Nutrients 2013, 5, 4174-4183; doi:10.3390/nu5104174
Maize Prolamins Could Induce a Gluten-Like Cellular Immune
Response in Some Celiac Disease Patients
Juan P. Ortiz-Sánchez 1, Francisco Cabrera-Chávez 2 and Ana M. Calderón de la Barca 1,*
1 Department of Nutrition, Research Center for Food and Development (CIAD, A.C.),
Carr. La Victoria, Km. 0.6, Hermosillo, Sonora 83304, Mexico; E-Mail: firstname.lastname@example.org
2 Nutrition Sciences and Gastronomy Unit, University of Sinaloa, Culiacan, Sinaloa 80019, Mexico;
* Author to whom correspondence should be addressed; E-Mail: email@example.com;
Tel.: +52-662-289-2400 (ext. 288); Fax: +52-662-280-0094.
Received: 1 August 2013; in revised form: 2 October 2013 / Accepted: 10 October 2013 /
Published: 21 October 2013
Abstract: Celiac disease (CD) is an autoimmune-mediated enteropathy triggered by
dietary gluten in genetically prone individuals. The current treatment for CD is a strict
lifelong gluten-free diet. However, in some CD patients following a strict gluten-free diet,
the symptoms do not remit. These cases may be refractory CD or due to gluten
contamination; however, the lack of response could be related to other dietary ingredients,
such as maize, which is one of the most common alternatives to wheat used in the
gluten-free diet. In some CD patients, as a rare event, peptides from maize prolamins could
induce a celiac-like immune response by similar or alternative pathogenic mechanisms to
those used by wheat gluten peptides. This is supported by several shared features between
wheat and maize prolamins and by some experimental results. Given that gluten peptides
induce an immune response of the intestinal mucosa both in vivo and in vitro, peptides
from maize prolamins could also be tested to determine whether they also induce a cellular
immune response. Hypothetically, maize prolamins could be harmful for a very limited
subgroup of CD patients, especially those that are non-responsive, and if it is confirmed,
they should follow, in addition to a gluten-free, a maize-free diet.
Keywords: celiac disease; cellular immune response; maize prolamins; zeins
Nutrients 2013, 5
Celiac disease (CD) is an immune-mediated enteropathy triggered by dietary wheat, rye and barley
gluten (water-insoluble proteins) in genetically predisposed individuals . Characteristic features of
CD involve crypt hyperplasia, intra-epithelial lymphocytosis and villus atrophy of the intestinal
mucosa. These injuries affect intestinal function and nutrient absorption, which can cause a variety of
gastrointestinal and extra-intestinal symptoms .
Intestinal mucosa damage in CD patients begins with an innate response that leads to a cellular
immune response . First, prolamin peptides from gluten, which are resistant to human digestion,
interact with a chemokine receptor, inducing zonulin release and a subsequent tight junction
disassembly . Then, the damaged barrier allows the arrival of gliadin peptides to the lamina propria,
where tissue transglutaminase (tTG) deamidates specific glutamine residues to confer an overall
negative charge. These peptides are bound to the human leucocyte antigen (HLA) DQ2 or DQ8
molecules, in antigen presenting cells, which present them to T-cells to develop the full immune
response required for CD . In addition to gluten peptides, self tTG is presented to T-cells, which
triggers an auto-immune response. Therefore, CD is considered an autoimmune disease.
CD symptoms disappear in the majority of patients after dietary gluten withdrawal; however, in
some patients, the symptoms are still present even after they adopt a strict gluten-free diet . This is
due to either refractory CD or to the presence of gluten as a contaminant or as a non-declared additive
in foods . Additionally, the lack of response to dietary gluten withdrawal in a very limited
subgroup of patients, could be due to other dietary proteins present in the gluten-free diet, such as
those from maize, which is a common alternative ingredient used in gluten-free diets.
