Common food allergens and their IgE-binding epitopes

Invited review article

Common food allergens and their IgE-binding epitopes

Hiroaki Matsuo a ,*,Tomoharu Yokooji b ,Takanori Taogoshi a

a Department of Pharmaceutical Services,Hiroshima University Hospital,Hiroshima,Japan

b

Department of Pathophysiology and Therapeutics,Institute of Biomedical and Health Sciences,Hiroshima University,Hiroshima,Japan

a r t i c l e i n f o

Article history:

Received 6May 2015Received in revised form 18June 2015

Accepted 23June 2015

Available online 29July 2015Keywords:Allergen Diagnosis Epitope

Food allergy

Immunoglobulin E

Abbreviations:

AA,amino acid;AAI,a -amylase inhibitor;IgE,immunoglobulin E;LMW-GS,low molecular weight glutenin subunits;

LTP,lipid transfer protein;OM,ovomucoid;OVA,ovalbumin;WDEIA,wheat-dependent exercise-induced anaphylaxis

a b s t r a c t

Food allergy is an adverse immune response to certain kinds of food.Although any food can cause allergic reactions,chicken egg,cow's milk,wheat,shell ?sh,fruit,and buckwheat account for 75%of food allergies in Japan.Allergen-speci ?c immunoglobulin E (IgE)antibodies play a pivotal role in the devel-opment of food allergy.Recent advances in molecular biological techniques have enabled the ef ?cient analysis of food allergens.As a result,many food allergens have been identi ?ed,and their molecular structure and IgE-binding epitopes have also been identi ?ed.Studies of allergens have demonstrated that IgE antibodies speci ?c to allergen components and/or the peptide epitopes are good indicators for the identi ?cation of patients with food allergy,prediction of clinical severity and development of tolerance.In this review,we summarize our current knowledge regarding the allergens and IgE epitopes in the well-researched allergies to chicken egg,cow's milk,wheat,shrimp,and peanut.

Copyright ?2015,Japanese Society of Allergology.Production and hosting by Elsevier B.V.This is an open access

article under the CC BY-NC-ND license (https://www.doczj.com/doc/c97070877.html,/licenses/by-nc-nd/4.0/).

Introduction

The prevalence of food allergy in Japan is estimated to be 5%e 10%among infants (aged 0e 6years)and 1.5%e 3%among school-aged children (aged >6years),and the prevalence among adults is thought to be similar to that of schoolchildren.1,2The prevalence of food allergy among pediatric patients in the U.S.and Europe is reported to be 8%and 6.9%,respectively,which is similar to that in Japan.The most common foods that induce immediate-type food allergy in Japan are chicken egg (38.2%of food allergy patients),cow's milk (15.9%),wheat (8%),shell ?sh (6%),fruit (6%),buckwheat (5%),?sh (4%),peanut (3%),and ?sh roe (3%).1The frequency of causative foods in the U.S.is different:peanut (25.2%),cow's milk (21.1%),shell ?sh (17.2%),tree nut (13.1%),chicken egg (9.8%),?n ?sh (6.2%),strawberry (5.3%),and wheat (5.0%).3In European patients,the most common causative foods in order of decreasing frequency

are cow's milk,wheat,chicken egg,?sh,soy,tree nut,shell ?sh,and peanut.4Despite these differences,there is a global trend toward an increased prevalence of food allergy.5,6

To understand the pathogenesis of food allergy and establish effective approaches for diagnosis,treatment,and prevention,detailed information on the allergen molecule is essential.Recently,a number of allergen molecules have been identi ?ed,and their three-dimensional (3-D)structures have been determined by advanced biological and analytical methods.The immunoglobulin E (IgE)recognition sites (IgE-binding epitopes)in allergens contribute to allergenicity.Therefore,it is important to identify the epitope structure for the development of new strategies for accu-rate diagnosis and allergen-speci ?c immunotherapy of food allergy as well as the production of hypoallergenic foods.The bene ?t of component-resolved diagnosis of food allergy using epitope peptides 7e 14and effective immunotherapy for peanut allergy with IgE-binding epitope modi ?ed recombinant allergen 15have been reported.Here,we provide an overview of the most common food allergen molecules from chicken egg,cow's milk,wheat,shrimp,and peanut,for which IgE-binding epitopes have been well characterized.

*Corresponding author.Department of Pharmaceutical Services,Hiroshima University Hospital,1-2-3Kasumi,Minami-ku,Hiroshima 734-8551,Japan.

E-mail address:hmatsuo@hiroshima-u.ac.jp (H.Matsuo).

Peer review under responsibility of Japanese Society of

Allergology.

Contents lists available at ScienceDirect

Allergology International

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Allergology International 64(2015)332e 343

Food allergens

Food allergy is an allergen-speci?c IgE-mediated type I response.Its pathogenesis is divided into two phases:1)the sensitization phase in which the allergen enters the body through the gastrointestinal tract,skin,or mucosa,where it encounters a na?ve immune system under Th2-dominant conditions,resulting in IgE production;and2)the induction phase,which occurs following the oral intake of the same allergen as in the sensitization phase, and which elicits allergic symptoms such as urticaria,itching, wheezing,dyspnea,and abdominal pain.These responses are caused by the release of chemical mediators such as histamine and leukotrienes from activated mast cells and basophils.Cross-linking of IgE receptors with an allergen is required for the activation of these cells;therefore,more than two IgE antibodies are required to bind to one allergen molecule.

Food allergens include proteins or glycoproteins that have a molecular weight of5e100kDa and the ability to cross-link IgE receptors.Although many potential allergens are enzymatically digested and denatured by the acidic environment of the stomach, some are resistant to these conditions.16Intact food allergens have been detected in the serum after oral food administration in ani-mals17e19and humans.20e22In addition,anti-ulcer agents that inhibit gastric digestion of the allergen have an effect on the sensitization and induction phases.23

A number of different forms of plant food allergies have been reported,including pollen-food allergy syndrome and latex-fruit syndromes,in which allergic symptoms are induced mainly in the mucous membranes after ingestion of the causative food.24e26The most comprehensively characterized allergen components associ-ated with plant food allergies are pro?lins,seed storage proteins (2S albumins,7S/11S globulins),and pathogenesis related proteins such as non-speci?c lipid transfer proteins(LTPs).These compo-nents,collectively named panallergens,are widely distributed among various plants and have cross-reactivity with related plant species.27e29Carbohydrate determinants have been also reported as cross-reacting IgE-binding motifs in several plant allergens.30,31

IgE-binding epitopes and T-cell epitopes in food allergens

IgE-binding epitopes can be divided into two types,linear (sequential)and conformational(discontinuous).Linear epitopes comprise continuous amino acid(AA)sequences,while confor-mational epitopes are formed by spatially adjacent AAs that are distantly located in the AA primary sequence of the proteins. Several methods of IgE-binding epitope mapping have been re-ported.32Arrays of overlapping peptides synthesized on a nitrocellulose membrane(SPOT membrane)33are frequently used to determine sequential epitopes.10,34,35Peptide microarrays, formed from hundreds of synthetic peptides printed on a glass slide,have been used to determine IgE-binding linear epito-pes.11,13,36e40The determination of conformational IgE epitopes, however,requires sophisticated techniques,such as X-ray crystal-lography of allergens and immunocomplexes,nuclear magnetic resonance,mutant generation,and in silico analysis.41,42In such cases,IgE epitopes are predicted based on the3-D structures of food allergens,which have been determined for lysozyme(Gal d4), b-lactoglobulin(Bos d5),latex(Hev b6),birch pollen(Bet v1),and peach(Pru p3).29,43,44Recently,conformational epitopes recog-nized by monoclonal antibodies speci?c for almond(Pru du6)and cashew(Ana o2)allergens were mapped by hydrogen/deuterium exchange footprint analysis.45e47Although this new technique is not directly applicable to the identi?cation of conformational epi-topes recognized by human polyclonal IgE antibodies,the infor-mation obtained for the epitopes of monoclonal antibodies is useful to predict the conformational epitopes of human IgE antibodies.

