New research shows Celiac's T-cells react to only a part of the gliadin structure- just 3 peptides. Perhaps a vaccine is possible?

                         Sci Transl Med 21 July 2010:
Vol. 2, Issue 41, p. 41ra51
DOI: 10.1126/scitranslmed.3001012

Comprehensive, Quantitative Mapping of T Cell Epitopes in Gluten in Celiac Disease

Abstract

Celiac disease is a genetic condition that results in a debilitating immune reaction in the gut to antigens in grain. The antigenic peptides recognized by the T cells that cause this disease are incompletely defined. Our understanding of the epitopes of pathogenic CD4⁺ T cells is based primarily on responses shown by intestinal T-cells in vitro to hydrolysates or polypeptides of gluten, the causative antigen. A protease-resistant 33-amino acid peptide from wheat α-gliadin is the immunodominant antigen, but little is known about the spectrum of T cell epitopes in rye and barley or the hierarchy of immunodominance and consistency of recognition of T-cell epitopes in vivo. We induced polyclonal gluten-specific T cells in the peripheral blood of celiac patients by feeding them cereal and performed a comprehensive, unbiased analysis of responses to all celiac toxic prolamins, a class of plant storage protein. The peptides that stimulated T cells were the same among patients who ate the same cereal, but were different after wheat, barley and rye ingestion. Unexpectedly, a sequence from ω-gliadin (wheat) and C-hordein (barley) but not α-gliadin was immunodominant regardless of the grain consumed. Furthermore, T cells specific for just three peptides accounted for the majority of gluten-specific T cells, and their recognition of gluten peptides was highly redundant. Our findings show that pathogenic T cells in celiac disease show limited diversity, and therefore suggest that peptide-based therapeutics for this disease and potentially other strongly HLA-restricted immune diseases should be possible.

1. Jason A. Tye-Din¹,²,³,*,
2. Jessica A. Stewart¹,*,
3. James A. Dromey¹,*,
4. Tim Beissbarth¹,*†,
5. David A. van Heel⁴,
6. Arthur Tatham⁵,
7. Kate Henderson⁶,
8. Stuart I. Mannering¹,‡,
9. Carmen Gianfrani⁷,
10. Derek P. Jewell⁸,
11. Adrian V. S. Hill⁹,
12. James McCluskey¹⁰,
13. Jamie Rossjohn⁶ and
14. Robert P. Anderson¹,³,§

+ Author Affiliations

1. ¹Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
2. ²Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
3. ³Department of Gastroenterology, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia.
4. ⁴Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
5. ⁵Cardiff School of Health Sciences, University of Wales Institute, Cardiff CF5 2YB, UK.
6. ⁶Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
7. ⁷Institute of Food Science, National Research Council, Via Roma 52, 83100 Avellino, Italy.
8. ⁸Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
9. ⁹Jenner Institute, University of Oxford, Oxford OX3 9DU, UK.
10. ¹⁰Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.

1. §To whom correspondence should be addressed. E-mail: banderson@wehi.edu.au

Footnotes

• ↵* These authors contributed equally to this work.

• ↵† Present address: Department of Medical Statistics, University Medicine Goettingen, 37099 Goettingen, Germany.

• ↵‡ Present address: St. Vincent’s Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.

• Citation: J. A. Tye-Din, J. A. Stewart, J. A. Dromey, T. Beissbarth, D. A. van Heel, A. Tatham, K. Henderson, S. I. Mannering, C. Gianfrani, D. P. Jewell, A. V. S. Hill, J. McCluskey, J. Rossjohn, R. P. Anderson, Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease.Sci. Transl. Med. 2, 41ra51 (2010).

• Copyright © 2010, American Association for the Advancement of Science

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Celiac disease-associated antibodies in patients with psoriasis and (non)correlation with HLA Cw6.

