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    TCRβ Clonality Improves Diagnostic Yield of TCRγ Clonality in Refractory Celiac Disease


    Jefferson Adams

    Celiac.com 04/02/2012 - A team of researchers recently set out to assess diagnostic yield of Vβ and Vγ clonality in refractory celiac disease (RCD). The team set out to verify whether analyzing both TCRβ and TCRγ clonality in duodenal biopsies from RCD patients improves diagnostic accuracy.


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    Photo: CC--kinshuksunilThe research team included Vittorio Perfetti, Laura Brunetti, Federico Biagi, Rachele Ciccocioppo, Paola I. Bianchi, and Gino R. Corazza. They are affiliated with the Coeliac Centre/First Department of Internal Medicine, and the Department of Medical Oncology at the Fondazione IRCCS Policlinico San Matteo of the University of Pavia in Italy.

    Refractory celiac disease is what is known as a pre-neoplastic condition, because many patients develop a kind of cancer called enteropathy-type T-cell lymphoma, which is a mature T-cell receptor α-β lymphoma that forms in the gut, and is often fatal.

    Recent research has been directed at a variety of intraepithelial intestinal lymphocytes. Polymerase chain reaction (PCR) analysis and sequencing shows that these lymphocytes both express the same lymphoma T-cell receptor variable region (V)γ.

    Also, the Biomedicine and Health-2 Concerted Action has created standardized, highly specific, and sensitive PCR assays for both Vγ and Vβ.

    The team set out to verify whether analyzing both rearrangements in duodenal biopsies from RCD patients increases the diagnostic accuracy of this method.

    For the study, the team analyzed duodenal biopsies from 15 RCD patients, 21 negative controls, and 2 positive controls with enteropathy-type T-cell lymphoma complicating celiac disease.

    The them conducted multiplex clonality analyses using Biomedicine and Health-2 protocols. They cloned and sequenced PCR products.

    They found monoclonal rearrangements in 5/15 samples from patients with RCD, two of which showed both rearrangements, two which showed Vβ, and just one Vγ clonality.

    Monoclonality was found in 4/8 of the RCD patients who subsequently died, whereas only 1/7 of the patients still alive presented a monoclonal rearrangement. Positive controls revealed both monoclonal rearrangements; rearrangements were not detected in 20 of 21 negative controls. Sequencing of the amplified fragments confirmed the results.

    Results showed that the combined analysis of both TCRβ and TCRγ rearrangements allowed recognition of monoclonal populations in patients who otherwise tested negative. Overall detection rates increased from 20%(Vγ only) to 33%(Vγ and Vβ),

    Increasing detection in patients who would otherwise test negative increases chances of early identification of RCD patients at high risk of death.

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    Guest Helen Rank

    Posted

    Very informative. This will give me some questions to ask the alergist. His celiac test came back negative. He has been on a gluten and milk free diet now for about 2 1/2 to three years. He still has problems with corn and pinto beans. I will not change his diet until we know what is going on with him. He is only 5 years old. When he was an little baby he couldn't keep his formula down. He was finally put on fresh goat's milk. That helped a little bit. But then he started to throw it up also. I hope that we can find what is making his so sick. I think the next Dr. is going to be an G.I. specialist's.