Antigen-speci?c responses of CD4tT-cells,especially helper T-cells and regulatory T-cells,contribute to the sensitization,desen-sitization,and tolerance induction of food allergy.48T-cell epitopes that bind to major histocompatibility class II molecules are at least 13AAs long.49The mapping of T-cell epitopes and IgE-binding epitopes provides useful information for the design of peptide and/or recombinant protein-based immunotherapy for food al-lergy.T-cell epitopes can be identi?ed using peptides of10e20 residues that overlap the entire AA sequence of the candidate allergen and allergen-speci?c T-cell lines derived from peripheral blood mononuclear cells.Then,peptides that induce T-cell prolif-eration contain T-cell epitopes.T-cell epitope sequences can be also predicted by computer-based in silico analysis.50However, numerous synthetic peptides need to be assayed with T-cells from patients to con?rm the biological reactivity of the predicted epi-topes.Although studies to identify T-cell epitopes are behind those of IgE-binding epitopes,T-cell epitopes of milk(Bos d5),egg(Gal d1and2),peach(Pru p3),and peanut(Ara h1and2),among others,have been reported.51e57

Chicken egg

Chicken(Gallus domesticus)eggs consist of white and yolk. Ovomucoid(OM,Gal d1),ovalbumin(OVA,Gal d2),ovotransferrin (Gal d3),and lysozyme(Gal d4)have been identi?ed as egg white allergens58(Table1),whereas serum albumin(a-livetin,Gal d5) and a fragment of the vitellogenin-1precursor(YGP42,Gal d6) have been reported as egg yolk allergens.65,66In studies of

Table1

Chicken egg allergens.

Protein name IUIS name MW(kDa)AA length Accession no.IgE-binding epitopes(amino acid number)Year Ref

Ovomucoid Gal d128186P01005(Gal d1.0101)4e20,46e59,91e104201337

1e10,11e20,47e56,113e12220078

32e42,40e50,56e66,71e75,80e90,

101e105,121e130,159e174,179e186

200259

1e14,11e24,31e44,51e64,61e74,

101e114,121e134

200160

1e20,49e56,85e96,115e122,175e186199761 Ovalbumin Gal d244386CAA23682(Gal d2.0101)126e135,142e155,160e173,165e177,

189e199,327e337,371e386

201462

39e50,96e103,192e201,244e249,252e261200363 Ovotransferrin Gal d377705e e e Lysozyme Gal d414129CAA23711(Gal d4.0101)11e27,57e83,108e122201464 Serum albumin Gal d569615e e e

Fragment of vitellogenin-1 precursor(YGP42)Gal d635285e e e

H.Matsuo et al./Allergology International64(2015)332e343333

component-resolved diagnosis of chicken egg allergy,measure-ments of Gal d1-and/or Gal d2-speci?c IgE reactivity improved the sensitivity of a serum-based test.67e69The prevalence of speci?c IgE to each allergen was43.5%for Gal d1,52.1%for Gal d2,13.0%for Gal d3,36.9%for Gal d4,4.3%for Gal d5,and18.5%for Gal d6in suspected chicken egg allergy patients.65,67

OM(Gal d1)

OM accounts for11%of egg white protein and has three struc-turally independent tandem domains(DI,DII,and DIII),which exert trypsin-inhibitory activity.70OM is highly heat-stable and protease digestion-resistant,and is the immunodominant allergen in chicken egg.71,72Signi?cant OM-speci?c IgE antibody levels indi-cate a risk of clinical reactions to both raw and cooked egg71,73,74 and OM-speci?c IgE also has some prognostic value in predicting which patients will outgrow egg allergy.The IgE-binding epitopes have been identi?ed by enzyme-linked immunosorbent assay and microarray techniques(Table1).8,37,59e61The number of epitopes and their locations differed among the studies,possibly because of the population studied,the overlapping peptide length,and the techniques used.J€a rvinen et al.8reported that patients with persistent egg allergy,but not patients who outgrew egg allergy, had IgE antibodies that recognized the AA1e10,AA11e20, AA47e56,and AA113e122in OM.These observations indicated that the presence of sequential epitope-speci?c serum IgE anti-bodies represents the basis of a screening method for persistent egg allergy.In a recent study using microarray techniques,two major B-cell epitopes(AA4e20and AA46e59)that coincided with the epitopes described previously were identi?ed,37indicating that AA4e20and AA46e59are clinically relevant epitopes.Although AA4e20and AA46e59were recognized by24%and32%of patients who tested positive for OM-speci?c IgE,one third of the patients did not recognize any linear epitopes of OM.37The3-D conforma-tion of OM,including carbohydrate modi?cations,is preferentially recognized by IgE in egg allergy patients.Thus,the detection of conformational epitopes is also of importance for the diagnosis and prognosis of egg OM allergy.

OVA(Gal d2)

OVA is the most abundant heat-labile phosphoglycoprotein in egg white(approximately54%)and is a dominant allergen in egg allergy.58Measurement of OVA-speci?c IgE is helpful for the diag-nosis of egg allergy,especially in children with anaphylaxis.68The ?ve IgE-binding epitopes of OVA,AA38e49,AA95e102, AA191e200,AA243e248,and AA251e260,have been mapped by Mine et al.63using SPOT membranes.A recent study using digested OVA with human and simulated gastroduodenal?uids showed that seven IgE-binding peptides,AA125e134,AA141e154,AA159e172, AA164e176,AA188e198,AA326e336,and AA370e385,remained after digestion.62In addition,the importance of AA370e385was indicated by the observation that this peptide is bound by80%of sera from egg allergy patients.

Ovotransferrin(Gal d3)

Ovotransferrin,an iron-binding protein,is a heat-labile and digestible allergen75,76accounting for12%of egg white proteins. Thirty-seven percent of egg-allergic patients were reportedly sensitized to this component.67Although the3-D structure has been elucidated,77both linear and conformational IgE-binding epitopes remain to be identi?ed.Lysozyme(Gal d4)

Lysozyme is well characterized physicochemically because of its

use as an antimicrobial agent in clinical situations and as a food

preservative.Jim e nez-Saiz et al.64reported three possible IgE-binding peptides,AA11e27,AA57e83,and AA108e122,in immu-

noreactive fragments of lysozyme digested with simulated gastric

and duodenal?uids.The lysozyme(AA24e129)fragment,which is

linked by disul?de bonds to two immunoreactive peptides,

AA57e83and AA108e122,is resistant to digestive enzymes,and

induces basophil activation.Thus,lysozyme contains linear IgE-

binding epitopes that are involved in the clinical manifestation of

chicken egg allergy.

Chicken serum albumin(Gal d5)

Chicken serum albumin(a-livetin)was identi?ed as the causa-tive allergen of bird-egg syndrome,which causes respiratory

symptoms following exposure to birds,with secondary symptoms

of allergy after egg ingestion.66The prevalence of chicken serum

albumin-speci?c IgE is relatively low in chicken egg allergy

patients.67,68

YGP42(Gal d6)

A35-kDa fragment of the vitellogenin-1precursor,known as the

YGP42protein(Gal d6),was also identi?ed as an egg yolk

allergen.65This protein is heat-and reduction-stable;however,IgE-

binding of this protein is reduced by treatment with gastric?uid.To

date,no B-cell epitopes have been identi?ed.

