celiac disease and autoinmmunity .pdf

Nom original: celiac disease and autoinmmunity.pdfTitre: Celiac Disease and Autoimmunity — The Missing IngredientAuteur: Rosenbaum James T.

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n e w e ng l a n d j o u r na l


m e dic i n e

Cl inic a l I m pl ic a t ions of B a sic R e se a rch
Elizabeth G. Phimister, Ph.D., Editor

Celiac Disease and Autoimmunity — The Missing Ingredient
James T. Rosenbaum, M.D.
You are preparing risotto for a dinner party.
Because you do not cook often, you attempt to
follow the recipe meticulously. But the product
of your labors is a bland dish that disappoints
you and your guests. And then it dawns on you
that you omitted an essential spice, the saffron.
Cooking risotto and having a disease are
vastly different events, but each depends on a
combination of circumstances. For disease, we
categorize those circumstances as genetic, environmental, and stochastic. On occasion, all the
factors that are necessary for disease seem to be
present, but fortunately no disease develops.
What is the missing ingredient?
Celiac disease, also known as gluten-sensitive
enteropathy, is an example of an illness for
which much is known about both the genetic
and environmental factors that lead to disease.
However, Bouziat and colleagues1 have recently
further defined the “recipe” that triggers disease.
This team made use of recombinant human viruses and transgenic mice that express human
genes predisposing to human disease. Their observations implicate the reovirus in the pathogenesis of celiac disease. Their analysis of human serum samples showed results consistent
with those in the mouse model, which suggests
that their conclusions are relevant to human
As is true of all complex, immune-mediated
diseases, dozens of genes have been implicated
as potential contributors to celiac disease.2 As is
also true for most immune-mediated diseases,
variant HLA genes are the most important. Unless you express one of the critical HLA alleles,
it is extremely unlikely that your body will ever
develop the sensitivity to gluten that leads to celiac disease.3 The main known function of HLA
molecules is to allow the presentation of antigen
from a cell such as a dendritic cell or a macro-

phage to a cell such as a T cell so that the T cell
can be educated to make an antigen-specific immune response. HLA-DQ2 and HLA-DQ8 designate proteins that have a known association with
celiac disease. These proteins activate T cells by
presenting a peptide fragment derived from gluten.4 This fragment is created by the enzymatic
activity of transglutaminase 2, which is also the
targeted autoantigen used in screening for possible gluten-sensitive enteropathy. So it would
seem that for celiac disease, the recipe is complete: a gene in the form of HLA, an environmental factor (the ingestion of gluten derived from
several grains), and an endogenous enzyme to
catalyze the formation of antigen and to serve as
a bystander autoantigen in the process. And the
combination should result in the characteristic
change of villous atrophy in the small intestine.
But this list of ingredients must be incomplete,
since celiac disease does not develop in 95 to
98% of persons who carry alleles that encode
either HLA-DQ2 or HLA-DQ8.5 Bouziat and colleagues found that a missing ingredient could be
a reovirus.
Reoviruses are not virulent in the mouse; they
infect the intestine without causing any symptoms. The investigative team separately infected
mice with two similar reoviruses, one strain
called Lang and a reassortant generated from a
strain called Dearing. The Lang virus activates
dendritic cells in the small intestine, whereas
the Dearing virus does not. The two viruses also
differ in their ability to induce a transcription
factor known as interferon regulatory factor 1
(IRF1), which is potentially the critical difference. When the transgenic mice expressing
HLA-DQ8 were infected with Lang and then fed
gluten, antibodies against gluten and activation
of transglutaminase developed in the small intestine. In contrast, transgenic mice that were

n engl j med 377;15 nejm.org  October 12, 2017

The New England Journal of Medicine
Downloaded from nejm.org on October 11, 2017. For personal use only. No other uses without permission.
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Clinical Implications of Basic Research