It has been demonstrated that zeins, the maize prolamins, are able to induce an inflammatory
response through contact with the mucosa in some CD patients . Furthermore, IgA antibodies from
some CD patients can recognize zeins , even after lime and/or enzymatic treatments . Perhaps,
in active CD, peptides derived from zeins could exacerbate the immune response in the intestinal
mucosa, because they have sequence characteristics and/or electronegative residues that resemble
2. Supporting Experimental Results
Table 1 summarizes the similarities between maize prolamin peptides and wheat celiac-toxic gluten
peptides that are involved in the pathogenesis of celiac disease. These results support the hypothesis
that peptides from zeins that are resistant to human digestion are able to induce a celiac-like immune
response in some CD patients by a similar mechanism to that triggered by wheat gluten peptides.
2.1. Incomplete Protein Digestion
Pepsin and trypsin, the main peptidases of the intestinal tract, cannot completely digest wheat
gluten, because they are unable to cut its 15% proline-containing polypeptides [11,12]. The result is
the release of peptides larger than nine amino acids, which are capable of eliciting innate and adaptive
immune responses . The proline content of zeins is also high (9%) and, although zeins contain
bonds that pepsin can cut, they also contain cysteine residues with disulfide bonds that obstruct
Nutrients 2013, 5
digestion by pepsin . All together, the ability of trypsin to digest zeins is low due to their low
number of cleavage sites, low solubility  and secondary conformation .
Table 1. Similarities between maize prolamin peptides and wheat celiac-toxic gluten
peptides that are involved in the pathogenesis of celiac disease (CD). NO: nitric oxide;
NOS: nitric oxide synthase; HLA-DQ2 or DQ8: human leucocyte antigen molecules;
IFN-γ: interferon gamma.
Step in CD
Characteristics of Celiac-Toxic Peptides from
Gastrointestinal peptidases do not digest the
proline-rich wheat gluten polypeptides completely,
which releases peptides larger than nine
amino acids [11,12].
Increased levels of NO were produced by
challenged granulocytes and NOS expression was
increased in enterocytes from CD patients’ small
intestine biopsies [17,18].
Characteristics of Maize Prolamins That
Could be Inducers for CD
Digestion of zeins is poor due to relatively
high concentrations of glutamine, proline
and cysteine residues [14–16].
Proteins from maize caused granulocyte
activation in a rectal challenge in six out of
13 CD patients tested .
peptides by tTG
increased affinity of
cells to bind
Gluten peptides deamidated by tTG in the lamina
propria contain negative charges [19–21].
Maize prolamins deamidated by TG
in vitro were better recognized than native
ones by IgA from some CD
patients’ sera .
HLA-DQ2 prefers negatively charged amino
acids from gluten peptides at the p4, p6 or p7
positions in the peptide, while HLA-DQ8 prefers
them at positions p1 or p9 .
Peptides from digested maize prolamins
have glutamine at positions p1 and p9 that
can be deamidated by tTG and bind to
HLA-DQ8 [23,24]. Other peptides can be
bound by HLA-DQ2 .
After processing, the deamidated gluten peptides
are presented to T-cells. Then, B-cells are induced
to proliferate and produce
T-cells from the intestine of one out of seven
CD patients stimulated by maize prolamins
and teff produced low IFN-γ as compared to
wheat, but higher than control and other
non-wheat grains . Additionally, IgA
antibodies against maize prolamins were
detected in several CD patients [10,27].
Although the levels of antibodies against
gluten decrease in some CD patients
following a gluten-free diet, antibodies
against maize prolamins remained high
until both gluten and maize were
Neither the intestinal lesions nor the CD
symptoms were alleviated with a
gluten-free diet when maize was
still eaten .
role of antibodies
Roles of tTG-specific antibodies induced by gluten
in CD patients could be: inhibiting epithelial cell
differentiation and inducing their proliferation,
increasing epithelial and blood vessel permeability
and affecting angiogenesis .
activation of T-cells
Activated T-cells drive the inflammatory response
that leads to the development of the characteristic
celiac lesions and the symptoms . T-cells
induce damage mostly by IFN-γ production .