Cow's milk

The physicochemical properties of allergens from cow's(Bos

domesticus)milk are well characterized(Table2).Fractionation of

milk yields two fractions,caseins and whey.Caseins(Bos d8)

include a s1-(Bos d9),a s2-(Bos d10),b-(Bos d11),k-(Bos d12),and g-caseins.Whey also called milk serum consists of a-lactalbumin

(Bos d4),b-lactoglobulin(Bos d5),bovine serum albumin(Bos d6), immunoglobulin(Bos d7),and lactoferrin.The prevalence of IgE reactivity to Bos d8(46.5%),Bos d4(27.6%),Bos d7(10.3%),and lactoferrin(10.3%)was demonstrated in patients with suspected cow's milk allergy.67These components,as well as cow's milk protein-speci?c IgE,are good prognostic markers of the persistence of cow's milk allergy.86,87

a-Lactalbumin(Bos d4)

a-Lactalbumin,a calcium-binding milk protein,has as a key role

in lactose biosynthesis.88Its high thermal stability was revealed by

analysis of recombinant a-lactalbumin.78The prevalence of a-lactalbumin-speci?c IgE in milk allergy patients varies from27.6% to62.8%depending on the study population.67,78,89The IgE-binding epitopes of a-lactalbumin,AA1e16,AA13e26,AA47e58,and AA93e102,have been identi?ed.79Hochwallner et al.78identi?ed six IgE-reactive peptides using a panel of19-or20-mer overlapping peptides spanning the entire protein.Three of these peptides, AA1e19,AA15e34,and AA105e123,are located on the surface of the protein.

b-Lactoglobulin(Bos d5)

b-Lactoglobulin is the most abundant protein in milk whey.The

major IgE-binding epitopes of b-lactoglobulin,AA1e16,AA31e60, AA67e86,and AA127e152,have been identi?ed.79Cerecedo et al.38

H.Matsuo et al./Allergology International64(2015)332e343 334

also used a panel of overlapping peptides in a microarray-based immunoassay to analyze the IgE-binding epitopes of b-lactoglob-ulin.The identi?ed IgE epitopes,AA58e77,AA76e95,and AA121e140,are recognized by more than75%of milk allergy pa-tients.AA58e77is signi?cantly associated with milk protein-reactive patients.Recent studies identi?ed AA1e16,AA56e70, and AA76e90as epitopes in Chinese patients.80These sequences are roughly in accordance with the epitopes detected in European patients described previously.

Bovine serum albumin(Bos d6)

Bovine serum albumin is an important allergen in milk,meat, and epithelia allergy.90e92There is cross-reactivity between serum albumin from cow,sheep,deer,pig,dog,and cat(meat and/or epithelia)90;therefore,albumins are implicated as panallergens in mammals.Although bovine serum albumin is the major allergen in beef allergy,93bovine serum albumin-speci?c IgE is found in only 3.8%of patients with cow's milk allergy.89Structural modi?cation by heat treatment and chemical denaturation does not affect the allergenicity of bovine serum albumin,94and several IgE-binding epitope sequences have been reported in beef allergy.95,96

Bovine gamma globulin(Bos d7)

Bovine gamma globulin is also an allergen in cow's milk and beef allergy.97Approximately10%of patients with cow's milk al-lergy are bovine gamma globulin-speci?c IgE positive.67

Caseins(Bos d8e12)

Casein(Bos d8)constitutes approximately80%of the proteins present in cow's milk.These phosphorylated proteins are heat-stable but are susceptible to digestive enzymes.98Casein is composed of four major proteins,a s1-casein(Bos d9),a s2-casein (Bos d10),b-casein(Bos d11),and k-casein(Bos d12),most of which exist in a colloidal particle known as the casein micelle.The molecular weight and AA length of caseins are listed in Table2.The proportions of casein in milk protein are37%for a s1-casein,37%for a s2-casein,13%for b-casein,and13%for k-casein.

a s1-Casein(Bos d9)

Approximately50%of serum samples from patients with cow's milk allergy react with a s1-casein,which has an unordered mo-lecular structure.89Nakajima-Adachi et al.83identi?ed AA181e199 in the C-terminal region as the immunodominant IgE-binding re-gion.Three regions of a s1-casein,corresponding to AA19e30, AA93e98,and AA141e150,were also identi?ed as IgE-binding peptides.84In recent studies,several IgE-binding epitopes were identi?ed by overlapping peptide mapping.38,81,82

a s2-Casein(Bos d10)

Busse et al.85identi?ed10sequential IgE-binding epitopes of a s2-casein,four of which AA83e100,AA143e158,AA157e172,and AA165e188,were detected in77%of patients.Cerecedo et al.38 mapped seven IgE-binding epitopes and showed that four, AA1e20,AA13e32,AA67e86,and AA181e207,were signi?cantly associated with the reactive group of patients.

b-Casein(Bos d11)

Six major and three minor IgE-binding epitopes of b-casein were identi?ed by Chatchatee et al.34Cerecedo et al.38also identi?ed four B-cell epitopes,three of which,AA25e50,AA52e74,and AA154e73,were found to be associated with allergic symptoms. Several IgE-binding epitopes remain as fragments of b-casein after gastrointestinal digestion.99

k-Casein(Bos d11)

Using overlapping peptide mapping,eight major IgE-binding peptides of k-casein were identi?ed,three of which,AA9e26, AA21e44,and AA47e68,were recognized by93%of patients with cow's milk allergy.34AA16e35and AA34e53in k-casein were also

Table2

Cow's milk allergens.

Protein name IUIS name MW(kDa)AA length Accession no.IgE-binding epitopes(amino acid number)Year Ref a-Lactalbumin Bos d414.2123AAA30615(Bos d4.0101)1e19,15e34,45e64,60e79,90e109,105e123201078

1e16,13e26,47e58,93e102200179 b-Lactoglobulin Bos d518.3162CAA32835(Bos d5.0101)1e16,56e70,76e90,136e150201280

58e77,76e95,121e140200838

1e16,31e60,67e86,127e152200179 Serum albumin Bos d667583e e e Immunoglobulin Bos d7160e e e e Caseins

(Bos d9e Bos d12)

Bos d820e30e e e e

a

S

1-Casein Bos d923.6199NP_851372(Bos d9.0101)6e20,11e35,126e140,171e185201381

16e35,28e50,73e92200838

17e36,39e48,69e78,83e102,109e120,

122e132,139e154,159e174,173e194

200182

181e199199883

19e30,93e98,141e150199684 a S2-Casein Bos d1025.2207NP_776953(Bos d10.0101)1e20,13e32,67e82,106e125,122e141,

157e182,181e207

200838

31e44,43e56,83e100,93e108,105e114,

117e128,143e158,157e172,165e188,

191e200

200185

b-Casein Bos d1124209XP_005902099(Bos d11.0101)25e50,52e74,121e140,154e173200838

1e16,45e54,55e70,83e92,107e120,

135e144,149e164,167e184,185e208

200134 k-Casein Bos d1219169NP_776719(Bos d12.0101)16e35,34e53200838

9e26,21e44,47e68,67e78,95e116, 111e126,137e148,149e166200134

H.Matsuo et al./Allergology International64(2015)332e343335

identi ?ed as IgE-binding dominant epitopes.38Thus,the N-termi-nal region (AA9e 68)of k -casein may play an important role in the allergenicity of this protein.The critical AAs for IgE-binding to linear epitopes of k -casein were identi ?ed by Han et al.100