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  • Related Articles

    Michelle Melin-Rogovin
    This article originally appeared in the Spring 2003 edition of Celiac.com's Scott-Free Newsletter.
    Refractory sprue. The specter of this condition is enough to cause fear in the hearts of many people living with celiac disease, yet this fear is based more on myth and misunderstanding than on medical science. For those who are concerned about their risk for developing refractory sprue, there is much that can be done. For those who have developed the condition, there are treatment options and new hope on the horizon. To begin, however, we must substitute fear with knowledge.
    What is refractory sprue?
    This question has been the subject of great scientific inquiry, and there are differing opinions on the relationship between celiac disease and refractory sprue. However, there are several general characteristics of refractory sprue that researchers seem to agree on:
    Presence of persistently damaged villi in the small intestine that are not repaired after the gluten free diet has been successfully initiated and/or maintained An increased presence of intraepithelial lymphocytes (IEL) in the small bowel Severe malabsorption Researchers think of celiac disease as the beginning of a spectrum of conditions that could, for a small percentage of patients, end up at the other end to be enteropathy associated T-Cell Lymphoma. Most people with celiac disease will respond to the gluten free diet and never move to the next stage in this spectrum. But for those that do, they will experience changes in their immune system and in the cells lining their intestine that could lead to cancer.
    The spectrum would start with celiac disease, and the next step would be the non-responsiveness of the immune system to the gluten-free diet, in other words, refractory sprue. Then in some cases, a condition called ulcerative jejunitis develops, and finally, the damaged lining of the intestine produces cancer cells that mimic the mutations of the abnormal immune system cells.
    How many people with celiac disease are affected by refractory sprue?
    First, there are no reported cases in the medical literature of celiac sprue in people under 20 years of age. Second, the number of celiacs affected by refractory sprue, while not known, appears to be very small. We know this because the current estimates for small bowel cancers in people affected by celiac disease, as reported at the 10th International Conference on Celiac Disease is less than 2.5%. Refractory sprue can result in small bowel cancers, but not in all cases.
    It is interesting to note that in a recent study of patients with "unresponsive" celiac disease, Dr. Joseph Murray and his colleagues found that of 49 patients evaluated, only nine actually had refractory sprue—25 were found to have gluten contamination in their diets. The most common symptoms presented by the patients who truly had refractory sprue were weight loss, steatorrhea and diarrhea, in that order.

    What makes refractory sprue different than celiac sprue?
    Again, there are several medical points of view on this, but all researchers would agree that one marker indicates the presence of refractory sprue, and it is not found in celiac disease.
    Abnormal Intraepithelial Lymphocytes (Immune Cells)
    The intraepithelial lymphocytes found in celiac disease have a normal-looking appearance under the microscope and they behave like normal celiac immune cells (they respond to gluten when they shouldnt). These lymphocytes have the ability to communicate with other cells using different types of messages on their cell surfaces. When diagnosing celiac disease, pathologists look for an increased number of IELs as an indication of celiac disease.
    In refractory sprue, however, there is a different kind of IEL that is found in great numbers. This immune cell does not look normal, and it ignores the presence or absence of gluten. This type of cell does not have the ability to communicate normally with other cells as it would be expected to do. However, it does have the ability to communicate with cancer cells, contributing to their development. It is not clear what causes this type of IEL to develop or mutate, contributing to refractory sprue.
    It is possible to have refractory sprue without having these abnormal lymphocytes; in this case, treatment with steroids often results in response to the gluten free diet and a reversal of the condition.
    French researchers have developed a test to determine whether a biopsy specimen reflects a normal course of celiac disease with a slow response to the diet, or the need for further testing because refractory sprue may be present. In paraffin wax, a specimen can be stained to determine whether or not the immune cells express CD8, a protein often found on intraepithelial lymphocytes in celiac disease. If CD8 is positive, the individual has celiac and is responding very slowly to the diet. If the sample is CD8 negative, refractory sprue could be the reason.
    How is refractory sprue diagnosed and treated?
    It must be established through a thorough diet history and antibody testing that the individual is adhering to a strict gluten-free diet. Then, all other gastrointestinal diseases have to be ruled out before a diagnosis of refractory sprue is made. Conditions to be ruled out include pancreatic insufficiency, lactose malabsorption, parasite infestation, intolerance to other food proteins, coexisting inflammatory bowel disease, and autoimmune enteropathy, among others.
    Diagnosis should include a test called an enteroscopy, which is a procedure that explores more of the small intestine, and often finds ulcerative jejunitis, a marker of damage in refractory sprue. In addition, because the abnormal IELs can proliferate throughout the gut, a colonoscopy is recommended to determine if lymphocytic colitis is present.
    Treatment options include the elemental diet (also used in Crohns Disease), total parenteral nutrition (tube feedings), steroids, immunosuppressive therapies such as Cyclosporine, Infliximab, and in some cases, chemotherapy. Treatment options depend on the extent of refractory sprue found on biopsy and the nature of the clinical symptoms involved.
    How can I reduce the chances of developing refractory sprue?
    Researchers agree that most cases of refractory sprue develop in people who were diagnosed very late in life or who didnt follow the diet completely. Note that it doesn't matter how much gluten was consumed in these patients, they still developed refractory sprue. So the best protection against developing refractory sprue is to follow the diet. Be honest with yourself, especially if you cheat a little. What are you eating? Are you sure there isnt a great gluten-free alternative out there? Hey, there's even beer nowadays, so don't dismiss the suggestion of great gluten-free brownies, cakes, pies, pasta, crackers, cookies, or whatever else you are craving.
    Deal with your feelings too. Its easy to get angry about how life is much harder for people with celiac disease—how everything related to food requires too much planning, preparation, and explanation. These feelings are perfectly justified, but they do not justify cheating on your diet. There are great "quick fix" cookbooks out there, even convenience meals that are gluten free. Do whatever it takes to stay healthy, and gluten-free for life.
    Don't forget regular visits to your gastroenterologist or internist. Follow-up care for people with celiac disease is incredibly important, even if the medical community hasn't recognized it yet. Regular antibody testing to monitor compliance with the diet is an extra level of protection that every celiac needs. A simple anti-gliadin antibody test (IGG and IGA), six months post diagnosis, a year post-diagnosis and then every year after that for the first three years is key. In fact, the most serious celiac disease complications tend to occur in the first three years after diagnosis. Veteran celiacs should have their antibody levels checked every couple of years.
    While refractory sprue remains a potential complication for any adult with celiac disease, a majority of adult celiacs in this country will not have to face this difficult condition. For those diagnosed, treatment options continue to improve and the disease is becoming easier to manage. Researchers continue to study refractory sprue in order to better understand how the condition behaves and to develop new treatments. For now, the best defense against refractory sprue is a good offense—living a completely gluten-free life.

