摘要
Fcα/μR是一种近年发现的能够与IgA、IgM结合的Fc受体,基因表达谱广泛,在小鼠多种脏器组织中均检测到其mRNA的表达。小鼠Fcα/μR(mFcα/μR)可以介导B细胞对免疫复合物的内吞,但是有关Fcα/μR生物学功能的更多研究尚在进行中。pIgR也是一种IgA、IgM受体,担负着将pIgA转运至粘膜细胞表面的重要使命,是机体粘膜免疫的重要分子。由于Fcα/μR与pIgR在染色体的基因定位相邻,且二者序列蛋白序列同源性较高,加之在与IgA、IgM结合功能方面具有相似性,因此,本论文将mFcα/μR与mpIgR进行了对比分析,以期为mFcα/μR的功能研究提供更有力的证据。
首先,本论文的研究从抗体的制备着手。通过原核表达的方法得到了mFcα/μR及mpIgR重要结构域蛋白,并以纯化过的表达蛋白为抗原免疫大鼠,制备了大鼠抗mFcα/μR及mpIgR单克隆、多克隆抗体。经过ELISA、Western blot、FACS及细胞免疫化学等方法的多次鉴定,挑选出了可以特异识别mFcα/μR及mpIgR的单克隆抗体,确定了多克隆抗体的抗原识别特异性。
为了探讨mFcα/μR的组织定位,本研究通过使用RT-PCR及免疫组织化学的方法对mFcα/μR及mpIgR的基因及蛋白水平的表达谱进行了检测和对比分析。实验证明,mFcα/μR比mpIgR的基因表达略广,在正常小鼠肝、心、脾、肺、肾、小肠、大肠、胸腺、睾丸、子宫及卵巢均有mRNA表达。但是在蛋白水平,通过使用不同的切片方法及尝试多种抗原修复条件对正常小鼠、DSS诱导肠炎模型小鼠及BSA免疫小鼠进行组织切片的免疫组织化学染色后,均未检测到mFcα/μR的表达。而同时对mpIgR的检测结果则基本与文献报道相符。综合以上实验结果,我们推测mFcα/μR可能与mpIgR发挥相似的作用,在二者同时存在时,mpIgR发挥主要作用,而mFcα/μR则保持较低的维持量表达。这种较低的表达水平可以在基因水平检测到,却可能已经超出免疫组织化学的检验灵敏度、从而无法在蛋白水平被检测到。当mpIgR功能缺陷(如mpIgR基因敲除)或mpIgR发挥功能障碍(如J链基因敲除)时,mFcα/μR可能会表达增强,从而代替mpIgR发挥转运IgA、IgM的功能。为了证明上述假设,还需开展大量的实验研究工作。
此外,我们还对大鼠Fcα/μR(rFcα/μR)的基因及蛋白表达情况进行了初步探讨。RT-PCR结果表明,rFcα/μR的基因表达谱与mFcα/μR相似,比rCD89及rpIgR表达略广,在正常大鼠肝、心、脾、肺、肾、小肠、大肠、胸腺、睾丸、子宫均有mRNA表达。使用与rFcα/μR有交叉识别的小鼠抗人Fcα/μR单抗对正常大鼠各脏器进行免疫组织化学分析,同样没有得到明显的阳性信号。由于抗体对甲醛固定后抗原的识别特异性尚不能确定,因此本部分研究结果的生物学意义还需进一步的实验验证。
本论文的工作为mFcα/μR的研究奠定了实验基础,并为mFcα/μR功能研究方向的确立提供了线索。
Fcα/μR is a newly found Fc receptor specifically for IgA and IgM.Its mRNA is expressed on several tissues in normal mouse.It was found that Fcα/μR was involved in the endocytosis of immune complexes by B cell.However,the biology function of Fcα/μR is still largely unknown at present,pIgR is also a receptor for IgA and IgM,which transcytose pIgA and pIgM cross epithelial cells,so it is an important protein in mucosal immunity. The gene location of Fcα/μR is near to pIgR on mouse and human chromosome 1,and they have high amino acid homology.In this work,we analyzed the difference between Fcα/μR and pIgR in gene expression and protein distribution,in order to explore functions of Fcα/μR.
