Reduced Paneth cell α-defensins in ileal Crohn's disease

Wehkamp, Jan; Salzman, Nita H.; Porter, Edith; Nuding, Sabine; Weichenthal, Michael; Petras, Robert E.; Shen, Bo; Schaeffeler, Elke; Schwab, Matthias; Linzmeier, Rose; Feathers, Ryan W.; Chu, Hiutung; Lima, Heriberto; Fellermann, Klaus; Ganz, Tomas; Stange, Eduard F.; Bevins, Charles L.

doi:10.1073/pnas.0505256102

Cited by 890 publications

(849 citation statements)

References 46 publications

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“…Paneth cells are the key producers of antimicrobial peptides in the small intestine, such as the α -defensins HD5 and HD6. A study of specimens taken from patients with ileal Crohn ' s disease found that these patients show decreased expression of Paneth cell HD5 and a concomitant reduction in total antimicrobial activity against both E. coli and Staphylococcus aureus ( 33 ). However, a similar decrease in α -defensin production was not seen in patients with Crohn ' s disease of the colon, UC patients, or those with pouchitis.…”

Section: Host Genetic Defects In Containing Commensal Microbiotamentioning

confidence: 89%

Intestinal Microbes in Inflammatory Bowel Diseases

Sartor¹,

Mazmanian²

2012

Am J Gastroenterol Suppl

176

151

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Section: Host Genetic Defects In Containing Commensal Microbiotamentioning

confidence: 89%

Intestinal Microbes in Inflammatory Bowel Diseases

Sartor¹,

Mazmanian²

2012

Am J Gastroenterol Suppl

176

151

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“…The present study suggests that HD5 expression coincides with PC development until a GA of 28 wk; in the period starting from 29 wk of GA, HD5 expression increases more rapidly than the number of PCs. PCs with their defensin expression, such as HD5, play a key role in the intestinal innate immunity and development of diseases (13)(14)(15). PCs with their defensin expression are previously described in the pathophysiology of Crohn's disease (15).…”

Section: Discussionmentioning

confidence: 99%

Paneth cells in the developing gut: when do they arise and when are they immune competent?

et al. 2016

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Background:Little is known about the perinatal development of Paneth cells (PCs) during gestation and the relation with necrotizing enterocolitis (NEC). We aimed to investigate when PCs arise and when they become immune competent during gestation. Methods: We included 57 samples of ileum tissue of fetuses/ infants with a gestional age (GA) between 9 and 40 wk taken as part of a standard autopsy procedure. Hematoxylin-eosin staining and anti-human defensin 5 immunohistochemistry were performed. We performed a semi-quantitative assessment of (immune-competent) PC numbers per 10 crypts per tissue section per GA. results: The number of PCs and the number of immunecompetent PCs increased with increasing GA (Spearman's ρ = 0.41, P = 0.002 and ρ = 0.61, P < 0.001, respectively). Whereas significantly higher PC numbers were observed after 37 wk gestation (median 7, range 0-12) compared to preterm infants (median 0, range 0-15; P = 0.002), we counted higher numbers of immune-competent PCs already in infants with GA above 29 wk (median 6, range 0-18) compared to infants with GA under 29 wk (median 2, range 0-9; P < 0.001). conclusion: The significant increase of immune-competent PCs starting from a GA of 29 wk mimics the rise in incidence of NEC during a similar postmenstrual age in preterm infants.P aneth cells (PCs) are specialized epithelial immune cells located in the base of the crypts of Lieberkühn located in the small intestine (1,2). PCs can be seen in the gut by the first trimester and are thought to mature during gestation (1,2). PCs protect the intestinal stem cells from pathogens by stimulating stem cell differentiation, shaping the intestinal microbiota, and assist in reparation of the gut (2). To this end, they secrete (among other things) human α-defensins (HD5/HD6) (3). These defensins protect the intestinal mucosa against bacterial invasion, and are thought to be associated with initiating and adapting immunity (3). How PCs develop after the first trimester and when PCs become immune competent remains uncertain.PCs are thought to play a role in the development of NEC, a common and devastating disease most commonly observed in preterm infants (4-6). NEC involves the preterm intestine and has a complex pathophysiology in which bacterial invasion and an excessive inflammatory response is an important contributing factor (5,6). Unfortunately, the exact pathophysiology is incompletely understood.It has been hypothesized that maturation of immune-competent PCs is crucial for NEC development (4,(6)(7)(8). In the preterm gut, PCs secrete defensins that might contribute to an excessive inflammatory response as observed in NEC (4). This hypothesis is derived from the observation that extremely-low-birth-weight human infants generally have the longest interval before the onset of NEC-with a peak incidence at the postmenstrual age of 29-33 wk (4,6-8). Despite the possible role for PC-maturation in the pathophysiology of NEC, little is known about PC-maturation and functioning in the immature intestine. Therefore, we ...

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“…Nod2 is highly expressed in Paneth cells of the small intestine [54,55] and Nod2 mutations are associated with ileal location of disease [56] . Studies in humans and mice have shown that normal Nod2 function is required for optimal defensin expression and therefore, impaired defensin expression and regulation may contribute to the increased CD susceptibility observed in Nod2 risk allele carriers [57][58][59] .…”

Section: Nod2 (Card15) Associations To Ileal CDmentioning

confidence: 99%

Inflammatory bowel disease: Genetic and epidemiologic considerations

Cho

2008

WJG

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Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn's disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.

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Reduced Paneth cell α-defensins in ileal Crohn's disease

Cited by 890 publications

References 46 publications

Intestinal Microbes in Inflammatory Bowel Diseases

Intestinal Microbes in Inflammatory Bowel Diseases

Paneth cells in the developing gut: when do they arise and when are they immune competent?

Inflammatory bowel disease: Genetic and epidemiologic considerations

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