    Jefferson Adams
    Celiac.com 12/28/2009 - A team of researchers recently set out to compare continual monitoring of intraepithelial lymphocyte immunophenotype and clonality against snapshot analysis in the surveillance of refractory celiac disease. The research team was made up of H. Liu, R. Brais, A. Lavergne-Slove, Q. Jeng, K. Payne K, H. Ye, Z. Liu, J. Carreras, Y. Huang, C. M. Bacon, R. Hamoudi, V. Save, L. Venkatraman, P. G. Isaacson, J. Woodward, and M. Q. Du of Addenbrooke's Hospital, Cambridge, UK.
    Often, people with refractory celiac disease suffer from abnormal immunophenotype and monoclonality of intraepithelial lymphocytes (IELs). No good studies have been done to compare the utility of continual monitoring of IEL immunophenotype and clonality in monitoring refractory celiac disease (RCD).
    To address this deficiency, and to gather some data for comparison, the team used CD3e/CD8 double immunohistochemistry and PCR-based clonality analysis of the rearranged TCR genes to evaluate diagnostic and follow-up biopsies from 33 people with proven celiac disease, 7 with suspected refractory celiac disease, 41 with proven refractory celiac disease, and 20 with enteropathy associated T-cell lymphoma (including 11 evolved from RCD).
    The team found aberrant immunophenotype (CD3epsilon(+)CD8(-) IEL >/=40%) and monoclonality in occasional celiac disease biopsies, either transiently in celiac patients not following a gluten free diet, or in those who later developed refractory celiac disease, suspected RCD, or enteropathy associated T-cell lymphoma (EATL). By comparison, they found aberrant immunophenotype and monoclonality respectively in 30 of 41 (73%) and 24 of 37 (65%) biopsies at the time of diagnosis for refractory celiac disease.
    Among the patients with refractory celiac disease showed no such abnormalities in their diagnostic biopsies, 8 of 10 (80%) and 5 of 11 (45%) cases showed aberrant immunophenotype and monoclonality respectively upon follow-up. Whether found in initial or follow-up biopsies, the ongoing development of both aberrant immunophenotype and monoclonality is a common facet of refractory celiac disease.
    One key point was that the presence of both persistent monoclonality and aberrant immunophenotype, especially <>/=>80% CD3epsilon(+)CD8(-) IEL, was a strong predictor of enteropathy associated T-cell lymphoma development in patients with RCD (P=0.001).
    From these findings, the team found concludes that the continual monitoring of both immunophenotype and clonality of IEL is superior to snapshot analysis for diagnosis and follow-up of refractory celiac disease, and could provide a useful tool for surveillance of patients at risk of developing EATL.
    Source:
    Gut. 2009 Dec 8.