First we prepared rat monoclone and polyclone antibodies against mouse Fcα/μR (mFcα/μR) and mouse pIgR(mpIgR).mFcα/μR and pIgR were expressed in E.coli and used as immunogen.Using ELISA,Western blot,FACS and immunocytochemistry,some mAbs was selected.We also identified the specificity of polyclone antibodies.
We detected mRNA expression of mFcα/μR and mpIgR in several tissues of normal mice. The results showed that mpIgR was not expressed as widely as mFcα/μR,which was found in liver,heart,spleen,lung,kidney,small intestine,large intestine,thymus,testicle,uterus and ovary.However,immunohistochemistry analysis showed that mFcα/μR was negative in all tissues tested.On the other hand,the mpIgR was found in many organs.So we speculate that mFcα/μR may have similar function with mpIgR,mpIgR was the main receptor when the body is under normal conditions.When mpIgR can't function properly, for example in pIgR knockout mouse or J chain knockout mouse,mFcα/μR may be expressed more and functions as mpIgR.More experiments are needed to support the hypothesis.
At the same time,we also detected mRNA expression of rat Fcα/μR.The result showed that rFcα/μR was expressed more widely than rpIgR and rCD89.However,we also got negative result when we detected the protein expression of rFcα/μR using a mouse mAb (anti-hFcα/μR).Although this is in agreement with mFcα/μR result,we still can not make a conclusion about rFcα/μR because of the uncertainty of the mAb's specificity.
Based on the above experiments and analysis,this work has provided a useful tool and some data for the study of mFcα/μR,and more work will be carried out in the future research.
引文
1.Kerr MA.The structure and function of human IgA.Biochemical Journal.1990;271(2):285-296.
2.Boes M.Role of natural and immune IgM antibodies in immune responses.Molecular Immunology.2000;37:1141-1149.
3.Pereira,P.,Forni,L.,Larsson,E.L.,et al.Autonomous activation of B and T cells in antigen-free mice.European The Journal of Immunology.1986;16:685-688.
4.Avrameas,S.Natural autoantibodies:from 'horror autotoxicus'to ‘gnothi seauton’.Immunology Today.1991;12:154.
5.Coutinho,A.,Kazatchkine,M.D.,Avrameas,S.Natural autoantibodies.Current Opintion in Immunology.1995;7:812-818.
6.Casali,P.,Schettino,E.W.Structure and function of naturaantibodies.Current Topics in Microbiology and Immunology.1996;210:167-179.
7.Boes M,Schmidt T,Linkemann K,Beaudette BC,et al.Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM.Proceedings of the National Academy of Sciences,U S A.2000;97:1184-1189.
8.Ehrenstein MR,Cook HT,Neuberger MS.Deficiency in serum immunoglobulin (Ig)M predisposes to development of IgG autoantibodies.The Journal of Experimental Medicine.2000;191:1253-1258.
9.Daeron M.Fc receptor biology.Annual Review of Immunology.1997;15:203-234.
10.Ravetch JV.Fc receptors.Current Opintion in Immunology.1997;9:121-125.
11.Ravetch JV,Clynes RA.Divergent roles for Fc receptors and complement in vivo.Annual Review of Immunology.1998;16:421-432.
12.Dombrowicz D,Flamand V,Brigman KK,et al.Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor alpha chain gene.Cell.1993;75:969-976.
13.Fujiwara H,Kikutani H,Suematsu S,et al.The absence of IgE antibody-mediated augmentation of immune responses in CD23-deficient mice.Proceedings of the National Academy of Sciences,U S A.1994;91:6835-6839.