J Clin Lab Anal. 2010 Jul 12;24(4):269-272

Authors: Singh S, Sonkar GK, , Singh S

Etiopathology of psoriasis is not completely understood. Patients with psoriasis show elevated sensitivity to gluten. The aim of this study was to see the expression of celiac disease (CD)-associated antibodies gliadin IgA, gliadin IgG, and tissue transglutaminase IgA, and their correlation with HLA Cw6 in patients with psoriasis. The study comprised 56 patients with psoriasis and 60 healthy controls (HC). The levels of antibodies were detected by using ELISA technique and HLA Cw6 typing was carried out by microcytotoxicity method. HLA Cw6 was significantly expressed in psoriasis cases when compared with HC (P<0.05). CD-associated antibodies gliadin IgA/IgG and tissue transglutaminase IgA were significantly higher in the serum of patient with psoriasis when compared with HC (P<0.05, <0.05, and 0.01, respectively). Serum anti tissue transglutaminase IgA (anti tTG IgA) was significantly higher in females when compared with males and expressed more in elderly patients. There was a significant positive correlation among the antibodies (anti gliadin IgA with anti gliadin IgG: r=0.67, P<0.05; anti gliadin IgA with anti tTG IgA: r=0.45, P<0.05, anti gliadin IgG with anti tTG IgA: r=0.26, P<0.05, respectively), whereas insignificant with HLA Cw6. Our study concludes that latent CD or CD-associated antibodies were present in patients with psoriasis and also concludes that HLA Cw6 has no association with expression of these antibodies in patients with psoriasis. J. Clin. Lab. Anal. 24:269-272, 2010. (c) 2010 Wiley-Liss, Inc.

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Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection.

Finally a study that explains a bit about why the celiac genes developed.   They are helpful against bacterial infections!

 

Am J Hum Genet. 2010 Jun 2;

Authors: Zhernakova A, Elbers CC, Ferwerda B, Romanos J, Trynka G, Dubois PC, de Kovel CG, Franke L, Oosting M, Barisani D, Bardella MT, , Joosten LA, Saavalainen P, van Heel DA, Catassi C, Netea MG, Wijmenga C

Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (F(st)) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504( *)A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.

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[Pleiotropic action of vitamin D3 with particular stress on its role in gastrointestinal diseases in children]

Could Vitamin D3 deficiency be another possible causitive factor for celiac disease?  This study thinks so.

from PubMed: celiac disease by Sledzińska K, Góra-Gebka M, Kamińska B, Liberek A

[Pleiotropic action of vitamin D3 with particular stress on its role in gastrointestinal diseases in children]

Med Wieku Rozwoj. 2010 Jan-Mar;14(1):59-67

Authors: Sledzińska K, Góra-Gebka M, Kamińska B, Liberek A

This review presents aspects of pleiotropic actions of vitamin D3, in particular amongst the development period population. It describes the relationship between vitamin D3andgastrointestinal diseases (inflammatory bowel disease, celiac disease, liver and pancreas pathologies), central nervous system and cardiovascular diseases. Moreover, we underline the role of vitamin D3 in the epidemiology and pathogenesis of malignancies and autoimmune diseases.

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When was celiac disease born?: the Italian case from the archeologic site of Cosa.

Would you believe  the first century AD?

 

J Clin Gastroenterol. 2010 Aug;44(7):502-3

Authors: Gasbarrini G, Miele L, Corazza GR, Gasbarrini A

A case of a young woman died in Italy during the first century AD is presented. She had short height (140 cm), clinical history of anemia, and a decreased bone mass with evidence of osteoporosis and bone fragility. The archeologic artifacts from the tomb and with the quality of burial architecture suggest that the tomb was built for a rich person in an area with extensive culture of wheat. The wellness of the area is supported by the lack of other bodies found with signs of malnutrition. Clinical presentation and the possible continuous exposure to wheat seem to suggest a case of celiac disease. This case could be the first case of this condition since that one described by Areteus of Cappadocia in 250 BC and could be helpful to clarify the phylogenetic tree of celiac disease.

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Lignans and Breast Cancer Survival

Dietary lignans improve breast cancer survival
Jacob Schor, ND, FABNO
July 20, 2010

Even a slight increase in dietary lignan may change survival statistics dramatically.

A paper published this month may change the way we think about diet and breast cancer for years to come.  Susan McCann from Roswell Research Center near Buffalo, New York teamed up with Lillian Thompson of the University of Toronto and mined data already collected on diet and breast cancer. 