    Jefferson Adams
    Celiac.com 05/04/2010 - A team of clinicians recently set out to assess the effectiveness of treating collagenous sprue with a combination of gluten-free diet and steroids.
    The team was made up of Alberto Rubio-Tapia, Nicholas J. Talley, Suryakanth R. Gurudu, Tsung-Teh Wu, and Joseph A. Murray. They are affiliated variously with the Division of Gastroenterology and Hepatology of the Mayo Clinics in Scottsdale, Arizona, Jacksonville, Florida, and Rochester, Minnesota, and the Division of Anatomic Pathology in Rochester Mayo Clinic.
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    24 patients (80%) showed a positive clinical response to treatment with a combination of a gluten-free diet and immunosuppressive drugs. Nine patients showed confirmed histologic improvement, while five patients experienced complete remission. Of two patients who died, one succumbed to complications from collagenous sprue, while one died of another illness.
    Most patients with collagenous sprue show a positive clinical response to a combination of gluten-free diet and steroids.
    Source:

     Clinical Gastroenterology and Hepatology 2010;8:344–349. doi:10.1016/j.cgh.2009.12.023

    Jefferson Adams
    Celiac.com 03/12/2014 - Researchers and clinicians consider refractory celiac disease (RCD) to be rare, but they don't actually have solid, reliable information about how common the condition actually is.
    A team of researches recently set out to establish rates of refractory celiac disease, and to identify corresponding risk factors in a Finnish population with high rates of clinically diagnosed celiac disease.
    The research team included T. Ilus, K. Kaukinen, L. J. Virta, H. Huhtala, M. Mäki, K. Kurppa, M. Heikkinen, M. Heikura, E. Hirsi, K. Jantunen, V. Moilanen, C. Nielsen, M. Puhto, H. Pölkki, I. Vihriälä, and P. Collin.
    For their study, the team looked at data on 44 treated RCD patients, 12,243 clinically diagnosed celiac disease patients, and a compared results against a control group of 1.7 million adult inhabitants.
    Specifically, the team compared clinical characteristics upon celiac disease diagnosis between the RCD patients and patients with uncomplicated disease.
    RCD affected 0.31% of diagnosed celiac disease patients, but just 0.002% in the general population.
    Of the enrolled 44 RCD patients, 68% showed type I RCD, 23% type II RCD, and 9% remained undetermined.
    Compared with the 886 patients with uncomplicated celiac disease, the 44 patients who developed RCD later in life were, when first diagnosed for celiac disease, significantly older (median 56 vs 44 years, P < 0.001), more likely to be male (41% vs. 24%, P = 0.012) and largely seronegative (30% vs. 5%, P < 0.001).
    More patients with evolving RCD showed severe symptoms upon celiac disease diagnosis, including weight loss in 36% (vs. 16%, P = 0.001) and diarrhea in 54% (vs. 38%, P = 0.050).
    These results show that refractory celiac disease is very rare in the general population.
    However, patients who are male, older, who experience severe symptoms or seronegativity when first diagnosed with celiac disease have a higher risk of developing refractory celiac disease. These patients should be closely monitored over time..
    Source:
    Alimentary Pharmacology & Therapeutics Volume 39, Issue 4, pages 418–425, February 2014. DOI: 10.1111/apt.12606

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    Jefferson Adams
    Celiac.com 06/19/2018 - Could baking soda help reduce the inflammation and damage caused by autoimmune diseases like rheumatoid arthritis, and celiac disease? Scientists at the Medical College of Georgia at Augusta University say that a daily dose of baking soda may in fact help reduce inflammation and damage caused by autoimmune diseases like rheumatoid arthritis, and celiac disease.
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    Rates of celiac disease were 0.4% in South America, 0.5% in Africa and North America, 0.6% in Asia, and 0.8% in Europe and Oceania; the prevalence was 0.6% in female vs 0.4% males. Celiac disease was significantly more common in children than adults.
    This systematic review and meta-analysis showed celiac disease to be reported worldwide. Blood test data shows celiac disease rate of 1.4%, while biopsy data shows 0.7%. The prevalence of celiac disease varies with sex, age, and location. 
    This review demonstrates a need for more comprehensive population-based studies of celiac disease in numerous countries.  The 1.4% rate indicates that there are 91.2 million people worldwide with celiac disease, and 3.9 million are in the U.S.A.
    Source:
    Clin Gastroenterol Hepatol. 2018 Jun;16(6):823-836.e2. doi: 10.1016/j.cgh.2017.06.037.