14.Ravetch JV,Kinet JP.Fc receptors.Annual Review of Immunology.1991;9:457-492.
15.Stief A,Texido G,Sansig G,et al.Mice deficient in CD23 reveal its modulatory role in IgE production but no role in T and B cell development.The Journal of Immunology.1994;152: 3378-3390.
16.Takai T,Li M,Sylvestre D,et al.FcR gamma chain deletion results in pleiotrophic effector cell defects.Cell.1994;76:519-529.
17.Takai T,Ono M,Hikida M,et al.Augmented humoral and anaphylactic responses in Fc gamma RⅡ-deficient mice.Nature.1996;379:346-349.
18.van de Winkel JQ Capel PJ.Human IgG Fc receptor heterogeneity:molecular aspectsand clinical implications.Immunology Today.1993;14:215-221.
19.Yu P,Kosco-Vilbois M,Richards M,et al.Negative feedback regulation of IgE synthesis by murine CD23.Nature.1994;369:753-756.
20.Sylvestre DL,Ravetch JV.Fc receptors initiate the Arthus reaction:redefining the inflammatory cascade.Science.1994;265:1095-1098.
21.Ercolani L,Novogrodsky A,Suthanthiran M,et al.Expression of Fc mu receptors by human T lymphocytes:effects of enzymes,metabolic inhibitors,and X-irradiation.The Journal of Immunology.1981;127:2044-2051.
22.Mathur A,Lynch RG,Kohler G Expression,distribution and specificity of Fc receptors for IgM on murine B cells.The Journal of Immunology.1988;141:1855-1862.
23.Nakamura T,Kubagawa H,Ohno T,Cooper MD.Characterization of an IgM Fc-binding receptor on human T cells.The Journal of Immunology.1993;151:6933-6941.
24.Ohno T,Kubagawa H,Sanders SK,Cooper MD.Biochemical nature of an Fc mu receptor on human B-lineage cells.Journal of Experimental Medicine.1990;172:1165-1175.
25.Pricop L,Rabinowich H,Morel PA,et al.Characterization of the Fc mu receptor on human natural killer cells.Interaction with its physiologic ligand,human normal IgM,specificity of binding,and functional effects.The Journal of Immunology.1993;151:3018-3029.
26.Whelan CA.A functional role for Fc mu receptors on human lymphocytes.Immunology Letters.1981;3:249-254.
27.Shibuya A,Sakamoto N,Shimizu Y,et al.Fca/u receptor mediates endocytosis of IgM-coated microbes.Nature Immunology.2000;1:441-446.
28.Shimizu Y,Hinda S,Yotsumoto K,et al.Fcα/μ receptor is a single gene-family member closely related to polymeric immunoglobulin receptor encoded on Chromosome 1.Immunogenetics.2001;53:709-711.
29.Sakamoto N,Shibuya K,Shimizu Y,et al.A novel Fc receptor for IgA and IgM is expressed on both hematopoietic and non-hematopoietic tissues.European Journal of Immunology.2001;31:1310-1316.
30.Yukiko Cho,Kenta Usui,Shin-ichiro Honda,et al.Molecular characteristics of IgA and IgM Fc binding to the Fca/uR.Biochemical and Biophysical Research Communications.2006;345:474-478.
31.Kenneth J.McDonald,Angus J.M.Cameron,Janet M.Allen,et al.Expression of Fc/Receptor by Human Mesangial Cells:A Candidate Receptor for Immune Complex Deposition in IgA Nephropathy.Biochemical And Biophysical Research Communications.2002;290:438-442.
32.Hu Rui-hai,Zhang Ying,Zhao Ming-hui.Transferrin receptor and Fc α/μ receptor may not be the major IgA1 receptor on human mesangial cells.Chinese Medical Journal.2005;118:781-785.
33.Akira Shibuya,shin-ichiro Honda.Molecular and functional characteristics of the Fc α/μR,a novel Fc receptor for IgM and IgA.Springer Seminars in Immunopathology.2006;28:377-382.
