Recent Developments in the Immunology of Inflammatory Bowel Disease

MacDonald, Thomas T.; Monteleone, Giovanni; Pender, Sylvia L. F.

doi:10.1046/j.1365-3083.2000.00658.x

Cited by 183 publications

(139 citation statements)

References 49 publications

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“…Increased FGF7 expression is an important response mechanism to damaged epithelial tissues in the skin, bladder, and kidney (47). Conversely, overexpression of FGF7 is thought to contribute to psoriasis and inflammatory bowel disease (48,49). FGF10͞7-FGFR2b signaling is also involved in the pathogenesis of bladder, colon, and prostate cancers (50)(51)(52).…”

Section: Fgf10-induced D2 Rotation Plays An Important Role In Fgf10-fmentioning

confidence: 99%

Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors

Yeh

Igarashi

Eliseenkova

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

170

201

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Binding specificity between fibroblast growth factors (FGFs) and their receptors (FGFRs) is essential for mammalian development and is regulated primarily by two alternatively spliced exons, IIIb (''b'') and IIIc (''c''), that encode the second half of Ig-like domain 3 (D3) of FGFRs. FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b). Here, we report the crystal structure of the ligand-binding portion of FGFR2b bound to FGF10. Unique contacts between divergent regions in FGF10 and two b-specific loops in D3 reveal the structural basis by which alternative splicing provides FGF10-FGFR2b specificity. Structure-based mutagenesis of FGF10 confirms the importance of the observed contacts for FGF10 biological activity. Interestingly, FGF10 binding induces a previously unobserved rotation of receptor Ig domain 2 (D2) to introduce specific contacts with FGF10. Hence, both D2 and D3 of FGFR2b contribute to the exceptional specificity between FGF10 and FGFR2b. We propose that ligand-induced conformational change in FGFRs may also play an important role in determining specificity for other FGF-FGFR complexes. Binding specificity between FGFs and FGFRs is critical for the proper regulation of FGF signaling. The physiological significance of FGF-FGFR specificity is best demonstrated in Apert syndrome, a severe craniosynostosis syndrome, where point mutations in FGFR2 alter ligand binding affinity and specificity (8-10). Alternative splicing of FGFR mRNA is the main mechanism by which FGFRs with different ligand-binding profiles are generated. In FGFR1 to -3, D3 is encoded by the invariant exon IIIa followed by one of two alternative exons, IIIb (''b'') or IIIc (''c''). This alternative splicing event is regulated in a tissue-specific fashion with b expression restricted to epithelial lineages and c to mesenchymal lineages (11)(12)(13)(14). Most FGFs activate more than one FGFR. The FGF7 subfamily is unique among FGFs because its members (FGF7, FGF10, and FGF22) are expressed exclusively by mesenchyme and interact specifically with the b splice variant of FGFR2 (FGFR2b) resident in overlying epithelium (15-17).FGF7 and FGF10 bind FGFR2b with similar high affinity and compete with each other for this binding (18,19). However, striking phenotypic similarities between the FGF10 and FGFR2b knockout mice have established FGF10 as the predominant ligand for FGFR2b in developmental patterning and organogenesis. Both FGFR2b-null and FGF10-null mice die at birth and show agenesis of the lungs and limbs, whereas FGF7-null mice are viable and have normal lungs and limbs (16,(20)(21)(22).The exceptional specificity between the FGF7 subfamily and FGFR2b, together with the pivotal role of FGF10-FGFR2b signaling during development, makes the FGF10-FGFR2b complex an ideal model system for deciphering the structural determinants of FGF-FGFR binding specificity. In this report, we describe the crystal structure of the FGF10-FGFR2b complex and confirm the structural findings by mutational analysis. FGF10-FGFR2b specificity incorporate...

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Section: Fgf10-induced D2 Rotation Plays An Important Role In Fgf10-fmentioning

confidence: 99%

Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors

Yeh

Igarashi

Eliseenkova

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

170

201

View full text Add to dashboard Cite

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“…Many diseases, including inflammatory bowel disease [8] , are associated with imbalances between Th1 (T helper cell type 1) and Th2 (T helper cell type 2) cytokines. Because these cell subpopulations tend to function antagonistically towards each another, the persistence of disease susceptibility and resistance depends on the profiles of the cytokines that each type secretes.…”

Section: Introductionmentioning

confidence: 99%

Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation

Grémy¹,

Benderitter²,

Linard³

2008

WJG

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“…fats and vitamins) (MacDonald et al, 1999;Cliffe et al, 2005). Enteropathy can stem from inappropriate immune responses to food antigens and components of the symbiotic intestinal bacterial flora, through components of the host's response to infection, as well as from the direct activities of the infectious organisms, via damage to the mucosa by released toxins or feeding activities (Castro, 1990;Behnke, 1991;Cooper et al, 1992;Garside et al, 2000;MacDonald et al, 2000;Graham et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The effect of the hookworm Ancylostoma ceylanicum on the mucosal architecture of the small intestine in hamsters

Alkazmi

Dehlawi

Behnke³

2006

J. Helminthol.

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Hookworms are known to cause marked changes to the intestinal mucosa, especially in relation to erosion of the villi. However, since the development of enteropathy has not been examined thoroughly through quantitative experiments on infected animals, the results of experiments conducted in hamsters infected with Ancylostoma ceylanicum are reported. Changes to intestinal architecture were first apparent between 12 and 14 days after infection, and then increased in intensity for 3-4 weeks, persisting for as long as worms were present (. 63 days). Following infection, the height of villi declined from a mean of 1002 mm in naïve controls to less than 200 mm and as low as 18 mm in one case. The depth of the crypts of Lieberkuhn increased from a baseline value of 166 mm in naïve controls to in excess of 600 mm within 6 weeks of infection. Mitotic figures had a baseline value of 5.5 per villus-crypt unit, and this rose to in excess of 25 in some experiments. Changes were dependent on the intensity of the parasite burden on day 20, but by 30 days after infection changes in all three values were maximal and density-dependent relationships were no longer clearly apparent. Villus height and crypt depth returned to near normal values within a week of the removal of worms, although group means for both remained different from naïve controls for at least 3 weeks after treatment. Cellular division, as reflected in numbers of mitotic figures, stayed elevated for over 5 weeks after removal of worms. The results suggest that enteropathy in hookworm infections stems from a combination of intestinal immune responses and from the grazing activities of the adult worms on the mucosal surface, but is not sufficient per se for expulsion of this parasite.

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Recent Developments in the Immunology of Inflammatory Bowel Disease

Cited by 183 publications

References 49 publications

Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors

Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors

Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation

The effect of the hookworm Ancylostoma ceylanicum on the mucosal architecture of the small intestine in hamsters

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