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2.2. The Inflammatory Process
Nitric oxide (NO) production is involved in the innate inflammatory response mediated by
macrophages in CD, and it has been detected in cultured gluten-challenged small intestine
biopsies . Additionally, there is an elevated expression of mRNA encoding the major inducible
isoform of NO synthase II (iNOS) in untreated CD patients . After rectal wheat gluten challenge in
CD patients, granulocyte activation precedes NO production. Furthermore, some patients have been
found to display signs of a similar inflammatory reaction after challenge with maize prolamins .
2.3. Deamidation of the Peptides
Gluten peptides are transported across the epithelial barrier to the lamina propria, where tTG
changes the glutamine residues to glutamic acid. Antigen-presenting cells then process these
negatively charged peptides and increase their affinity for the major histocompatibility complex
(MHC) class II molecules, HLA-DQ2 and HLA-DQ8. These immunogenic peptide fragments can
stimulate HLA-DQ2- and HLA-DQ8-restricted T-cells and trigger an adaptive response in the lamina
propria [19–21]. Maize prolamins likely are also deamidated by tTG, because IgA from CD patients
was more immunoreactive against maize prolamins extracted from maize bread, treated with microbial
transglutaminase, than against maize prolamins from untreated bread .
2.4. Affinity of HLA/DQ8 Molecules to Bind Peptides
Adaptive responses to gluten initiate when dendritic cells phagocytose gliadin peptides and present
them to undifferentiated T helper cells, whose activation is crucial for the development of CD. Peptide
deamidation by tTG increases the affinity of HLA-DQ2/DQ8 for these peptides. HLA-DQ2 has an
affinity for negatively charged amino acids at the p4, p6 or p7 positions in the peptide, while
HLA-DQ8 has an affinity for those residues at positions p1 and p9 . The primary amino acid
sequences of maize zeins can fit into these HLA binding sites once they are deamidated. Through
in silico analysis, Darewicz et al.  identified a high degree of homology between two zein peptides
and the celiac-toxic peptides from prolamins found in wheat, barley and rye (gliadins, hordeins and
secalins, respectively). Moreover, we have identified a peptide sequence (α-zein 58–91) that is resistant
to complete digestion and which has characteristics that would allow it to bind to HLA-DQ8 . In
addition to this peptide, Table 2 provides the sequence of a 33-mer (α2-gliadin 56–88) peptide that is a
potent T-cell stimulator .
Table 2. Theoretical peptide sequences that bind to HLA-DQ2/DQ8 molecules. After
deamidation by tTG , glutamine residues (underlined) became glutamic acid, which is
an electronegative residue that binds to p4 and 6 in HLA-DQ2 and p1 and 9 in HLA-DQ8.
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2.5. Processing and Presentation of Peptides
Peptides of gliadin are deamidated by tTG, phagocytosed, processed and transported to the cell
surface in dendritic cells via MHC class II molecules. Subsequently, the peptides are presented to
infiltrated T helper cells that recognize deamidated peptides and trigger the proliferation of specific
B-cells and the production of IgA anti-gliadin and anti-transglutaminase antibodies . Some celiac
patients contain B-cells that produce anti-maize prolamin IgA antibodies that do not cross-react with
anti-wheat prolamins [10,27].
2.6. Role of Antibodies
After the DQ2-/DQ8-dependent activation of CD4+ T-cells, B-cells are stimulated and produce
auto-antibodies. These auto-antibodies in the intestinal lumen could be involved in disease
pathogenesis in various ways. For instance, they could be involved in inhibiting epithelial cell
differentiation, augmenting epithelial cell proliferation, increasing epithelial and blood vessel
permeability and affecting angiogenesis . In some CD patients on a gluten-free diet, including
maize-based foods, the anti-gliadin and anti-tTG antibody titers diminished, but the symptoms
persisted [29,30]. Total symptom remission in these cases was achieved only with a gluten- and
maize-free diet . It is possible that partial production of anti-tTG antibodies, in addition to
anti-zein antibodies, continued to affect the intestinal mucosa when dietary maize was present.
