Search

Background & Aims: Recent studies have suggested that the enteric nervous system can modulate gut immunity. Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) of the CD39 family regulate purinergic signaling by sequential phosphohydrolysis of extracellular ATP, a pro-inflammatory signaling molecule. Herein, we test the hypothesis that E-NTPDases modulate neuro-immune crosstalk in gut inflammation. Methods: We determined expression patterns of NTPDase-2 and NTPDase-3 in murine and human colon. Experimental colitis was induced by dextran sodium sulfate (DSS) in mice deficient in NTPDase-2 or NTPDase-3. We compared plasma ADPase activity from Crohn’s patients to healthy controls, and correlated levels of ADPase activity with Crohn’s disease activity. Results: NTPDase-2 and 3 were mainly expressed in cells of the enteric nervous system in both murine and human colon. When compared to wild type, DSS-induced colitis was exacerbated in NTPDase-2 null mice, as measured by both clinical disease activity and histology, while NTPDase-3 null mice merely developed more severe anemia. Colonic macrophages isolated from NTPDase-2 null mice displayed a more pro-inflammatory phenotype compared to wild type. Crohn’s patients had decreased plasma ADPase activity when compared to healthy controls. The enzyme activity sensitive to an inhibitor against NTPDase-2 and NTPDase-3 showed the most striking difference and was inversely correlated with Crohn’s disease activity. Conclusions: NTPDase-2 and 3 are ecto-enzymes expressed in the enteric nervous system in both murine and human colon, and are protective against gut inflammation in experimental colitis and exhibit alterations in human Crohn’s disease. These observations suggest that purinergic signaling modulated by non-CD39 NTPDases governs neuro-immune interactions that are relevant in Crohn’s disease.

Background & Aims: Recent studies have suggested that the enteric nervous system can modulate gut immunity. Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) of the CD39 family regulate purinergic signaling by sequential phosphohydrolysis of extracellular ATP, a pro-inflammatory signaling molecule. Herein, we test the hypothesis that E-NTPDases modulate neuro-immune crosstalk in gut inflammation. Methods: We determined expression patterns of NTPDase-2 and NTPDase-3 in murine and human colon. Experimental colitis was induced by dextran sodium sulfate (DSS) in mice deficient in NTPDase-2 or NTPDase-3. We compared plasma ADPase activity from Crohn’s patients to healthy controls, and correlated levels of ADPase activity with Crohn’s disease activity. Results: NTPDase-2 and 3 were mainly expressed in cells of the enteric nervous system in both murine and human colon. When compared to wild type, DSS-induced colitis was exacerbated in NTPDase-2 null mice, as measured by both clinical disease activity and histology, while NTPDase-3 null mice merely developed more severe anemia. Colonic macrophages isolated from NTPDase-2 null mice displayed a more pro-inflammatory phenotype compared to wild type. Crohn’s patients had decreased plasma ADPase activity when compared to healthy controls. The enzyme activity sensitive to an inhibitor against NTPDase-2 and NTPDase-3 showed the most striking difference and was inversely correlated with Crohn’s disease activity. Conclusions: NTPDase-2 and 3 are ecto-enzymes expressed in the enteric nervous system in both murine and human colon, and are protective against gut inflammation in experimental colitis and exhibit alterations in human Crohn’s disease. These observations suggest that purinergic signaling modulated by non-CD39 NTPDases governs neuro-immune interactions that are relevant in Crohn’s disease.

Item does not contain fulltext, Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

Item does not contain fulltext, Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

Item does not contain fulltext, Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

The final, definitive version of this article has been published in the Journal, LUPUS, 16/10, 2007, © SAGE Publications Ltd, 2007 by SAGE Publications Ltd at the LUPUS page: http://lup.sagepub.com/ on SAGE Journals Online: http://online.sagepub.com

The original publication is available at www.springerlink.com.

The original publication is available at www.springerlink.com.