Time-related differences in the binding of IgE and IgG4to epi-topes of b -lactoglobulin,a -lactalbumin,and caseins between pa-tients with early recovery or persistent cow's milk allergy have been investigated.101,102Furthermore,IgE and IgG4epitope binding was also analyzed to predict the outcome of oral immunotherapy in cow's milk allergy using peptide arrays.103The results of this study showed that monitoring the binding of IgE and IgG4to epitope peptides of caseins has predictive value for the development of tolerance to cow's milk or the outcome of oral immunotherapy.Wheat

Wheat (Triticum aestivum )is an important allergen source that elicits various clinical types of food allergy,such as immediate

wheat allergy,baker's asthma,wheat contact dermatitis,and wheat-dependent exercise-induced anaphylaxis (WDEIA).The total protein content of wheat ?our ranges from 8%to 12%,and can be classi ?ed as water/salt-soluble proteins (albumin and globulin)and the insoluble protein,gluten.Wheat pro ?lin (Tri a 12),non-speci ?c LTP (Tri a 14),a -amylase inhibitors (AAI,Tri a 15,Tri a 28e 30),wheat germ agglutinin (Tri a 18),thioredoxin (Tri a 25),thiol reductase homolog (Tri a 27),triosephosphate isomerase (Tri a 31),1-cys-peroxiredoxin (Tri a 32),serpin (Tri a 33),glyceraldehyde-3-phosphate dehydrogenase (Tri a 34),dehydrin (Tri a 35),a -pur-othionin (Tri a 37),serine proteinase inhibitor (Tri a 39),thaumatin-like protein,peroxidase,and glutathione S-transferase in the sol-uble fraction have been identi ?ed as allergens in patients with baker's asthma,wheat food allergy and wheat contact urticaria (Table 3).112e 115a /b -Gliadin (Tri a 21),g -gliadin (Tri a 20),u 1,2-gliadin,u 5-gliadin (Tri a 19),low molecular weight glutenin sub-units (LMW-GS,Tri a 36),and high molecular weight glutenin subunits (Tri a 26)in wheat gluten have been reported as allergens

Table 3

Wheat allergens.Protein name

IUIS name

MW (kDa)

AA length

Accession no.

IgE-binding epitopes

(AA sequence or number)Year

Ref

Water/salt-soluble protein Pro ?lin

Tri a 1214e e

e

e e Non-speci ?c lipid transfer protein 1Tri a 14990P2429624e 33,37e 46,81e 90

2011104a -Amylase inhibitors Monomeric 0.28Tri a 1512e e e e e Dimeric 0.19Tri a 2813e e e e e Tertameric CM1/CM2

Tri a 2913e e e e e CM3

Tri a 3016e e e e e CM16/CM17

e 17e e e e e Agglutinin Tri a 1817e e e e e Thioredoxin

Tri a 2513e e e e e Thiol reductase homologue Tri a 2727e e e e e Triosephosphate isomerase Tri a 3126e e e e e 1-Cys-peroxiredoxin Tri a 3224e e

e

e e Serpin

Tri a 3340398CAB5271046e 68,76e 92,271e 293,364e 3842012105Glyceraldehyde-3-phosphate-dehydrogenase Tri a 3440e 42e e e e e Dehydrin

Tri a 3512e e

e

e e a -Purothionin

Tri a 3712111AFQ605402e 31,42e 71,62e 912014106Serine protease inhibitor-like protein Tri a 39

9e e e e e Glutathione transferase e 25e e e e e Thaumatin like protein e 18e e e e e Peroxidase

e

36e e e

e

e Water/salt-insoluble protein a /b -Gliadin

Tri a 21

28e 35

299

P04725

VRVPVPQLQP,QEQVPLVQQQ,VQQQQFPGQQ,QQQFPGQQQQ,YLQLQPFPQP,QILQQILQQQ,LQIPEQSQCQ,QEQKQQLQQQ,SFQQPQQQYP,LALQTLPAMC,YIPPHCSTTI 2011,2005

104,107

g -Gliadin Tri a 2028e 35280BAN29066(Tri a 20.0101)QPQQPFPQ

2013108308P08453

QPQQPFPQ

2012109QQX 3X 4PQ (X 3?L,S,Q;X 4?L,V,F)2005107u 1,2-Gliadin e 40261Q9FUW7

QPQQPFPQ

2012

109

QQPX 5PX 6Q (X 5?I,T,F;X 6?V,Q,I)

2011,2005104,107u 5-Gliadin

Tri a 1965420

BAE20328

(Tri a 19.0101)

QQX 1PX 2QQ (X 1?L,F,S,I;X 2?Q,E)

2011,2005104,107QQIPQQQ,QQFPQQQ,QQSPEQQ,QQSPQQQ,QQYPQQQ,PYPP,

QQFHQQQ,QSPEQQQ,YQQYPQQ,QQPPQQ

2005,2004

35,110

High molecular weight glutenin subunits Tri a 2688827QQPGQ,QQPGQGQQ,QQSGQGQ 200510Low molecular weight glutenin subunits Tri a 3632e 40369

Q9ZNY0

HQQQPIQQQP,QQPIQQQPQQ,QQFPQQQPCS,PFVHPSILQQ,QCSPVAMPQS,LPQIPQQSRY,QSRYEAIRAI 2011104

QQQPP

1996111

H.Matsuo et al./Allergology International 64(2015)332e 343

336

that cause WDEIA.113,116,117Gliadins and glutenins are allergens that also cause baker's asthma and common immediate wheat allergy in some cases.118,119In addition,LTP in the water/salt-soluble fraction was reported to cause WDEIA.112,113These?ndings demonstrate the comparative speci?city of the causative allergens to each clinical type of wheat allergy,although some allergens contribute to the development of two or more clinical types of this allergy.It should be noted that the biological activity of some wheat allergens re-ported in this review have not been determined using techniques such as the skin prick test or the basophil histamine release test.

Water/salt-soluble wheat allergens

Tri a12is recognized by speci?c IgE antibodies in patients with baker's asthma,grass pollen allergy,and food allergy to wheat.115,120e122However,the prevalence of IgE reactivity to wheat pro?lin in patients with food allergy and respiratory allergy is low.115Tri a14was identi?ed as an allergen in food allergy patients after ingestion of wheat products,123e126as well as in patients with baker's asthma127and WDEIA.118Monomeric AAI0.28(Tri a15), dimeric AAI0.19(Tri a28),tetrameric AAI CM1/CM2(Tri a29),AAI CM3(Tri a30),and AAI CM16are allergens in pediatric patients with wheat allergy,126patient's with baker's asthma,121,128and those with work-related wheat dermatitis.129

Tri a18,25,32e35,and39were identi?ed as allergens in pa-tients with baker's asthma and/or food allergy.103,105,122,130e133Four IgE-binding epitopes of Tri a33,AA46e48,AA76e92,AA271e293, and AA364e384,were identi?ed using overlapping peptide map-ping,105and3-D modeling showed that these epitopes are partially located on the surface of the protein.No differences were identi?ed in the IgE-binding epitope peptides associated with food allergy and baker's asthma.105

