Antibody against α-gliadin 33-mer peptide: Is the key initiating factor for development of multiple sclerosis during gluten sensitivity? Academic research paper on "Clinical medicine"

Journal of Medical Hypotheses and Ideas (2015) 9, 38-44

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Antibody against a-gliadin 33-mer peptide: Is the c^Ma* key initiating factor for development of multiple sclerosis during gluten sensitivity?

Aram Mokarizadeh a,b,% Parisa Esmaeili a,b, Hamid Soraya c, Kambiz Hassanzadeh a, Ali Jalili a b, Mohammad Abdi a, Mohammad Reza Faryabi a

Available online at www.sciencedirect.com

Journal of Medical Hypotheses and Ideas

journal homepage: www.elsevier.com/locate/jmhi

a Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj 6617713446, Iran

b Department of Immunology and Hematology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj 6617713446, Iran

c Department of Pharmacology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran

Received 9 December 2014; revised 4 February 2015; accepted 7 February 2015 Available online 21 March 2015

KEYWORDS

Anti a-gliadin antibody; Multiple sclerosis; Gluten sensitivity

Abstract Despite great advances in clarifying the pathogenesis of multiple sclerosis (MS), the exact underlying mechanism has not been definitely established. However, the responsibility of cross-reactive antibodies as the initiating factor in MS pathogenesis is a novel idea. Recently, an antibody against-a-gliadin 33-mer peptide which is found in most patients with gluten sensitivity have shown to cross-react significantly with various neural antigens including asialoganglioside, synapsin, and myelin basic protein (MBP). Furthermore, evidence indicates that IL-17, circulating immune complexes and even antibodies produced during gluten sensitivity can contribute to blood-brain barrier (BBB) permeability. Accordingly, extravasation of these anti-a-gliadin antibodies (AGA; especially IgG isotype) through the impaired BBB thought to target asialoganglioside, synapsin, and MBP in neurons. This opsonization may trigger a series of cascade pathways including complement activation, antibody-dependent microglial cytotoxicity against neurons, secretion of inflammatory mediators, myelin sheath damage, chemokine expression, CNS inflammation, BBB disruption and then leukocyte infiltration. The present hypothesis introduces

* Corresponding author at: Cellular and Molecular Research Center, and Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj 6617713446, Iran. Tel.: +98 8731827415; fax: +98 8733664674. E-mail addresses: a.mokarizadeh@muk.ac.ir, mokarizadeh.a@gmail.com (A. Mokarizadeh).

2251-7294 © 2015 Tehran University of Medical Sciences. Published by Elsevier Ltd.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). URL: www.tums.ac.ir/english/ doi:http://dx.doi.org/10.1016/j.jmhi.2015.02.002

a new antibody-dependent alternative pathway which may lead to multiple sclerosis (MS) during gluten sensitivity.

© 2015 Tehran University of Medical Sciences. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Gluten is the most widely used food to trigger development of multiple autoimmune diseases and neurological disorders. It can be found in wheat (being the main source), spelt, barley, rye, and malts. Following intake of gluten-containing diet, intestinal microbial flora cleaves gluten to insoluble glutenin and soluble gliadin which is divided into three main types of a, k, and m. Antigenic properties of gluten is largely attributed to an immunodominant 33-mer peptide (amino acid sequence LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF) found in a-gliadin. This antigenicity may be due to the fact that gluten and gliadin used today is not the same ones used over the past decades. Really, apart from the genetic modification, gluten has also been undergone a remarkable hybridization and deamination over the years. Although these procedures have been widely used to improve the yield and to make it easier to use, but it may induce biochemical and sequential changes in gluten/gliadin structure that may result in gluten sensitivity in human [1,2].

Gluten sensitivity (also gluten intolerance) is a spectrum of disorders including celiac disease (CD) and irritable bowel syndrome (IBS) in which gluten intake in genetically susceptible individuals (carry genotypes DR4, DQ8 and/or DR3, DQ2) cause a variety of histopathological manifestation such as intraepithelial lymphocytosis, lamina properia inflammation, and vilous atrophy. Gluten sensitivity has often been considered as a Th1 and Th17-mediated disease and IgG or IgA anti-gliadin antibodies (AGA) are found in approximately 40-50% of patients [3-5].