1.http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=21450630
2.http://gbrowse.informatics.jax.org/cgi-bin/gbrowse/mouse_current/?start= 132628448;stop= 132642 286;ref=Chrl
3.Shimizu Y,Hinda S,Yotsumoto K,et al.Fcα/μ receptor is a single gene-family member closely related to polymeric immunoglobulin receptor encoded on Chromosome 1.Immunogenetics.2001;53:709-711.
4.Shibuya A,Sakamoto N,Shimizu Y,et al.Fc α/μ receptor mediates endocytosis of IgM-coated microbes.Nature Immunology.2000;1:441-446.
5.Akira Shibuya,shin-ichiro Honda.Molecular and functional characteristics of the Fcα/μR,a novel Fc receptor for IgM and IgA.Springer Seminars in Immunopathology.2006;28:377-382.
6.Imrnunocytochemistry.The Official Journal of the UK National External Quality Assessment Scheme for Imrnunocytochemistry,56:29-32.
7.http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=31981569
8.Piskurich JF,Blanchard MH,Youngman KR,et al.Molecular cloning of the mouse polymeric Ig receptor.Functional Regions of the molecule are conserved among five mammalian species.The Journal of Immunology.1995;154:1735-1747.
9.Martin MG,Gutierrez EM,Lam JT,et al.Genomic cloning and structural analysis of the murine polymeric receptor (plgR)gene and promoter region.Gene.1997;201 (1-2):189-197.
10.Takeshi Yanagihara,Yoshihiro Kumagai,Yoshihiko Norose,et al.Age-dependent decrease of polymeric Ig receptor expression and IgA elevation in ddY mice:a possible cause of IgA nephropathy.Laboratory Investigation.2004;84:63-70.
11.YukikoCho,Kenta Usui,Shin-ichiro Honda,et al.Molecular characteristics of IgA and IgM Fc binding to the Fca/uR.Biochemical and Biophysical Research Communications.2006;345:474-478.
12.Coyne RS,Siebrecht M,Peitsch MC,et al.Mutational analysis of polymeric immunoglobulin receptor/ligand interactions.Evidence for the involvement of multiple complementarity determining region (CDR)-like loops in receptor domain I.The Journal of Biological Chemistry.1994;269 (50):31620-5.
13.Okayasu I,Hatakeyama S,Yamada M,et al.A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice.Gastroenterology.1990;98:694-702.
14.Cooper HS,Murthy SN,Shah RS,et al.Clinicopathologic study of dextran sulfate sodium experimental murine colitis.Laboratory Investigation.1993;69:238-249.
15.Charles O.Elson,R.Balfour Sartor,Gary S.Tennyson,et al.Experimental models of inflammatory bowel disease.Gastroenterology.1995;109:1344-1367.
16.Julia M.Phillips-Quagliata,Samir Patel,Jing-Kang Han,et al.The IgA/IgM receptor expressed on a murine B cell lymphoma is poly-Ig receptor.The Journal of Immunology.2000;165:2544-2555.
17.Ve'roniqueDecot,GaetaneWoerly,MarcLoyens,et al.Heterogeneity of expression of IgA receptors by human,mouse,and rat eosinophils.The Journal of Immunology.2005;174:628-635.
18.http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=l09498592
19.http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id= 109497836
1.Shibuya A,Sakamoto N,Shimizu Y,Shibuya K,Osawa M,et al.Fca/u receptor mediates endocytosis of IgM-coated microbes.Nature.Immunology.2000;1:441-446.
2.AkiraShibuya,Shin-ichiroHonda.Molecular and functional characteristics of the Fca/uR,a novel Fc receptor for IgM and IgA.Springer Seminars in Immunopathology.2006;28:377-382.