Other risk factors

Gluten in diet

HLA genes



Other genes

Figure 1. Susceptibility to Celiac Disease.
The majority of autoimmune and immune-mediated diseases result from a
combination of genetic and environmental factors. In the case of celiac disease, contributors such as HLA-DQ2 and HLA-DQ8 and ingestion of gluten
in the diet are essential. These factors, however, are not sufficient, and other
genetic factors (e.g., some that affect cytokines and others that affect the
innate immune response) and other environmental factors (e.g., the bacterial
microbiome) also contribute. Bouziat and colleagues1 recently found that a
reovirus infection could be a critical environmental factor. The label “other
risk factors” has been included in the figure because, at least in the mouse
model, a combination of HLA-DQ8 genetic makeup, gluten in the diet, and
reovirus infection was insufficient to cause the characteristic change of villous atrophy in the small intestine.

infected with Dearing did not have these responses. Bouziat et al. also found that patients
with celiac disease were more likely to have antibodies to reovirus than were healthy controls,
although the significance of this finding was
borderline. However, a subgroup of patients with
celiac disease had much higher levels of antibodies against reovirus than did healthy controls. These patients also had dysregulated expression of IRF1, which supports a role for
reovirus infection in this subgroup of patients.
A variety of other viral infections such as rotavirus can probably serve as cofactors to activate

n engl j med 377;15

the intestinal immune response and create a
predisposition to celiac disease.
The recipe described herein is a simplification. HLA is the most important gene that has
been associated with celiac disease, but it is not
the only gene. Additional factors that have been
implicated in the development of celiac disease
include the bacterial microbiome, the innate immune system, various cytokines (e.g., interleukin-15), and the enzyme fucosyltransferase 2.5
Moreover, the combination in a mouse of Lang
reovirus infection, the HLA transgene, and the
feeding of gluten produced antibodies to gluten
but not villous atrophy, which indicates that in
the model described by Bouziat et al., at least
one “ingredient” in the recipe for a true model
of celiac disease is still lacking (Fig. 1).
However, it is clear that in the mouse, at
least, a virus that by itself causes no symptoms
can combine with genetic factors and other environmental factors to result in a potentially
harmful immune response. And it is not difficult
to extrapolate findings regarding celiac disease
to other diseases that are influenced by a strong
HLA class II effect, such as type 1 diabetes,
rheumatoid arthritis, and systemic lupus. If a
virus is an essential part of the trigger, preventing or treating that viral infection may become
effective prophylaxis: perhaps vaccination could
block the development of autoimmunity. Preparing a dinner that fails to please is a disappointment; preventing the development of disease is a
triumph of medical science.
Disclosure forms provided by the author are available at
From the Legacy Devers Eye Institute and Oregon Health and
Science University, Portland.
1. Bouziat R, Hinterleitner R, Brown JJ, et al. Reovirus infection triggers inflammatory responses to dietary antigens and
development of celiac disease. Science 2017;356:44-50.
2. Lundin KE, Wijmenga C. Coeliac disease and autoimmune
disease — genetic overlap and screening. Nat Rev Gastroenterol
Hepatol 2015;12:507-15.
3. Shiina T, Inoko H, Kulski JK. An update of the HLA genomic region, locus information and disease associations: 2004.
Tissue Antigens 2004;64:631-49.
4. Bergseng E, Dørum S, Arntzen MO, et al. Different binding
motifs of the celiac disease-associated HLA molecules DQ2.5,
DQ2.2, and DQ7.5 revealed by relative quantitative proteomics of
endogenous peptide repertoires. Immunogenetics 2015;67:73-84.
5. Verdu EF, Galipeau HJ, Jabri B. Novel players in coeliac disease pathogenesis: role of the gut microbiota. Nat Rev Gastroenterol Hepatol 2015;12:497-506.
DOI: 10.1056/NEJMcibr1706917
Copyright © 2017 Massachusetts Medical Society.


October 12, 2017

The New England Journal of Medicine
Downloaded from nejm.org on October 11, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.

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