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  • Jefferson Adams
    Jefferson Adams

    IL-15 Triggered Pathway in Intraepithelial Lymphocytes Emerges as New Factor in Type II Refractory Celiac Disease and Enteropathy-associated T Cell Lymphoma

    Celiac.com 05/19/2010 - Enteropathy-associated T cell lymphoma is a serious complication of celiac disease, and a major cause of mortality in untreated celiac disease.

    One possible trigger for Enteropathy-associated T cell lymphoma development is chronic exposure of intraepithelial lymphocytes (IELs) to strong anti-apoptotic signals, that is, signals that interfere in the normal mortality of the IEL cells. These signals are triggered by IL-15, a cytokine that is over-expressed in the enterocytes of people with celiac disease.

    However, researchers have not yet fully mapped the signaling pathway by which IL-15 transmits these anti-apoptotic signals. Researchers consider type II refractory celiac disease (RCDII) to be a middle step between celiac disease and enteropathy-associated T cell lymphoma.

    Eliminating abnormal IELs at the RCDII stage would likely block EATL development. So far, though, scientists have not found successful immunosuppressive and/or chemotherapeutic approaches able to accomplish this, and RCDII outcomes remain very poor.

    A team of researchers recently set out to map the IL-15–driven survival pathway in human IELs, and to determine whether IL-15 triggered pathway in human intraepithelial lymphocytes represents a possible new target in type II refractory celiac disease and enteropathy-associated T cell lymphoma.

    The research team was made up of Georgia Malamut, Raja El Machhour, Nicolas Montcuquet, Séverine Martin-Lannerée, Isabelle Dusanter-Fourt, Virginie Verkarre, Jean-Jacques Mention, Gabriel Rahmi, Hiroshi Kiyono, Eric A. Butz, Nicole Brousse, Christophe Cellier, Nadine Cerf-Bensussan, and Bertrand Meresse.

    The are variously affiliated with INSERM U989, the Université Paris Descartes, Faculté de Médecine René Descartes, the Department of Gastroenterology, AP-HP, Hôpital Européen Georges Pompidou, the Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), INSERM U1016, the Department of Pathology, AP-HP, of the Hôpital Necker-Enfants Malades in Paris, with the Division of Mucosal Immunology, Department of Microbiology and Immunology at the Institute of Medical Science at the University of Tokyo in Japan, and the Inflammation Department of AMGEN Inc., in Seattle, Washington, USA.

    Their current findings reveal that the survival signals IL-15 directs to freshly isolated human IELs, and to human IEL cell lines derived from celiac disease patients with type II refractory celiac disease, depend on anti-apoptotic factors Bcl-2 and/or Bcl-xL.

    The signals require IL-15Rβ, Jak3, and STAT5 for proper function, but functioned independently of PI3K, ERK, and STAT3. In support of these findings, the team recorded elevated levels of Bcl-xL, phospho-Jak3, and phospho-STAT5 in IELs from patients with active celiac disease and RCDII.

    Moreover, by incubating patient duodenal biopsies with a fully humanized human IL-15–specific Ab, the team effectively blocked Jak3 and STAT5 phosphorylation.

    Also, treatment with IL-15–specific Ab caused IEL cell mortality, and wiped out the massive IEL build-up in mice over-expressing human IL-15 in their gut epithelium.

    The study marks the first successful mapping of the IL-15–driven survival pathway in human IELs, and demonstrates that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.

    These findings will likely help to pave the way for the development of successful immunosuppressive and/or chemotherapeutic treatments that destroy abnormal IELs at the RCDII stage and help to block EATL development, improving outcomes for RCDII patients.

    Source:

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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, science, and advanced research, and scientific methods. He previously served as Health News Examiner for Examiner.com, and devised health and medical content for Sharecare.com. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.