    Jefferson Adams
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    Dr. Ron Hoggan, Ed.D.
    Celiac.com 06/15/2018 - There seems to be widespread agreement in the published medical research reports that stuttering is driven by abnormalities in the brain. Sometimes these are the result of brain injuries resulting from a stroke. Other types of brain injuries can also result in stuttering. Patients with Parkinson’s disease who were treated with stimulation of the subthalamic nucleus, an area of the brain that regulates some motor functions, experienced a return or worsening of stuttering that improved when the stimulation was turned off (1). Similarly, stroke has also been reported in association with acquired stuttering (2). While there are some reports of psychological mechanisms underlying stuttering, a majority of reports seem to favor altered brain morphology and/or function as the root of stuttering (3). Reports of structural differences between the brain hemispheres that are absent in those who do not stutter are also common (4). About 5% of children stutter, beginning sometime around age 3, during the phase of speech acquisition. However, about 75% of these cases resolve without intervention, before reaching their teens (5). Some cases of aphasia, a loss of speech production or understanding, have been reported in association with damage or changes to one or more of the language centers of the brain (6). Stuttering may sometimes arise from changes or damage to these same language centers (7). Thus, many stutterers have abnormalities in the same regions of the brain similar to those seen in aphasia.
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    Whatever the reason that stuttering has not been reported in the medical literature in association with gluten ingestion, a number of personal disclosures and comments suggesting a connection between gluten and stuttering can be found on the Internet. Abid Hussain, in an article about food allergy and stuttering said: “The most common food allergy prevalent in stutterers is that of gluten which has been found to aggravate the stutter” (10). Similarly, Craig Forsythe posted an article that includes five cases of self-reporting individuals who believe that their stuttering is or was connected to gluten, one of whom also experiences stuttering from foods containing yeast (11). The same site contains one report of a stutterer who has had no relief despite following a gluten free diet for 20 years (11). Another stutterer, Jay88, reports the complete disappearance of her/his stammer on a gluten free diet (12). Doubtless there are many more such anecdotes to be found on the Internet* but we have to question them, exercising more skepticism than we might when reading similar claims in a peer reviewed scientific or medical journal.
    There are many reports in such journals connecting brain and neurological ailments with gluten, so it is not much of a stretch, on that basis alone, to suspect that stuttering may be a symptom of the gluten syndrome. Rodney Ford has even characterized celiac disease as an ailment that may begin through gluten-induced neurological damage (13) and Marios Hadjivassiliou and his group of neurologists and neurological investigators have devoted considerable time and effort to research that reveals gluten as an important factor in a majority of neurological diseases of unknown origin (14) which, as I have pointed out previously, includes most neurological ailments.
    My own experience with stuttering is limited. I stuttered as a child when I became nervous, upset, or self-conscious. Although I have been gluten free for many years, I haven’t noticed any impact on my inclination to stutter when upset. I don’t know if they are related, but I have also had challenges with speaking when distressed and I have noticed a substantial improvement in this area since removing gluten from my diet. Nonetheless, I have long wondered if there is a connection between gluten consumption and stuttering. Having done the research for this article, I would now encourage stutterers to try a gluten free diet for six months to see if it will reduce or eliminate their stutter. Meanwhile, I hope that some investigator out there will research this matter, publish her findings, and start the ball rolling toward getting some definitive answers to this question.
    Sources:
    1. Toft M, Dietrichs E. Aggravated stuttering following subthalamic deep brain stimulation in Parkinson’s disease--two cases. BMC Neurol. 2011 Apr 8;11:44.
    2. Tani T, Sakai Y. Stuttering after right cerebellar infarction: a case study. J Fluency Disord. 2010 Jun;35(2):141-5. Epub 2010 Mar 15.
    3. Lundgren K, Helm-Estabrooks N, Klein R. Stuttering Following Acquired Brain Damage: A Review of the Literature. J Neurolinguistics. 2010 Sep 1;23(5):447-454.
    4. Jäncke L, Hänggi J, Steinmetz H. Morphological brain differences between adult stutterers and non-stutterers. BMC Neurol. 2004 Dec 10;4(1):23.
    5. Kell CA, Neumann K, von Kriegstein K, Posenenske C, von Gudenberg AW, Euler H, Giraud AL. How the brain repairs stuttering. Brain. 2009 Oct;132(Pt 10):2747-60. Epub 2009 Aug 26.
    6. Galantucci S, Tartaglia MC, Wilson SM, Henry ML, Filippi M, Agosta F, Dronkers NF, Henry RG, Ogar JM, Miller BL, Gorno-Tempini ML. White matter damage in primary progressive aphasias: a diffusion tensor tractography study. Brain. 2011 Jun 11.
    7. Lundgren K, Helm-Estabrooks N, Klein R. Stuttering Following Acquired Brain Damage: A Review of the Literature. J Neurolinguistics. 2010 Sep 1;23(5):447-454.
    8. [No authors listed] Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 43-1988. A 52-year-old man with persistent watery diarrhea and aphasia. N Engl J Med. 1988 Oct 27;319(17):1139-48
    9. Molteni N, Bardella MT, Baldassarri AR, Bianchi PA. Celiac disease associated with epilepsy and intracranial calcifications: report of two patients. Am J Gastroenterol. 1988 Sep;83(9):992-4.
    10. http://ezinearticles.com/?Food-Allergy-and-Stuttering-Link&id=1235725 
    11. http://www.craig.copperleife.com/health/stuttering_allergies.htm 
    12. https://www.celiac.com/forums/topic/73362-any-help-is-appreciated/
    13. Ford RP. The gluten syndrome: a neurological disease. Med Hypotheses. 2009 Sep;73(3):438-40. Epub 2009 Apr 29.
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    Jefferson Adams
    Celiac.com 06/14/2018 - Refractory celiac disease type II (RCDII) is a rare complication of celiac disease that has high death rates. To diagnose RCDII, doctors identify a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs). 
    However, researchers really don’t have much data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII. Such data could provide useful comparison information for patients with RCDII, among other things.
    To that end, a research team recently set out to try to get some information about the frequency and importance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII. The research team included Shafinaz Hussein, Tatyana Gindin, Stephen M Lagana, Carolina Arguelles-Grande, Suneeta Krishnareddy, Bachir Alobeid, Suzanne K Lewis, Mahesh M Mansukhani, Peter H R Green, and Govind Bhagat.
    They are variously affiliated with the Department of Pathology and Cell Biology, and the Department of Medicine at the Celiac Disease Center, New York Presbyterian Hospital/Columbia University Medical Center, New York, USA. Their team analyzed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active celiac disease, 172 celiac disease on gluten-free diet, 33 RCDI, and three RCDII patients and 14 patients without celiac disease. 
    Clonal TCR-GRs are not infrequent in cases lacking features of RCDII, while PCPs are frequent in all disease phases. TCR-GR results should be assessed in conjunction with immunophenotypic, histological and clinical findings for appropriate diagnosis and classification of RCD.
    The team divided the TCR-GR patterns into clonal, polyclonal and prominent clonal peaks (PCPs), and correlated these patterns with clinical and pathological features. In all, they detected clonal TCR-GR products in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with gluten-free diet. They found PCPs in all disease phases, but saw no significant difference in the TCR-GR patterns between the non-RCDII disease categories (p=0.39). 
    They also noted a higher frequency of surface CD3(−) IELs in cases with clonal TCR-GR, but the PCP pattern showed no associations with any clinical or pathological feature. 
    Repeat biopsy showed that the clonal or PCP pattern persisted for up to 2 years with no evidence of RCDII. The study indicates that better understanding of clonal T cell receptor gene rearrangements may help researchers improve refractory celiac diagnosis. 
    Source:
    Journal of Clinical Pathologyhttp://dx.doi.org/10.1136/jclinpath-2018-205023