The antigenic changes of a-gliadin have also resulted in its immunological cross-reaction with many tissue antigens such as hepatocyte, glutamic acid decarboxylase-65, adrenal 21-hydroxylase, and myocardial peptide. Accordingly, the relationship between gluten sensitivity and development of autoimmune injury to the skin, joints, liver, thyroid, and pancreas has been reported [3]. Furthermore, significant cross-reaction of a-gliadin-specific antibodies with nervous system proteins such as asialoganglioside (major constituents of neuronal cell membranes), synapsin (protein presents in the nerve terminal of axons, specifically in the membranes of synaptic vesicles) and myelin basic protein (one of the key structural elements of the myelin sheath) may suggest a potential role for gliadin in the initiation of CNS autoimmunity [2].

Since destruction of myelin sheaths of neurons by autoimmune responses is the main histopathological feature of multiple sclerosis and its experimental model (EAE; experimental autoimmune encephalomyelitis), a-gliadin seems to have the same potential to develop demyelination of CNS by evoking cross-reactive responses against various neural antigens.

Although many studies have reported that leukocyte infiltration through an impaired BBB is the early starter of MS disease [6,7] but in the present hypothesis ''extravasation of serum anti-a gliadin antibodies through the impaired BBB'' has considered as an upstream event that may lead to leukocyte infiltration and CNS demyelination during gluten sensitivity.

Hypothesis

Fig. 1 provides an overview for the details and steps which may lead to MS during gluten sensitivity. The list outlined below divides the pathogenesis of anti-a gliadin antibody mediated MS into four major steps:

1. Gluten intake in genetically susceptible people (individuals who carry risk alleles for both CD and MS) can lead to generation of antibodies (both IgG and IgA isotypes) especially against a deaminated immunodominant 33-ami-noacid peptide of a-gliadin. Previously it has been shown that this antibody can bind to neural antigens of asialogan-glioside, synapsin, and MBP.

2. The intact BBB is impermeable to serum anti-a-gliadin antibodies. Nonetheless, during gluten sensitivity, IL-17 produced by TH17 subset and/or circulating small immune complexes may contribute to BBB permeability to serum antibodies (especially IgG isotype). Moreover, high affinity of serum anti-gliadin antibodies (AGA) for the blood-brain barrier vasculature can promote and/or accelerate BBB breaching. In this way, serum anti-a-gliadin antibodies (especially IgG isotype) can gain access to the CNS parenchyma.

3. Targeting of asialoganglioside (which is highly concentrated in glial and axonal structures at the nodes of ranvier) by anti-a-gliadin antibodies may lead to activation of complement system, Fc-receptor mediated phagocytosis by microglial cells, and/or antibody-dependent cell cytotoxicity (ADCC). Simultaneously, secretion of inflammatory mediators (prostaglandin E2, nitric oxide, chemokines such as CC-chemokine ligand 2 (CCL2), and pro-inflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha) by activated microglial cells can contribute to myelin sheath damage. Moreover, inflammatory responses within the CNS induce BBB endothelial to activate and express cell adhesion molecules.

Even though expression of MBP in inner layers of intact myelin sheath makes it primarily inaccessible to immune system, but emergence of MBP epitopes following myelin sheath damage may expose it to cross-reactive antibodies. Therefore, targeting of MBP in myelin sheath by anti-a-gliadin-antibodies may contribute to a series of inflammatory responses as mentioned in the previous step.

1. An inevitable consequence of such CNS inflammation is a broken BBB to recruit leukocytes in response to chemoki-nes and/or danger signals released from the inflamed foci. The recruited cells may include neutrophils, monocytes, dendritic cells, B cells, and peripheral myelin- and gliadin-reactive T cells. Afterwards, presentation of myelin epitopes to TCD4 cells by the corresponding HLA class II alleles and subsequent polarization into TH1 and/or TH17 subsets

Gluten intake in genetically susceptible individuals

Degradation of gluten to insoluble glutenin and soluble gliadins (a, y, and w)

Passage of gluten-derived peptides across the epithelial barrier

Deamination of proteins/peptides by tissue GTase

Up take of deaminated proteins/peptides by APCs which express HLA-DQ2 and DQ8

Processing of a-gliadin peptides (immunodominant 33-mer peptide)