Tri a27was identi?ed as an allergen that causes wheat protein contact dermatitis and wheat food allergy.114,134,135It is considered that the N-linked glycan moieties with fucose residues contained in this allergen are involved in IgE-binding.136The highest frequencies of Tri a27-speci?c IgE were reported in patients with baker's asthma.121Tri a37was recently reported as a novel wheat allergen speci?c for patients with wheat food allergy.137Twenty percent of patients with wheat food allergy had Tri a37-speci?c IgE,whereas the frequency was only3%among patients with baker's asthma.137 The IgE-binding epitopes in this allergen have been mapped to three regions of the protein,AA2e31,AA42e71,and AA62e91.106 Water/salt-insoluble wheat allergens

Gliadins and glutenins are water/salt-insoluble wheat proteins that have been identi?ed as causative allergens in patients with wheat food allergy,baker's asthma,and WDEIA.10,35,107,113,117u5-Gliadin(Tri a19)is a major allergen in WDEIA138,139and children

with immediate allergy to ingested wheat.140Because of the pres-ence of a repetitive domain,there are many IgE epitope sequences in u5-gliadin;however,the consensus sequence comprising QQX1PX2QQ(X1?L,F,S,I;X2?Q,E,G)has been identi?ed as the IgE-binding epitope in Japanese and European patients.35,104,107,110 The measurement of speci?c IgE to u5-gliadin and its IgE-binding epitopes in the diagnosis of patients with wheat food allergy including WDEA has been reported.10,141e145However,the Tri a19-speci?c IgE test alone could not be used to diagnose all patients with wheat food allergy.146,147g-Gliadin(Tri a20)is a causative allergen in patients with food allergy to wheat and those with baker's asthma.113,117Furthermore,g-gliadin-speci?c IgE was also detected in Japanese patients with WDEIA following transdermal sensitization with hydrolyzed wheat protein.108,148The IgE-binding epitope sequence of QPQQPFPQ in g-gliadin identi?ed in Japanese patients sensitized via the dermal route was identical to the epitope

sequence identi?ed in European patients sensitized orally with

hydrolyzed wheat proteins.109a/b-Gliadin(Tri a21)and a1,2-gliadin are also important causative allergens in wheat food al-

lergy,WDEIA,and baker's asthma.104,107,113,146The IgE-binding

epitopes for these allergens were identi?ed in patients with

wheat allergy104,107and in addition,the sequences of QQPFP and

PQQPF in gliadin were epitopes in atopic dermatitis-related wheat

allergy.149

LMW-GS(Tri a36)was identi?ed as an allergen that induces

wheat food allergy123,150,151and WDEIA152in European patients.

There are several types of LMW-GS encoded by genes located on

group1chromosomes at the Glu-A3,Glu-B3,and Glu-D3loci,153

and patients with wheat allergy exhibited IgE-reactivity to

different LMW-GS.150Although the LMW-GS GluB3-23,B16,and

P73epitopes are well characterized,147,150,152only GluB3-23is

de?ned as Tri a36in the IUIS allergen database.147Tanabe et al.111

identi?ed the QQQPP motif in LMW-GS as a major IgE-binding

epitope responsible for atopic dermatitis in patients sensitized

with wheat.

High molecular weight glutenin subunits(Tri a26)has been

identi?ed as an allergen responsible for WDEIA in Japanese patients

and its IgE-binding epitopes,QQPGQ,QQPGQGQQ,and QQSGQGQ,

have been?ne-mapped.10We showed that the combined detection

of IgE antibodies speci?c to epitope peptides or recombinant pro-

teins of Tri a26and Tri a19improved the sensitivity and speci?city

of the diagnosis of WDEIA.10,154

Shrimp

Seafood allergy is a common food allergy.The prevalence of?sh

and shell?sh allergies is estimated at0.2%e0.3%and0.6%,respec-

tively.155Allergy to crustacean shell?sh,which include shrimp,

prawns,lobsters,and crabs,seems to affect school-aged children

and adults predominantly.1Crustacean-allergic patients can show

cross-reactivity to different types of shell?sh as well as molluscan

shell?sh,such as gastropods(abalones,limpets,snails),bivalves

(scallops,oysters,mussels),and cephalopods(squid,octopus).

Studies of shrimp allergens are the most advanced among the

shell?sh allergies.156There are various types of edible shrimp

worldwide,with White Paci?c shrimp(Litopenaeus vannamei),

black tiger(Penaeus monodon),kuruma prawn(Marsupenaeus

japonicus),and Japanese spiny lobster(Panulirus japonicas)the

most commonly eaten in Japan.The allergens responsible for

crustacean allergies are also well studied.Tropomyosin,arginine

kinase,sarcoplasmic calcium-binding protein,myosin light chain,

troponin C,and triosephosphate isomerase have been identi?ed as

allergens in Penaeus monodon,L.vannamei,Crangon crangon(North

Sea shrimp),Homarus americanus(American lobster),and some

crabs(Table4).156,159e161

Tropomyosin(group1)

Tropomyosin is associated with the actin and troponin compo-

nents of muscle cells,and isoforms of tropomyosin were identi?ed

in several shrimp species,including Pandalus borealis(Pan b1),

Penaeus monodon(Pen m1),Penaeus aztecus(Pen a1),Penaeus

indicus(Pen i1),Metapenaeus ensis(Met e1),L.vannamei(Lit v1),

Crangon crangon(Cra c1),and H.americanus(Hom a1).Although

tropomyosins from crustaceans share high homology(up to98%),

the AA sequence identity of crustacean and molluscan tropomyosin

is much lower(approximately60%).160The major continuous IgE

epitopes were identi?ed in Pen a1157and Lit v1158using over-

lapping peptide mapping.Nine IgE-binding peptides in Pen a1

were identi?ed,?ve of which,AA37e63,AA82e105,AA115e150,

H.Matsuo et al./Allergology International64(2015)332e343337

AA190e 210,and AA246e 284,corresponded with the epitopes of Lit v 1.The sequences LEX 1X 2L or LEX 1X 2N (X 1?D,E,N or K,X 2?D or E)in AA1e 36(LEKDN),AA37e 63(LENDL),AA82e 105(LEEDL),and AA246e 284(LEDLE)were identi ?ed as common IgE-binding motifs in Lit v 1.158The immunodominant regions of Pan b 1were also mapped by Myrset et al.162Arginine kinase (group 2)

Arginine kinase was identi ?ed in three types of shrimp (Cra c 2,163

Lit v 2,164Pen m 2165).Eight IgE-binding epitopes were iden-ti ?ed in Lit v 2,158with the highest diagnostic ef ?ciency shown in the test for AA232e 255peptide-speci ?c IgE.13Recent studies showed that Pen m 2is an important allergen recognized by Th2cells in patients with shrimp allergy.166

Myosin light chain (group 3and Cra c 5)

Myosin light chain (Lit v 3,Pen m 3)was ?rst identi ?ed in L.vannamei 167and Penaeus monodon .168Cra c 5was also con ?rmed as a novel type of IgE-binding myosin light chain with only 13%AA sequence identity to Lit v 3.163Six IgE-binding sequences were identi ?ed in Lit v 3.158

Sarcoplasmic calcium-binding protein

Sarcoplasmic calcium-binding protein was identi ?ed as an allergen in three types of shrimp (Cra c 4,163Lit v 4,169and Pen m 4170).Three IgE-binding regions were identi ?ed in Lit v 4.158Troponin C (group 6)and triosephosphate isomerase (Cra c 8)Troponin C (Cra c 6163and Pen m 6171)and triosephosphate isomerase (Cra c 8163)were identi ?ed as allergens in patients with shrimp allergy but have not been reported in L.vannamei and

Penaeus monodon ,suggesting they are minor or local shrimp allergens.