  • Related Articles

    Jefferson Adams
    Celiac.com 08/17/2008 - One of the important ways doctors distinguish between the two types of refractory celiac disease is by looking at differences in intra-epithelial T lymphocytes (IELs) in intestinal biopsies. People with refractory celiac disease who show normal IELs are said to have refractory celiac disease I, while those with abnormal IELs are said to have refractory celiac disease II.
    A team of doctors based in the Netherlands recently set out to assess the effectiveness of computed tomography (CT) in diagnosing refractory celiac disease, and enteropathy-associated T-cell lymphoma (EATL). EATL is a generally rare, but particularly aggressive form of bowel cancer that is the leading cause of death in adults with celiac disease.
    The study team was made up of doctors Maarten Mallant, Muhammed Hadithi, Abdul-Baqi Al-Toma, Matthijs Kater, Maarten Jacobs, Radu Manoliu, Chris Mulder, and Jan Hein van Waesberghe.
    The team looked at 46 patients with clinically proven celiac disease, refractory celiac disease I, refractory celiac disease II, or EATL including 18 males and twenty-eight females. The first group contained 14 patients with uncomplicated celiac disease and 10 with type I refractory celiac disease. The second group contained 15 patients with type II refractory celiac disease and 7 patients with EATL. 5 patients from group II showed lymphandenopathy, compared to none in the first group. 20 patients from group I showed a higher number of small mesenteric vessels compared to just 11 from group II.
    This is significant because increased numbers of small mesenteric vessels are associated with an absence of refractory celiac disease II and EATL, while reduced numbers of small mesenteric vessels are associated with a higher rate of refractory celiac disease II and EATL.
    The team evaluated the two groups within eleven categories: abnormal intestinal fold patterns; bowel wall thickness, excess fluid; intestinal insussuction; ascites; lymphadenopathy; increases in lymph node numbers; mesenteric vascular changes; and spleen size. One other area the doctors found important was in differences in the average thickness of the bowel wall. Group I showed thinner bowel walls compared to group II. In group I, average bowel thickness ranged from 4mm to 11mm, with an average thickness of 7.0mm. In group II, average bowel thickness ranged from 5mm to 15mm, with an average thickness of 10.0mm. So, group II showed about 30% thicker bowel walls than group I.
    The doctors’ conclusions reaffirmed the need for a biopsy before confirming a diagnosis of celiac disease. Regarding the use of CT, the team found CT unnecessary for cases of uncomplicated celiac disease, but found CT very useful in cases of complicated and pre-cancerous celiac disease.
    The study team also found that pattern reversal and/or loss of jejunal folds is specific to celiac disease, though they had an admittedly small sample of just 24 of their 46 patients, so their measures are far from definitive.
    All of this drives home the importance of encouraging early and accurate screening for celiac disease. Ideally, we will get to the point where, like many European countries, we will begin to catch celiac disease before it ever becomes refractory, and before it ever develops into EATL.
    Until then, stay informed and take an active role in maintaining your own health.
    World J Gastroenterol 2007; 13(11): 1696-1700


    Jefferson Adams
    Celiac.com 01/20/2009 - Refractory celiac disease is a serious condition that occurs when celiac symptoms and intestinal damage continue even when the patient consumes a gluten-free diet.
    There are two types of refractory celiac disease (RCD). In RCD type I,  immuno-phenotype of intraepithelial lymphocytes (IELs) are normal and polyclonal, while RCD) type II, is noted for the presence of an abnormal intraepithelial lymphocyte (IEL) population (CD7+ CD3− CD4/8-cytoplasmic CD3+). More than half of people with this condition develop enteropathy-associated T-cell lymphoma (EATL), a rare but virulent form of cancer with high mortality rates.
    A team of doctors recently set out to examine the relationship between lymphoma development and intraepithelial gamma/delta T-lymphocytes in the small intestine of patients with all types of celiac disease, as compared to the general population.
    The team was made up of Wieke H.M. Verbeek, M.D., B. Mary E. von Blomberg, Ph.D., Petra E.T. Scholten, B.Sc., D. Joop Kuik, M.Sc., Chris J.J. Mulder, M.D. Ph.D., and Marco W.J. Schreurs, Ph.D., all from Amsterdam’s VU University Medical Center.
    A certain type of IELs called TCRγ/δ+ IELs may play an important role in repairing mucosa, maintaining homeostasis, and guarding against tumor development. TCRγ/δ+ IELs in the human intestine have recently shown promise in the regulation of uncomplicated celiac disease.
    In the study, the research team wanted to see if patients with RCD II had fewer TCRγ/δ+ IELs than either RDC I, or celiac disease, an thus provide a possible explanation for ongoing mucosal damage and inflammation, and the development of abnormal T cells that tend to morph into EATL.
    The team used a method called multi-parameter flow cytometric immuno-phenotyping on IELs obtained from recent small bowel biopsy specimens from a fairly large, distinct celiac disease and control groups (N = 87).
    Patients with RCD II showed a much lower ratio of TCRγ δ+ IELs compared to either RCD I or celiac disease patients. Whereas, patients with uncomplicated celiac disease showed significantly higher numbers of TCRγ δ+ IELs than were found in the control group. The results showed the relationship between TCRγ δ+ IELs and aberrant IELs to be negative. It is interesting to note that TCRγ δ+ IELs numbers do rise in RCD II patients after effective treatment.
    The negative relationship between TCRγ δ+ and abnormal IELs, together with their known role in regulating uncomplicated celiac disease, suggests that TCRγ δ+ IELs may play a crucial role in helping the body to repair mucosa, maintain homeostasis and possibly even guard against tumor development.
    These cells may serve as important markers, along with the abnormal T cells, to help distinguish between types of celiac disease, and to gage the effectiveness of treatment efforts.
    Am J Gastroenterol 2008;103:3152–3158


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