Presentation of immunodominant peptides to naive TCD4 cells

Differentiation of naive TCD4 cells to TH1 and TH17 subsets which secrete IFN-y and IL-17 respectively

Contribution of secreted inflammatory cytokines (IL-17, IFN-y) to epithelial barrier damage and enteropathy

More passage of gliadin and intact gluten across the damaged epithelial barrier

Promotion of THl and Thl7 differentiation and increase secretion of IFN-y and IL-17

Formation of circulating small immune complexes

Contribution to blood-brain barrier (BBB) leakaee

Increased production of IgG and IgA antibodies specific to a-gliadin

Passage of serum anti-gliadin antibodies across the BBB

Targeting of asiaioganglioside in neurons by anti-a-giladin 33-mer peptide antibodies

Triggering complement activation, Fc-receptor mediated phagocytosis, ADCC, and respiratory burst by microglial cells

Secretion of Inflammatory mediators (PGE2, NO, CCL2, IL-10, IL-6, TNF-a and ROS) by activated microglial cells

Myelin sheath damage and CNS Inflammation 1 -

Break down of BBB and expression of adhesion molecules in BBB endothelium

Infiltration of granulocytes, monocytes, and peripheral a-gliadln-and myelin-reactive lymphocytes Into the CNS

Promotion of CNS demyelination

Onset of Multiple Sclerosis

Fig. 1 Schematic representation for the proposed role of anti-a-gliadin antibody in initiation of MS.

promote cytotoxic and inflammatory responses of infiltrated leukocytes. These inflammatory events sustain the BBB break down and CNS demyelination.

Evaluation of hypothesis

The present hypothesis can be tested or validated on the basis of EAE studies. The study will be conducted to confirm the abilities

of a-gliadin-specific antibodies to cross the BBB through various mechanisms and trigger autoimmune demyelination.

Transgenic mice expressing risk alleles for both CD and EAE at 6-8 weeks old will be randomly divided into two groups. Mice will be subcutaneously immunized with complete freund adjuvant (CFA) for control group or a-gliadin 33-mer peptide emulsified in CFA for treatment group, respectively. On days 0 and 2, mice will be intraperitoneally injected with pertussis toxin. Following immunization, the diet will be

switched to gluten-containing food [8,9]. Mice will be sacrificed at different time points and brain and spinal cord tissues will be harvested. After preparation of histopathological sections, using an antibody to mouse IgG and then HRP conjugated secondary antibody, immunohistochemical (IHC) staining procedure should be performed to detect presence of antibodies within the CNS. Simultaneously, H&E and luxol fast blue staining methods will be used to probe infiltrated mononuclear cells and demyelinated regions [10]. Early detection of antibodies will indicate that passage of antibodies through the BBB is prior to infiltration of inflammatory cells. Moreover, detection of demyelination in antibody localized regions along with a delayed leukocyte infiltration will confirm the accuracy of the hypothesis.

Discussion

It has been shown that anti-CNS immune responses can be initiated outside the CNS by pathogens or allergens expressing epitopes similar to an endogenous CNS antigen (a molecular mimic) [11]. Accordingly, the dietary allergens may serve as an antigenic stimulus in the etiology of MS by emerging a cross-reactive immune response to myelin antigen(s). In the case of EAE, it has been shown that butyr-ophilin (BTN; a milk protein which have same epitopes with MOG) can eighter induce or alternatively suppress encephal-itogenic T cells to myelin oligodendrocyte glycoprotein (MOG; a major myelin antigen for the autoimmune response in both MS and EAE) via cross-reactivity or molecular mimicry [12].

Similarly, in the case of gluten sensitivity, antibodies produced against an a-gliadin 33-mer peptide have been shown to cross-react with a variety of neural antigens including asialoganglioside, synapsin, and MBP [2]. However, an intact BBB can effectively restrict contribution of these auto-reactive responses to CNS autoimmunity. Accordingly, the disrupted BBB has been mentioned as the main prerequisite for developing MS in all proposed mechanisms [13]. In the case of gluten sensitivity which is often defined as the TH1/TH17 mediated autoimmunity, BBB permeability can be increased by IL-17 derived from activated TH17 subset. Previously, it has been demonstrated that during EAE, IL-17 through induction of NADPH-oxidase-dependent reactive oxygen species (ROS) can activate the endothelial contractile machinery by occludin down-regulation in BBB tight junctions [14].