Several studies conducted to investigate component-resolved diagnosis using recombinant shrimp allergens and IgE-binding epitope peptides showed that measuring IgE binding to tropomy-osin and sarcoplasmic calcium-binding protein is useful for the prediction of clinical reactivity in patients with shrimp allergy although the measurement of IgE speci ?c for other allergens and epitopes is necessary for the accurate diagnosis of shrimp allergy.7,13Peanut

Twelve allergens have been identi ?ed in association with pea-nut (Arachis hypogaea )allergy (Table 5).These are designated Ara h 1to Ara h 13,with the exception of Ara h 4,which has been renamed Ara h 3.02.176Ara h 2,Ara h 6,and Ara h 7,which belong to the 2S albumin family,are seed storage proteins and have homol-ogous AA sequences and secondary structures.177Ara h 2and Ara h 6are the most clinically relevant allergens in peanut allergy.178,179Ara h 1(7S globulin)and Ara h 3(11S globulin)are seed proteins belonging to the cupin superfamily,which contains a conserved barrel domain.180,181Ara h 5is a member of the pro ?lin family with 72%AA sequence identity to birch pollen pro ?lin (Bet v 2),and is a class II type labile food allergen.182Ara h 8,a pathogenesis related protein-10(Bet v 1)homolog,is also a class II food allergen.It is a major allergen and produces allergic symptoms in birch pollen-allergic patients after the ingestion of peanuts.183,184Ara h 9,a non-speci ?c LTP,was identi ?ed as a peanut allergen in patients who have peach allergy and are positive for Pru p 3-speci ?c IgE.185,186Most of these patients did not have IgE antibodies spe-ci ?c to Ara h 1,Ara h 2,and Ara h 3,indicating that Ara h 9is an important allergen in peanut allergy.Oleosins (Ara h 10and Ara h 11)are obtained from peanut oil bodies.187,188In a recent study,the IgE-binding epitopes of Ara h 10and Ara h 11were identi ?ed using

Table 4

Shrimp allergens.Protein name

IUIS name MW (kDa)AA length Accession no.

IgE-binding epitopes (amino acid number)Year Ref Tropomyosin Penaeus aztecus (Brown shrimp)

Pen a 137284AAZ76743(Pen a 1.0101)1e 36,37e 63,61e 81,82e 105,115e 150,142e 162,157e 183,190e 210,246e 2842002157Litopenaeus vannamei (White shrimp)Lit v 137

284ACB38288(Lit v 1.0101)43e 57,85e 105,133e 148,187e 202,247e 2842010158Pandalus borealis (Northern shrimp)Pan b 1e e e e e Metapenaeus ensis (Greasyback shrimp)Met e 1e e e e e Penaeus indicus

(Indian white shrimp)Pen i 1e e e e e Penaeus monodon (Black tiger shrimp)Pen m 1e e e e e Crangon crangon (North sea shrimp)Cra c 1e e

e

e e Arginine kinase

Lit v 240

356ABI98020(Lit v 2.0101)1e 18,25e 42,64e 96,121e 141,142e 159,160e 192,232e 2552010158Pen m 2e e e e e Cra c 2e e

e

e e Myosin light chain 2Lit v 320

177ACC76803(Lit v 3.0101)13e 30,22e 48,49e 66,58e 90,79e 99,118e 1412010158Pen m 3e e

e

e e Sarcoplasmic

calcium e binding protein Lit v 420

193ACM89179(Lit v 4.0101)10e 36,49e 72,130e 1472010158Pen m 4e e e e e Cra c 4e e e e e Myosin light chain 1Cra c 518e e e e e Troponin C

Cra c 620e e e e e Pen m 6e e e e e Triosephosphate isomerase

Cra c 8

28

e

e

e

e

e

H.Matsuo et al./Allergology International 64(2015)332e 343

338

in silico methods.189In addition,Kobayashi et al.190identi?ed the IgE-binding epitope of peanut oleosin3,which differs from those of Ara h10and Ara h11.Ara h12and Ara h13,which are defensins directed against fungal pathogens,were identi?ed as allergens by Petersen et al.191Although they have been listed as peanut allergens by the WHO/IUIS Allergen Nomenclature Subcommittee,the details have not been reported.The prevalence of IgE binding to Ara h 10e13has not yet been elucidated.From the viewpoint of component-resolved diagnosis of peanut allergy,Ara h1,2,3,6,and 9are signi?cant allergens that correlate with reactivity and/or severity,although the sensitivity and speci?city of each component is population-dependent.192e194

7S globulin(Ara h1)

Ara h1is a glycosylated seed storage protein.IgE binding to Ara h1has a low sensitivity to heating and digestion with pepsin.195,196 Twenty-three IgE-binding epitopes were identi?ed throughout the protein by overlapping peptide mapping,172and a further epitope, AA361e385,was reported by Shref?er et al.11Six of these epitopes, AA90e97,AA98e104,AA108e115,AA124e131,AA134e143,and AA144e151,are pepsin-resistant.197B?gh et al.198identi?ed?ve conformational epitope motifs in Ara h1by competitive immu-noscreening of a phage-displayed random peptide library,and epitope mimics were found to cluster in three areas of Ara h1. Furthermore,phage-display technology was used to analyze the difference between IgE and IgG epitopes of Ara h1.199Elucidation of IgE and IgG epitope recognition patterns could be a valuable tool for the diagnosis of peanut allergy.

11S globulin(Ara h3)

Ara h3is post-transcriptionally cleaved to form two protein fragments by an asparaginyl endopeptidase after the formation of an intermolecular disul?de bond.Thus,23-kDa and36-kDa spots are observed by2D-PAGE under reducing conditions.181Analysis of the IgE-binding epitope sequences in Ara h3in three different overlapping peptide array experiments showed that four epitopes, AA30e44,AA237e251,AA276e290,and AA300e312,were important in peanut allergy.12,175

2S albumin(Ara h2and6)

Ara h2,which consists of two isoforms,Ara h2.01and Ara h 2.02,is highly resistant to boiling and proteolytic digestion.200,201 Seven to ten IgE-binding epitopes were identi?ed in Ara h2us-ing overlapping peptide immunoassays.12,39,173,174In addition,post-translational proline hydroxylation of Ara h2contributes to linear IgE epitopes.202

Ara h6shares55%identity with the AA sequence of Ara h2and some of the IgE epitopes of Ara h6are cross-reactive with those of Ara h2.173As with Ara h2,the resistance of Ara h6to heat and digestive enzymes was reported.201Seven IgE-binding epitopes were identi?ed for Ara h6by Otsu et al.,173and the linear IgE-binding epitopes of Ara h2and Ara h6were useful in predicting clinical reactions in patients with peanut allergy.

Protein structures of Ara h1e3,5,and8were elucidated by X-ray crystal structure analysis.181,203e206B-cell epitopes of Ara h1e3, 5e13were predicted using in silico methods,and the predicted epitope sequences of Ara h1e3correlated with the epitopes identi?ed experimentally,189suggesting that computational pre-diction of epitopes may contribute to improved accuracy of peanut allergy diagnosis.

Conclusions

Advances in molecular biology and analytical chemistry in the past three decades have facilitated the identi?cation of food aller-gens and their sequential IgE-binding epitopes.The production of recombinant allergens and the use of3-D structural analysis have

Table5

Peanut allergens.