3.YukikoCho,Kenta Usui,Shin-ichiro Honda,et al.Molecular characteristics of IgA and IgM Fc binding to the Fca/uR.Biochemical and Biophysical Research Communications.2006;345:474-478.
4.Pierre PG,Havaux XB,Langendries A et al.In:Mestecky J Russell MW,Jackson S,Michalek SM,Tlaskalova-Hogenova H,Sterzl J,eds.Advances in Mucosal Immunology:Mouse Secretory Component.New York:Plenum Press,1995;629-632.
5.M.Asano,M.Saito,H.Suguroy,H.Nomura.Active Synthesis of Mouse Polymeric Immunoglobulin Receptor in the Epithelial Cells of the Distal Urinary Tubule in Kidney.Scandinavian Journal of Immunology.2004;60:267-272.
6.Takeshi Yanagihara,Yoshihiro Kumagai,Yoshihiko Norose,et al.Age-dependent decrease of polymeric Ig receptor expression and IgA elevation in ddY mice:a possible cause of IgA nephropathy.Laboratory Investigation.2004;84:63-70.
7.Shin-ichiroShimada,MarikoKawaguchi-Miyashita,AkiraKushiro,et al.Generation of Polymeric Immunoglobulin Receptor-Deficient Mouse with Marked Reduction of Secretory IgA.The Journal of Immunology.1999;163:5367-5373.
8.Finn-Eirik Johansen,Marcela Pekna,Inger Natvig Norderhaug.Absence of Epithelial Immunoglobulin A Transport,with Increased Mucosal Leakiness,in Polymeric Immunoglobulin Receptor/Secretory Component-deficient Mice.The Journal of Experimental Medicine.1999;190:915-921.
9.Y.NAKAMURA,S.NOSAKA,M.SUZUKI,et al.Dietary fructooligosaccharides up-regulate immunoglobulin A response and polymeric immunoglobulin receptor expression in intestines of infant mice.Clinical and Experimental Immunology.2004;137:52-58.
10.Ranveig Braathen,Anders Sandvik,Goril Berntzen,et al.Identification of a Polymeric Ig Receptor Binding Phage-displayed Peptide That Exploits Epithelial Transcytosis without Dimeric IgA Competition.The Journal of biological chemistry.2006;281:7075-7081.
11.George Banting,Brigitte Brake,Paola Braghetta,et al.Intracellular targetting signals of polymeric immunoglobulin receptors are highly conserved between species.Federation of European Biochemical Societies.1989;254:177-183.
12.James C.Rice,Tao Peng,Jeff S.Spence,et al.Pyelonephritic Escherichia coli Expressing P Fimbriae Decrease Immune Response of the Mouse Kidney.Journal of the American Society of Nephrology.2005;16:3583-3591.
13.Charles Pilette,Youssef Ouadrhiri,Francoise Dimanche,et al.Secretory Component Is Cleaved by Neutrophil Serine Proteinases but its Epithelial Production Is Increased by Neutrophils through NF-kB and p38 Mitogen-Activated Protein Kinase-Dependent Mechanisms.American Journal of Respiratory Cell and Molecular Biology.2003;28:485-498.
14.AgnesE.Hamburger,AnthonyP.West,Jr.PamelaJ.Bjorkman.et al.Crystal Structure of a Polymeric Immunoglobulin Binding Fragment of the Human Polymeric Immunoglobulin Receptor.Structure,2004;12:1925-1935.
15.Coyne RS,Siebrecht M,Peitsch MC,et al.Mutational analysis of polymeric immunoglobulin receptor/ligand interactions.Evidence for the involvement of multiple complementarity determining region (CDR)-like loops in receptor domain I.The Journal of Biological Chemistry.1994;269:31620-31625.
16.Bakos MA,Widen SG,Goldblum RM et al.Expression and purification of biologically active domain I of the human polymeric immunoglobulin receptor.Molecular Immunology.1994;31:165-168.