Alternatively, circulating immune complexes found in the majority of patients with gluten-sensitive enteropathy (GSE) has thought to contribute to vasculitis and BBB leakage. During gluten enteropathy, the increased permeability of the gut to gluten and gliadin has been shown to contribute to formation of small immune complexes through specific interaction with serum AGA [15,16]. Since these small immune complexes are difficulty cleared by phagocytes, they may concentrate and deposit in vessels' wall. Subsequently, activation of the complement system on microvessel walls may lead to disruption of BBB [17,18].

Also, high affinity of serum anti-gliadin antibodies for the blood-brain barrier vasculature in patients with CD has been proposed to be involved in altering BBB permeability by induction of structural changes [19]. Consistent with above evidence, an isolated vasculitis of the CNS has been shown in one patient with celiac disease [20].

Additionally, many acute stresses (such as hypoxia, hyperthermia, transient hypertension, and anesthesia), some chemicals and toxins have been demonstrated to increase BBB permeability [21].

Since the ability of serum antibodies to pass through the disrupted BBB has been proven, numerous reports have indicated a relationship between circulating antibodies and CNS disorders.

Kuang et al. (2004) has reported that extravasation of nonspecific serum IgG through the transiently opened BBB cause to activation of microglial and endothelial cells [22]. Moreover, during epileptogenesis, the BBB leakage to non-specific serum IgG has been shown to cause a remarkable eosinophilia, shrinkage, and ultra-structural degenerative changes in neurons [23].

Alternatively, intraperitoneal injection of IgG samples from amyotrophic lateral sclerosis (ALS) and/or from guinea pig with experimental autoimmune gray matter disease (EAGMD) has been shown to initiate an inflammatory reaction in the spinal cord characterized by the recruitment of activated microglial cells [24].

Ulvested et al. (1994) has been shown that interaction of IgG with Fc-y receptor on cultured human microglia cells can induce respiratory burst, ADCC and phagocytosis of antibody-coated targets [25]. Moreover, intra-cortex injection of auto-serum IgG in rats has been shown to cause intra parenchymal neutrophil infiltration, microglial activation and endothelial ICAM-1 expression [26]. Demyelination has also been shown to be induced by toxic products of activated microglial cells such as TNF-a, proteases, reactive oxygen and nitrogen species [27,28].

Additionally, presence of antigen-antibody immune complexes within the CNS has been shown to cause a series of events including activation and recruitment of microglia cells, complement cascade activation, long-lasting robust inflammatory responses, BBB disruption and also leukocyte recruitment [29-32]. Also, intra-cerebroventricular injection of the terminal complement complex (MAC; C5b-9) in rats has been reported to induce a CNS inflammation followed by leukocyte infiltration [33].

All of the above evidences indicate that each of IgG extravasation, immune complex formation and/or complement activation in CNS can result in CNS inflammation, BBB disruption and then leukocyte infiltration. Accordingly, extravasation of serum anti-gliadin antibodies through the impaired BBB (eighter induced by IL-17 or alternatively by circulating immune complex), seems to have the same potencies to trigger above-mentioned events via cross-reaction with neural antigens.

In the case of gluten sensitivity, although an association between anti-gluten or anti-gliadin serum antibodies and CNS autoimmune diseases such as MS has been reported [34-37] but there are few reports regarding extravasation of AGA through BBB and its consequences.

However, detection of anti-gliadin antibodies in the CSF of a patient with a neurological autoimmune disorder (Ramsay Hunt Syndrome) may support the ability of AGA to breach the BBB [38].

Also high levels of IgG antibody against gliadin in individuals with gluten ataxia, schizophrenia and a subset of children with autism may highlight contribution of humoral immune responses to CNS pathology [39-41]. Apart from the possible

role of other environmental co-factors, these differential effects of AGA in CNS may be partly attributed to different genetic background of patients and also genetic diversity of a-gliadin which determine its antigenic/cross-reaction patterns.