Protein name IUIS name MW(kDa)AA length Accession no.IgE-binding epitopes(amino acid number)Year Ref

Cupin(Vicillin-type, 7S globulin)Ara h164626AAB00861(Ara h1.0101)139e147,175e183(most dominant)200812

26e33*,48e57,66e73*,90e97*,98e104,

108e115,124e131,134e143,144e151,

295e302,312e319,325e334,345e352,

361e385,393e402,409e418,463e468,

498e507*,525e534,539e548,551e560,

559e568,578e587,598e605(*dominant

epitope)

2004,199711,172

Conglutin(2S albumin)Ara h217.5160ABQ96212(Ara h2.01)31e36,43e53,63e68,92e103,106e118,

120e128,130e139,140e152

2014173

31e36(most dominant)200812

30e39,44e59,62e67,70e80,92e103,

110e116,130e136

200539

18e27,24e31,30e39,42e51,52e59,

62e67,68e75,120e125,130e135,146e152

1997174

Ara h615124ABQ96216(Ara h6.0101)1e13,23e33,41e47,58e70,73e85,

97e106,107e119

2014173 Ara h716e17e e e e e

Cupin(Legumin-type, 11S globulin,Glycinin)Ara h360510AAC63045(Ara h3.0101)301e309(most dominant)200812

30e44,237e251,276e290,300e3121999175

Pro?lin Ara h514e e e e e Pathogenesis-related

protein10(PR-10)

Ara h817e e e e e

Non-speci?c lipid-transfer

protein type1

Ara h99.1e e e e e

Oleosin Ara h1018e e e e e Ara h1114e e e e e Defensin Ara h12 5.2e e e e e Ara h138.4e e e e e

H.Matsuo et al./Allergology International64(2015)332e343339

also contributed to this progress.The results of these studies have enhanced our understanding of the mechanisms of food allergy at the molecular level.Although there are a number of limitations associated with studies of food allergen components and epitopes, the detection and quanti?cation of serum IgE antibodies speci?c to allergen components and epitope peptides are useful for the diagnosis and prognosis of food allergy.In addition,clari?cation of the sensitization patterns of allergen components in individual patients might facilitate allergen-speci?c immunotherapy of food allergy.However,numerous issues remain to be investigated.For example,conformational IgE epitopes and T-cell epitopes have not yet been identi?ed for most food allergens,even those for which the3-D structure has been determined.Furthermore,many aller-gens remain unidenti?ed because of biodiversity,especially in seafood,and the disposition and digestion of food allergens after ingestion have not been clari?ed.Future studies should focus on full IgE and T-cell epitope mapping in individual patients to improve the diagnosis,therapy,and prevention of food allergy. Con?ict of interest

The authors have no con?ict of interest to declare.

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Generation of a comprehensive panel of crustacean allergens from the North Sea Shrimp Crangon crangon.Mol Immunol2011;48:1983e92.

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峄山碑及译文

《峄山碑》全文及译文 《峄山碑》是秦始皇二十八年（公元前219年）东巡时所刻，下面是小编为大家带来的峄山碑全文及译文，欢迎阅读。 碑文 皇帝立国，维初在昔，嗣世称王 讨伐乱逆，威动四极，武义直方 戎臣奉诏，经时不久，灭六暴强 廿有六年，上荐高号，孝道显明 既献泰成，乃降专惠，亲巡远方 登于绎山①，群臣从者，咸思攸长 追念乱世，分土建邦，以开争理 功战日作，流血于野，自泰古始 世无万数，陀及五帝，莫能禁止 廼今皇帝，壹家天下，兵不复起 灾害灭除，黔首康定，利泽长久 群臣诵略，刻此乐石，以箸经纪 注：①绎山：指峄山。 皇帝日：“金石刻尽，始皇帝所为也。今袭号而金石刻辞不称，始皇帝其于久远也。如后嗣为之者，不称成功盛德。”丞相臣斯、臣去疾，御史大夫臣德。昧死言，臣请具刻诏书，金石刻因明白矣。臣昧死请，制日可。 注释： 皇帝立国，维初在昔，嗣世称王 （维是发语词，不翻。嗣世，一代代，继承。这三句，是一句话。） 讨伐乱逆，威动四极，武义直方 （武义直方，就相当于说正义战争。） 戎臣奉诏，经时不久，灭六暴强 （戎臣，就是带兵的将领。灭六暴强即诛灭六国。） 廿有六年，上荐高号，孝道显明

（皇帝二十六年，公元前221年。群臣上表，请求秦王称皇帝号。就叫上荐高号。这个孝道，是说秦国各代国君，均有统一之志，始皇帝的统一，乃是完成祖先之道。）既献泰成，乃降专惠，亲巡远方 （溥惠，尃惠。溥就是普。我用的书里面，百度百科里面，都错成了专字。既献泰成，乃降尃惠，亲巡远方。应该是这样子才对。既，就是完成了的意思。泰成，就是大成。完成了统一大业。普惠，把恩泽给了所有的人。寴车巛，就是亲巡。从车和从辵，都是表示动作的形符。坐车出巡，就是车巛。） 登于绎山①，群臣从者，咸思攸长 （登上峄山，大家都发起了怀古之悠情。） 追念乱世，分土建邦，以开争理 （过去是乱世，起因于分土建国，就是封建制。所以，大家才会去争斗。） 功战日作，流血于野，自泰古始 （功战就是攻战。自太古以来就是如此。） 世无万数，，阤yi3及五帝，莫能禁止 （无数代以来，到五帝时代，都不能禁止。阤，延续。） 廼今皇帝，壹家天下，兵不复起 （如今统一了，不再打仗了。） 灾害灭除，黔首康定，利泽长久 （黔首，就是百姓。） 群臣诵略，刻此乐石，以箸经纪 （诵略，因为皇帝的功德是说不完的，所以，大臣说的，只是大略。是为诵略。经纪，就是法度，秩序。） 以上内容，是始皇帝的刻辞。下面，是秦二世的内容。上面的是四言诗。下面的，是散文了。 皇帝曰：‘金石刻尽始皇帝所为也，令袭号而金石刻辞不称始皇帝。其于久远也，如后嗣为之者，不称成功盛德。丞相臣斯、臣去疾、御史大夫臣德昧死言：‘请具刻诏书，金石刻因明白矣。’臣昧死请。制曰：“可’。” 译文 皇帝立国，维初在昔，嗣世称王 讨伐乱逆，威动四极，武义直方戍臣奉诏，经时不久，灭六暴强