2.7. Activation of T-Cells
The activation of gliadin-reactive CD4+ T-cells results in the production of cytokines that drive
an inflammatory response, which leads to the development of the characteristic CD lesions and
symptoms . Gluten-specific T-cells induce tissue damage mostly by the production of interferon
(IFN)-γ . There is some evidence of T-cells being simulated by maize prolamins: intestinal T-cells
cultured from CD patients were challenged with maize prolamins in vitro, and T-cells from one out of
seven samples produced IFN-γ as a result of T-cell stimulation . Although this patient response
was not specific, maize and teff peptides produced higher levels of IFN-γ (145.6 and 154.4 pg/mL,
respectively) than the negative control (10.9 pg/mL) and others “non-toxic” grains (≈110 pg/mL).
Dietary gluten withdrawal has been demonstrated to induce mucosal recovery and the
disappearance of CD symptoms. Nevertheless, some patients on gluten-free diet have forms of CD that
do not respond to this diet. This could be due to a higher sensibility of these patients to “gluten-free”
foods that still contain some traces of gluten  or to the presence of other cereal prolamins, such as
those in maize in a very limited subgroup of CD patients.
3. Potential Links between Zeins and CD
Based on the similarities between wheat and maize prolamins discussed above, we can infer that the
innate and adaptive responses to zeins would be similar to the response against gliadins in CD patients.
Nevertheless, it is necessary to identify whether zeins contain immunodominant and minor epitopes
similar to those found in gliadins after proteolysis. Some authors have found that there is no effect on
T-cell activation or pro-inflammatory cytokine secretion when CD patient biopsies were treated with
Nutrients 2013, 5
whole pepsin-trypsin digested prolamins from maize [26,35]. Therefore, there is a need to evaluate the
effect of isolated immunogenic peptides from maize prolamins, which can be obtained by in silico
The evaluation of the response of immune cells to gliadins includes the increased expression of
surface receptors and the production of different cytokines for both tissue and immune cells. Some of
these receptors include HLA-DR (human leucocyte antigen), CD54 or ICAM-1 (intercellular adhesion
molecule), CD3 (in mature T-cells), CD25 (interleukin-2 receptor) and CD69 (in activated T-cells and
natural killer cells) [36,37]. Cytokines that would be produced include interferon gamma, interleukins
(IL) 2 and 15 and zonulin [13,38–40]. To evaluate the immune response, an analysis of the protein
expression of these markers can be performed after CD patient biopsies are challenged with zein
peptides. These ex vivo digested-peptide challenge analyses are considered useful tools to evaluate the
safety of non-gluten prolamins in a gluten-free diet [26,40].
There is evidence that after a short gluten challenge in treated CD patients, gluten-specific T-cells
are present in peripheral blood [41–44]. After this in vivo challenge, peripheral blood mononuclear
cells can be isolated and activated with gluten peptides for quantitative detection of pro-inflammatory
cytokines and direct detection of HLA-DQ2 tetramer specific for gliadins. For both cytokine
measurements and the detection of an immune response, these techniques would be very useful in the
evaluation of the effect of maize prolamins on the immune response in CD patients.
Although reaction to maize prolamins in CD patients appears to be a rare event, the confirmation
that they play a role in the pathogenesis of CD will be useful information for the follow-up of some
non-responsive celiac patients. It is estimated that approximately 10% to 18% of these cases
are refractory CD, which represents a more severe CD, with a clear malignity and a less favorable
prognosis . Therefore, it is important to assess these clinical cases, because uncontrolled CD can
lead to several malabsorption problems, osteoporosis and other autoimmune diseases .
Maize is one of the most commonly consumed grains in the gluten-free diet. Despite the low
content of zeins in maize-containing foods compared with that of gliadins in wheat-containing foods,
maize could be responsible for persistent mucosal damage in a very limited subgroup of CD patients. If
our hypothesis is proven, zeins could be classified as harmful for some CD patients, especially those
showing a poor response to a gluten-free diet.
Financial support was from the Mexican Conacyt (grant CB-2008-01-106227) and Ph.D. fellowship
for J.P. Ortiz-Sanchez (101386). Authors are grateful to V. Mata-Haro, R. Sotelo-Mundo and
M.I. Ortega for comments on the manuscript and to M.Sci. A. Bolaños for editing assistance.
Conflicts of Interest
The authors declare no conflict of interest.
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