The data came from 1,122 women diagnosed with breast cancer between 1996 and 2001 that was collected as part of a study looking at lifetime alcohol consumption and breast cancer (WEB Study). Dr. Thompson recently published a comprehensive analysis that lists the lignan content of foods common in the Canadian diet.

With the diet information from the WEB Study and the ability to analyze lignan content and knowledge of the ‘vital status’ of the study participants updated in 2006, there was adequate data; the association between dietary lignan intake and survival was analyzed. Hazard ratios (HR) for dietary lignan intake with all cause, and breast cancer mortality were calculated.

Postmenopausal women followed in the study who consumed the most lignan had a significantly lower risk of dying from any cause and especially from breast cancer when compared to women who ate only small amounts of lignan containing foods.

The women were consuming the most lignan in their diets at the start of the study had about half the risk of dying as those who ate little lignan. When upper versus lower quartiles of lignan intake were compared, there was a 51% (HR 0.49, 95% CI 0.26-0.91) reduction of all cause mortality in those consuming the higher lignan levels.

These same women were far less likely to die of breast cancer.  They had a 71% decreased risk of dying of breast cancer (HR 0.29, 95% CI 0.11-0.76).  High intakes of dried beans (HR 0.61, 95% CI 0.36-1.03) may have also lowered risk of overall mortality and breast cancer mortality (HR 0.53, 95% CI 0.24-1.14), though these numbers did not reach statistical significance.   [1]

This is the first paper we know of that examines the association of lignan intake prior to breast cancer diagnosis and the risk of dying.  This is relevant.  Dying after all is the bottom line when we are talking about cancer isn’t it? These findings suggest that postmenopausal women should be making an active effort to increase dietary lignan intake.

Ever since the data from the from the Women's Healthy Eating and Living (WHEL) trial was published that suggest that high fruit and vegetable and low fat diets have relatively little effect on breast cancer prognosis, those of us in clinical practice have sought to define what a ‘good’ diet should be for patients at risk for or diagnosed with breast cancer. [2]

Encouraging high lignan intake is easier said than done as few patients will understand what  ‘lignans’ are and what foods contain contain a substantial amount.  For the women enrolled in this study, the main food sources of lignans were dark bread, peaches, coffee, broccoli and winter squash. 

Other foods are far better sources. While coffee may contain up to 30 mcg/100 ml, and equal weight of kale contains several thousand mcg of lignans.  Flaxseed contain over 300,000 mcg/100 gram and sesame seeds almost 40,000 mcg.   [3]

In the McCann and Thompson study, average lignan intake averaged only 244 mcg/day.  In the postmenopausal women, consuming  <155 mcg/day yielded a HR for overall and breast cancer mortality of 1.00. As consumption levels increased, HR dropped; the lowest risk of dying was seen in women consuming >318 mcg per day.  Reaching these levels should be easy to accomplish, for example 0.1 grams of flax seed provide close to this dose of lignan.  A chart of lignan content of foods is posted at:http://www.dietaryfiberfood.com/lignan.php

This study was not a clinical trial; perhaps that is why these results seem almost too good to be true.  In other words, this may not work as effectively in real life.  Still if incorporating a few specific high lignan foods into to the diet can reduce breast cancer mortality even a fraction of the amount seen in these data, it is certainly worth trying.

1. McCann SE, Thompson LU, Nie J, Dorn J, Trevisan M, Shields PG, et al. Dietary lignan intakes in relation to survival among women with breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study. Breast Cancer Res Treat. 2010 Jul;122(1):229-35.
2. Pierce JP. Diet and breast cancer prognosis: making sense of the Women's Healthy Eating and Living and Women's Intervention Nutrition Study trials. Curr Opin Obstet Gynecol. 2009 Feb;21(1):86-91.
3. Milder IJ, Arts, IW, Van de Putte B., Venema DP, and Hollman, PH. Lignan contents of Dutch plant foods: a database including lariciresinol, pinoresinol, secoisolariciresinol, and matairesinol. British Journal of Nutrition, 93:393-402. 2005

http://www.dietaryfiberfood.com/lignan.php

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