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晋灵公不君（宣公二年） 原文： 晋灵公不君。厚敛以雕墙。从台上弹人，而观其辟丸也。宰夫胹熊蹯不熟，杀之，寘诸畚，使妇人载以过朝。赵盾、士季见其手，问其故而患之。将谏，士季曰：“谏而不入，则莫之继也。会请先，不入，则子继之。”三进及溜，而后视之，曰：“吾知所过矣，将改之。”稽首而对曰：“人谁无过？过而能改，善莫大焉。诗曰：‘靡不有初，鲜克有终。’夫如是，则能补过者鲜矣。君能有终，则社稷之固也，岂惟群臣赖之。又曰：‘衮职有阙，惟仲山甫补之。’能补过也。君能补过，衮不废矣。” 犹不改。宣子骤谏，公患之，使鉏麑贼之。晨往，寝门辟矣，盛服将朝。尚早，坐而假寐。麑退，叹而言曰：“不忘恭敬，民之主也。贼民之主，不忠；弃君之命，不信。有一于此，不如死也！”触槐而死。 秋九月，晋侯饮赵盾酒，伏甲将攻之。其右提弥明知之，趋登曰：“臣侍君宴，过三爵，非礼也。”遂扶以下。公嗾夫獒焉。明搏而杀之。盾曰：“弃人用犬，虽猛何为！”斗且出。提弥明死之。 初，宣子田于首山，舍于翳桑。见灵辄饿，问其病。曰：“不食三日矣！”食之，舍其半。问之，曰：“宦三年矣，未知母之存否。今近焉，请以遗之。”使尽之，而为之箪食与肉，寘诸橐以与之。既而与为公介，倒戟以御公徒，而免之。问何故，对曰：“翳桑之饿人也。”问其名居，不告而退。——遂自亡也。 乙丑，赵穿①攻灵公于桃园。宣子未出山而复。大史书曰：“赵盾弑其君。”以示于朝。宣子曰：“不然。”对曰：“子为正卿，亡不越竟，反不讨贼，非子而谁？”宣子曰：“呜呼!‘我之怀矣，自诒伊戚。’其我之谓矣。” 孔子曰：“董狐，古之良史也，书法不隐。赵宣子，古之良大夫也，为法受恶。惜也，越竞乃免。” 译文： 晋灵公不行君王之道。他向人民收取沉重的税赋以雕饰宫墙。他从高台上用弹弓弹人，然后观赏他们躲避弹丸的样子。他的厨子做熊掌，没有炖熟，晋灵公就把他杀了，把他的尸体装在草筐中，让宫女用车载着经过朝廷。赵盾和士季看到露出来的手臂，询问原由后感到很忧虑。他们准备向晋灵公进谏，士季说：“如果您去进谏而君王不听，那就没有人能够再接着进谏了。还请让我先来吧，不行的话，您再接着来。”士季往前走了三回，行了三回礼，一直到屋檐下，晋灵公才抬头看他。晋灵公说：“我知道我的过错了，我会改过的。”士季叩头回答道：“谁能没有过错呢？有过错而能改掉，这就是最大的善事了。《诗经》说：‘没有人向善没有一个开始的，但却很少有坚持到底的。’如果是这样，那么能弥补过失的人是很少的。您如能坚持向善，那么江山就稳固了，不只是大臣们有所依靠啊。

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消化病科疾病分级诊疗指南 嗜酸性粒细胞性胃肠炎（EG） 嗜酸性粒细胞性胃肠炎是以胃肠道嗜酸性粒细胞浸润、胃肠道水肿增厚为特点的胃肠道炎症性疾病，临床表现为腹痛或不适、恶心、呕吐等，部分可出现肠梗阻及腹水，病变亦可累及肝胆系统，引起黄疸。 嗜酸性粒细胞性胃肠炎分类 一、按部位分类 1.局限性：多见于中老年，病变仅累及胃，约占EG26%，此型又称嗜酸性粒细胞性胃炎。胃窦部最常见，主要表现为上腹部的痉挛性疼痛、恶心呕吐等，胃内的肿块可以导致恶变或胃流出道梗阻。 2.弥漫性：多见于中青年，主要表现为上腹部痉挛性疼痛、恶心及呕吐，发作有规律，可能与进食某种食物有关，约占50%患者可出现肠梗阻表现。 二、按浸润程度分类（Klein分型） 1.粘膜型：此型病变主要累及胃肠粘膜。患者可有过敏性病史及较高的血IgE浓度，其临床表现为胃肠道蛋白丢失、贫血、吸收不良、体重下降及腹泻等； 2.肌层型：此型病变主要累及肌层，其临床表现为梗阻，这种梗阻有时需要手术治疗，另外，还偶有胃肠道出血和瘘

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列阵，摆开阵势。 [3]邴夏：齐国大夫。御，动词，驾车。御齐侯，给齐侯驾车。齐侯，齐国国君，指齐顷公。 [4]逢丑父：齐国大夫。右：车右。 [5]解张、郑丘缓：都是晋臣，郑丘是复姓。郤（x ）克，晋国大夫，是这次战争中晋军的主帅。又称郤献子、郤子等。 [6]姑：副词，姑且。翦灭：消灭，灭掉。朝食：早饭。这里是吃早饭的意思。这句话是成语灭此朝食的出处。 [7]不介马：不给马披甲。介：甲。这里用作动词，披甲。驰之：驱马追击敌人。之：代词，指晋军。 [8] 未绝鼓音：鼓声不断。古代车战，主帅居中，亲掌旗鼓，指挥军队。兵以鼓进，击鼓是进军的号令。 [9] 病：负伤。 [10]张侯，即解张。张是字，侯是名，人名、字连用，先字后名。 [11]合：交战。贯：穿。肘：胳膊。 [12]朱：大红色。殷：深红色、黑红色。 [13]吾子：您，尊敬。比说子更亲切。 [14]苟：连词，表示假设。险：险阻，指难走的路。 [15]识：知道。之，代词，代苟有险，余必下推车这件事，可不译。 [16]师之耳目：军队的耳、目（指注意力）。在吾旗鼓：在我们

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嗜酸性粒细胞

嗜酸性粒细胞 嗜酸性粒细胞是白细胞的一种。白细胞根据形态差异可分为颗粒和无颗粒两大类。颗 粒白细胞（粒细胞）中含有特殊染色颗粒，用瑞氏染料染色可分辨出三种颗粒白细胞 即中性粒细胞、嗜酸性粒细胞和嗜碱性粒细胞；无颗粒白细胞包括单核细胞和淋巴细 胞。嗜酸性粒细胞具有粗大的嗜酸性颗粒，颗粒内含有过氧化物酶和酸性磷酸酶 【参考值】：嗜酸性粒细胞占白细胞总数的0.5%-3%；其绝对值为0-0.7×10^9/L。 血液中嗜酸性粒细胞的数目有明显的昼夜周期性波动，清晨细胞数减少，午夜时细胞 数增多。这种细胞数的周期性变化是与肾上腺皮质释放糖皮质激素量的昼夜波动有关 的。当血液中皮质激素浓度增高时，嗜酸性粒细胞数减少；而当皮质激素浓度降低时， 细胞数增加。嗜酸性粒细胞的胞质内含有较大的、椭圆形的嗜酸性颗粒。这类白细胞 也具有吞噬功能。 1.嗜酸性粒细胞增多 （1）.过敏性疾病 2）.寄生虫病（3）.皮肤病（4）.血液病（5）.某些恶性肿瘤（6）. 某些传染病 7）.其他：风湿性疾病、脑腺垂体功能减低症、过敏性间质性肾炎等也常 伴有嗜酸性粒细胞增多 2.嗜酸性粒细胞减少（eosinopenia）： 常见于伤寒、副伤寒初期，大手术、烧伤等应激状态，或长期应用肾上腺皮质激 素后，其临床意义甚小。 红细胞平均体积 【参考值】自动分析仪法为男性83～93FL；女性82～92FL 生理学变异】 1.升高新生儿升高约12%，妊娠约高5%。饮酒约升高4%，吸烟约升高3%。口服避孕药约升高1%。 2.降低激烈的肌肉活动约降低4%，6个月以前的儿童约降低10%。 【药物影响】 1.升高可引起巨幼红细胞贫血的药物有巴比妥酸盐、鲁米那（叶酸代谢障碍）、导眠能、苯妥英钠、非那西丁（偶尔）、氨苯喋啶、雌激素、降糖灵（致叶酸或 vitB12缺乏）、呋喃类、新霉素、异烟肼、环丝氨酸、氨基苯甲酸（诱致消化道吸收障碍所致）、氨基水杨酸、氨甲喋呤、秋水仙碱（伴vitB12缺乏），其中抗惊厥药约升高3%。 2.降低新双香豆素可发生小细胞低色素性贫血。 【病理学变异】