17.Norihisa Sakamoto,Kazuko Shibuya,Katsumi Yotsumoto,et al.A novel Fc receptor for IgA and IgM is expressed on both hematopoietic and non-hematopoietic tissues.European Journal of Immunology.2001;31:1310-1316.
18.http://www.ncbi.nlm.nih.govAJmGene/ESTProfileViewer.cgi?uglisr=Mm.31821
19.http://www.ncbi.nlm.nih.govAJniGene/ESTProfileViewer.cgi?uglist=Mm.276414
20.M.Asano,M.Saito,H.Suguro,et al.Active Synthesis of Mouse Polymeric Immunoglobulin Receptor in the Epithelial Cells of the Distal Urinary Tubule in Kidney.Scandinavian Journal of Immunology.2004;60:267-272.
21.Janet F.Piskurich,May H.Blanchard,Kenneth R,et al.Molecular cloning of the mouse polymeric Ig receptor.Functional regions of the molecule are conserved among five mammalian species.The Journal of Immunology.1995;154:1735-1747.
22.Danica K.Hickey,Russell C.Jones,Shisan Bao.Intranasal immunization with C.muridarum major outer membrane protein (MOMP)and cholera toxin elicits local production of neutralising IgA in the prostate.Vaccine.2004;22:4306-4315.
23.Krajci P,Solberg R,Sandberg M,et al.Molecular cloning of the human transmembrane secretory component (poly-Ig receptor)and its mRNA expression in human tissues.Biochemical and Biophysical Research Communications.1989;158:783-789.
24.Tomasi TB,Yurchak AM.The synthesis of secretory component by the human thymus.The Journal oflmmunology.1972;108:1132-1135.
25.Abramowsky CR,Swinehart GL.Secretory immune responses in human kidneys.American Journal of Pathology.1986;125:571-577.
26.Rice JC,Megyesi J,Safirstein RL,Goldblum RM.Renal stress affects the level of polymeric immunoglobulin mRNA and urinary protein excretion of secretory component.Clinical immunology and Immunopathology.1995;76:S29.
27.Rice JC,Spence JS,Megyesi J,Safirstein RL,Goldblum RM.Regulation of the polymeric immunoglobulin receptor by water intake and vasopressin in the rat kidney.American Journal of Physiology.1998;274:F966-F977.
28.Krajci P,Meling GI,Andersen SN Secretory component mRNA and protein expression in colorectal adenomas and carcinomas.British Journal of Cancer.1996;73:1503-1510.
29.VeroniqueDecot,GaetaneWoerly,MarcLoyens,et al.Heterogeneity of Expression of IgA Receptors by Human,Mouse,and Rat Eosinophils.The Journal oflmmunology.2005;174:628-635.
30.http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id= 109498592
31.http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id= 109497836
32.http://www.ncbi.nlm.nih.gov/UniGene/ESTProfileViewer.cgi?uglist=Rn.198469
33.http://www.ncbi.nlm.nih.govAJniGene/ESTProfileViewer.cgi?uglist=Rn.29112
34.http://www.ncbi.nlm.nih.gov/UniGene/clust.cgi?UGID=409813&TAXID=10116&SEARCH=poly meric%20immunoglobulin%20receptor%20rat
35.http://www.ncbi.nlm.nih.gov/UniGene/ESTProfileViewer.cgi?uglist=Rn.54456
36.Solari R,Racine L,Tallichet C,et al.Distribution and processing of the polymeric immunoglobulin receptor in the rat hepatocyte:morphological and biochemical characterization of subcellular fractions.Journal of Histochemistry and Cytochemistry.1986;34:17-23.
37.Kaushic C,Frauendorf E,Wira CR.Polymeric immunoglobulin A receptor in the rodent female reproductive tract:influence of estradiol in the vagina and differential expression of messenger ribonucleic acid during estrous cycle.Biology of Reproduction.1997;57:958-66.
