in 54 multiplex Australian families, and confirmed its importance in a significant proportion of Crohns disease families; we further refined the localization to a region near to D16S409, obtaining a maximum LOD score of 6.3 between D16S409 and D16S753.

CARD15/NOD2 risk alleles in the development of Crohn's disease in the Australian population.

We have previously reported strong evidence for linkage between IBD1 and Crohns disease (CD) in Australian Crohns disease families. Three risk alleles for Crohns disease, (Arg702Trp (C/T), Gly908Arg (G/C) and 980fs981 (‐/C), were recently identified in the CARD15/NOD2 gene on chromosome 16, implicating this as the IBD1 locus. Using a novel diagnostic PCR‐RFLP, we have examined the frequency of these alleles in 205 multiplex IBD families, 107 sporadic Crohns disease cases and 409 normal individuals. We demonstrate that the three risk alleles are more frequent in Crohns disease, than in controls, with allelic frequencies of 0.11, 0.02 and 0.07 respectively. Heterozygosity for individual variants conferred a three‐fold increase in risk for Crohns disease while substantially higher risks were associated with being homozygous or compound heterozygous. Despite a significantly lower population allele frequency for the frameshift mutation than reported by other groups, we see a similar contribution by this allele to the risk of developing Crohns disease. While the three risk alleles influence susceptibility to Crohns disease in Australia, we show that these alleles do not fully explain the linkage evidence and suggest that there are very likely additional IBD1 susceptibility alleles yet to be described in Australian CD at the NOD2 locus. We also show a second linkage peak in Australian CD that provides some support for a second disease susceptibility locus on chromosome 16.

Lymphoma and other lymphoproliferative disorders in inflammatory bowel disease: A review

The lymphoproliferative disorders (LDs) are a heterogeneous group of at least 70 conditions that result from the clonal proliferation of B, T, and NK cells. Inflammatory bowel disease (IBD)‐associated lymphomas are typically B‐cell LD, while T‐cell or Hodgkins lymphomas are rare.

The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene‐environment interaction

Background and Aims: The inflammatory bowel diseases (IBDs) Crohns disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome‐wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11‐12, also known as the IBD4 locus. To further characterize this locus, we assessed gene‐environment interaction (IBD4 × smoking) and phenotypic heterogeneity in a large cohort of IBD‐affected sibling pairs as part of an ongoing international collaborative effort. Patients and Methods: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. Results: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P ≤ 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively). Conclusions: The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene‐environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4.

Dextran sodium sulphate‐induced colitis activity varies with mouse strain but develops in lipopolysaccharide‐unresponsive mice

Bacteria and their products have been implicated in the pathogenesis of chronic Inflammatory Bowel disease. The aim of this study was to investigate the potential role of lipopolysaccharides (LPS) in the development of intestinal injury by comparing the effects of the dextran sodium sulphate (DSS)‐induced model of colitis in LPS‐sensitive and ‐insensitive mice. Experimental colitis was induced in LPS‐sensitive mice (C3H/He) and their LPS‐insensitive congenic strain (C3H/HeJ). Colitis was assessed clinically using a disease activity index (derived from the three main clinical signs; diarrhoea, rectal bleeding and weight loss) and by histological scoring of the diseased colon. The clinical signs and disease activity index did not differ between the LPS‐sensitive and ‐insensitive costrains. Similarly, histological scores did not differ significantly for either C3H strain at any time point during exposure to DSS. However, there were differences in the inflammatory response when different strains were compared (C3H vs CBA): the effects of DSS in C3H mice were immediate, more severe and mainly involved the caecum and ascending colon. These findings suggest that LPS from colonic bacteria do not play a primary role in the initiation of DSS‐induced colitis and demonstrate clear differences in the responsiveness of different mouse strains to DSS.

Advances in the management of inflammatory bowel disease

Our understanding of inflammatory bowel diseases (IBD) is constantly evolving, and many new treatment options have emerged recently. This review critically examines the evidence for these new developments and aims to provide an overview for medical professionals involved in the care of patients with IBD. Proposed changes in the use of aminosalicylates, immunosuppressants and biological agents are described, and the evidence for several promising novel agents is reviewed.

Early predictors of colectomy and long‐term maintenance of remission in ulcerative colitis patients treated using anti‐tumour necrosis factor therapy

Anti‐tumour necrosis factor (TNF) agents are used as induction and maintenance therapy in ulcerative colitis (UC) refractory to standard therapy and as rescue therapy in acute severe UC (ASUC).

Effects of bacterial products on enterocyte-macrophage interactions in vitro.

We describe a coculture model of a human intestinal epithelial cell line and human peripheral blood monocytes in which monocytes differentiate into cells with features of resident intestinal macrophages. Caco-2 cells are grown on the lower surface of a semipermeable filter with pore size of 3 μm (Transwells) until they differentiate into enterocytes. Peripheral-blood monocytes are added and the co-culture incubated for two days. Monocytes migrate through the pores of the membrane, come into direct contact with the basolateral surfaces of the epithelial cell monolayer, and develop characteristics of resident intestinal macrophages including downregulation of CD14 expression and reduced pro-inflammatory cytokine responses (IL-8, TNF and IL-1β) to bacterial products. The apical application of lipopolysaccharide (LPS) and muramyl dipeptide (MDP) resulted in an increased number of integrated monocytes, but abrogated the downregulation of CD14 expression and the diminished cytokine responses. MDP also reduced tight-junctional integrity, whilst LPS had no effect. These data indicate that LPS and MDP have significant pathophysiological effects on enterocyte-monocyte interactions, and confirm other studies that demonstrate that enterocytes and their products influence monocyte differentiation. This model may be useful in providing insights into the interaction between monocytes, epithelial cells and intestinal bacteria in health and disease.

1 Ulcerative colitis: a genetic disease?

A number of lines of evidence support the hypothesis that ulcerative colitis is an inherited disorder in a proportion of cases. First, there is a pattern of familial aggregation. Second, there are differences in the prevalence of the disease in different ethnic groups. Finally, the concordance rate in monozygotic twin pairs is higher than that of dizygotic twin pairs, although not as high as the concordance rates observed in Crohns disease. Genetic models of the inheritance patterns suggest that ulcerative colitis is probably caused by one major gene, although that gene (or genes) remains to be identified. While at least one localization for susceptibility to Crohns disease now seems certain, efforts to localize and characterize the susceptibility genes involved in the inheritance of ulcerative colitis are still underway. While the genes of the major histocompatibility complex have been imputed as causal in susceptibility to ulcerative colitis, a consensus of proof continues to elude us.

Risk of non-melanoma skin cancer with thiopurine use in inflammatory bowel disease

See article in J. Gastroenterol. Hepatol. 2012; 27: 385–389.