Altogether, the role of gluten sensitivity in predisposition to MS disease and also the possible involved mechanism(s) remain a controversial issue and require additional research. Even though a significant increase in titer of anti-gliadin antibodies has been reported in some patients with MS [35,42,43], but the specific role of these antibodies in the patho-genesis of MS has remained unknown. Apart from sporadic case reports [44-46], few studies have reported an increased prevalence of celiac disease among MS patients [35,47]. Conversely, some other studies have not found a relationship between celiac disease and MS [48,49]. These discrepancies may be explained by these facts that not all CD patients have anti-a-gliadin antibodies and also, the etiology of MS is linked to a variety of genetic and environmental factors beyond glia-din. Furthermore, onset of MS during gluten sensitivity may need to both genetic susceptibility and long-lasting gluten/glia-din intake where early incidence of enteropathic disorders necessitates patients to leave this diet.

Concerning the important role of genetic predisposition in pathogenesis of both diseases (MS and CD), it should be noted that even though the identified HLA risk alleles or haplotypes for MS and CD is different (HLA-DQ2 and DQ8 haplotypes for CD, and HLA-DR1*1501 and DR2 haplotypes for MS) but co-expression of different allele combinations in a certain population (individuals who carry risk alleles for both CD and MS) is likely. Therefore, the increased prevalence of CD among patients with MS may be largely explained within this subpopulation. Additionally, a limited genetic overlap (PRKCQ and IL-12 loci) has been found between MS and CD [50].

Further reasons for responsibility of cross-reactive antibodies as initiating factor in MS pathogenesis may refer to three outlined below facts. First, according to size/molecular weight-based permeability of the BBB to various macro-molecules, IgG passage is prior to passage of cells even in the case of impaired BBB [51,52]. The second fact is that even though circulating myelin specific auto-reactive T cells are found in both healthy individuals and MS patients [53-55], but in patients with neurodegenerative diseases which almost have the impaired BBB, the incidence of MS has not shown to increase significantly. Additionally, susceptibility of female individuals to MS may be highly explained by their more predispositions to produce cross-reactive antibodies.

Conclusion

Collectively, the present hypothesis first introduces a-gliadin as one of the potent dietary allergens which may be involved in MS pathogenesis. Furthermore, as a new concept in MS etiology, anti a-gliadin 33-mer peptide antibodies are proposed to play a key role in the initiation of autoimmune response in MS during gluten sensitivity. In this paradigm, BBB breakdown, CNS inflammation, and subsequent leukocyte infiltration are the consequences of interactions between inflammatory cytokines, AGA and various circulating, BBB, and neural antigens.

Overview box

First Question: What do we know already about the subject?

The role of gluten sensitivity in predisposition to MS disease and also the possible involved mechanism(s) remain a controversial issue and require additional research. Moreover, even though a significant increase in titers of anti-gliadin antibodies has been reported in some patients with MS, but the specific role of these antibodies in the pathogenesis of MS has remained unknown.

Second Question: What does your proposed theory add to the current knowledge available, and what benefits does it have?

The present hypothesis has explained the pathways by which anti-a-gliadin antibodies may trigger initiation of autoimmune response in MS during gluten sensitivity.

Third Question: Among numerous available studies, what special further study is proposed for testing the idea?

Transgenic mice (expressing risk alleles for both CD and EAE) at 6-8 weeks old will be subcutaneously immunized with complete freund adjuvant (CFA) for control group or a-gliadin 33-mer peptide emulsified in CFA for treatment group, respectively. On days 0 and 2, mice will be intraperitoneally injected with pertussis toxin. Following immunization, the diet will be switched to gluten-containing food. Mice will be sacrificed at different time points and brain and spinal cord tissues will be harvested. After preparation of histopathological sections, IHC staining procedure should be performed to detect presence of antibodies within the CNS. Simultaneously, H&E and luxol fast blue staining methods will be used to explore mononuclear cell infiltration and demyelina-tion. Early detection of antibodies will indicate that crossing of antibodies through the BBB is prior to inflammatory cells. Moreover, detection of demyelination in antibody localized regions along with a delayed leukocyte infiltration will confirm the accuracy of the hypothesis.

Conflict of interest

The authors claim no conflict of interest.

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