38.Richardson JM,Kaushic C,Wira CR Polymeric immunoglobin (Ig)receptor production and IgA transcytosis in polarized primary cultures of mature rat uterine epithelial cells.Biology of Reproduction.1995;53:488-498.
39.http://www.ncbi.nlm.nih.gov/UniGene/clust.cgi?UGID=1238072&TAXID=10116&SEARCH=CD8 9%20rat
40.Charles O.Elson,R.Balfour Sartor,Gary S.et al.Experimental models of inflammatory bowel disease.Gastroenterology.1995;109:1344-1367.
41.Charles O.Elson,Yingzi Cong,Robin Lorenz et al.New developments in experimental models of inflammatory bowel disease.Current Opinion in Gastroenterology.2004;20:360-367.
42.Charles O.Elson,Yingzi Cong,Vance J.McCracken et al.Experimental models of inflammatory bowel disease reveal innate,adaptive,and regulatory mechanisms of host dialogue with the microbiota.Immunological Reviews.2005;206:260-276.
43.M.Asano,M.Saito,H.Suguroy,et al.Active Synthesis of Mouse Polymeric Immunoglobulin Receptor in the Epithelial Cells of the Distal Urinary Tubule in Kidney.Scandinavian Journal of Immunology.2004;60:267-272.
44.Takeshi Yanagihara,Yoshihiro Kumagai,Yoshihiko Norose,et al.Age-dependent decrease of polymeric Ig receptor expression and IgA elevation in ddY mice:a possible cause of IgA nephropathy.Laboratory Investigation.2004,84:63-67.
45.Abramowsky CR,Swinehart GL.Secretory immune responses in human kidneys.American Journal of Pathology.1986;125:571-577.
46.van der Boog PJ,van Kooten C,van Zandbergen G,et al.Injection of recombinant FcalphaRI/CD89 in mice does not induce mesangial IgA deposition.Nephrology Dialysis Transplantation.2004;19: 2729-2736.
47.Amore A,Coppo R,Nedrud JG The role of nasal tolerance in a model of IgA nephropathy induced in mice by Sendai virus.Clinical Immunology.2004;113:101-108.
48.Emancipator,S.N.,and M.E.Lamm..IgA nephropathy and related diseases.In Handbook of Mucosal Immunology.P.L.Ogra,M.E.Lamm,J.R.McGhee,J.Mestecky,W.Strober,and J.Bienenstock,eds.Academic,San.Diego,CA,1994:663.
49.Giugliano LG,Ribeiro STG,Vainstein MH,et al.Free secretory component and lactoferrin of human milk inhibit the adhesion of enterotoxigenic Escherichia coli.Journal of Medical Microbiology.1995;42:3-9.
50.Homer L.Twigg Ⅲ.Humoral immune defense (antibodies):recent advances.Proceedings of the American Thoracic Society.2005;2:417-421.
51.Jiao X,Hirano T,Hou Y,et al.Specific immune responses and enhancement of murine pulmonary clearance of Moraxella catarrhalis by intranasal immunization with a detoxified lipooligosaccharide conjugate vaccine.Infection and Immunity.2002;70:5982-5989.
52.Jarvinen LZ,Hogenesch H,Suckow MA,et al.Induction of protective immunity in rabbits by coadministration of inactivated Pasteurella multocida toxin and potassium thiocyanate extract.Infection and Immunity.1998;66:3788-3795.
53.Griffiths GD,Bailey SC,Hambrook JL,et al.Local and systemic responses against ricin toxin promoted by toxoid or peptide vaccines alone or in liposomal formulations.Vaccine.1998;16:530-535.
54.Shimada S,Kawaguchi-Miyashita M,Kushiro A,et al.Generation of polymeric immunoglobulin receptor-deficient mouse with marked reduction of secretory IgA.The Journal of Immunology.1999;163:5367-5373.
55.Johansen FE,Pekna M,Norderhaug IN,et al.Absence of epithelial immunoglobulin A transport,with increased mucosal leakiness,in polymeric immunoglobulin receptor/secretory component-deficient mice.The Journal of Experimental Medicine.1999;190:915-922.
56.Tjarnlund A,Rodriguez A,Cardona PJ,et al.Polymeric IgR knockout mice are more susceptible to mycobacterial infections in the respiratory tract than wild-type mice.International Immunology.2006;18:807-816.
57.Hendrickson BA,Rindisbacher L,Corthesy B,et al.Lack of association of secretory component with IgA in J chain-deficient mice.The Journal of Immunology.1996;157:750-754.
58.Abdalla Rifai,Kim Fadden,Sherie L.Morrison,et al.The N-Glycans determine the differential blood clearance and hepatic uptake of Human Immunoglobulin (Ig)Al and IgA2 Isotypes.The Journal of Experimental Medicine.2000;191:2171-2181.
59.Moura,I.C.,M.N.Centelles,et al.Identification of the transferrin receptor as a novel immunoglobulin (Ig)Al receptor and its enhanced expression on mesangial cells in IgA nephropathy.The Journal of Experimental Medicine.2001;194:417.
60.JuliaM.Phillips-Quagliata,SamirPatel,Jing-KangHan,et al.The IgA/IgM receptor expressed on a murine B Cel lymphoma Is poly-Ig receptor.The Journal oflmmunology.2000;165:2544-2555.
61.Julia M.Phillips-Quagliata,Ana M.C.Faria,Jingkang Han,et al.IgG2a and IgA Co-Expression by the natural autoantibody-producing murine B lymphoma T560.Autoimmunity.2001;33:181-197.
1.Lamm ME.Interaction of antigens and antibodies at mucosal surfaces.Annual Review of Microbiology.1997;51:311-340.
2.Brandtzaeg P,et al.Mucosal immunity-a major adaptive defence mechanism.Behring Institute Mitteilungen.1997;98:1-23.
3.Norderhaug IN,Johansen FE,Schjerven H,et al.Regulation of the formation and external transport of secretory immunoglobulins.Critical Reviews in Immunology.1999;19:481-508.
4.Kaerzel CS,Mostov K.Immunoglobulin transport and the polymeric immunoglobulin receptor.In:Mestecky J,Bienenstock J,Lamm M,Stober W,McGhee J,Myer I.Eds.Mucosal Immunology.3rd edn.San Diego:Academic Press 2005,211-250.
5.Conley ME,Delacroix D L.Intravascular and mucosal immunoglobulin A.two separate but related systems of immune defense? Annals of internal medicine 1987;106:892-899.
6.Tomasi TB Jr,Tan E M,Solomon A,Prendergast R A.Characteristics of an immune system common to certain external secretions.The Journal of Experimental Medicine.1965;121:101-124.
7.Mostov KE,Kraehenbuhl J-P,Blobel G Receptor-mediated transcellular transport of immunoglobulin:synthesis of secretory component as multiple and larger transmembrane forms.Proceedings of the National Academy of Sciences of the United States of America.1980;77:7257-7261.
8.Charlotte S.Kaetzel.The polymeric immunoglobulin receptor:bridging innate and adaptive immune responses at mucosal surfaces.Immunological Reviews.2005;206:83-99.
9.Martin MG,et al.Characterization of the 5'-flanking region of the murine polymeric IgA receptor gene.The American Journal of Physiology.1998;275:G778-G788.
10.Johansen F E.Bosloven B A,Krajci P.Brandtzaeg P.A composite DNA element in the promoter of the polymeric immunoglobulin receptor regulates its constitutive expression.European Journal of Immunology.1998;28:1161-1171.
11.Hempen P M,et al.Transcriptional regulation of human polymeric Ig receptor gene:analysis of basal promoter elements.The Journal of Immunology.2002;169:1912-1921.
12.Solorzano-Vargas RS,et al.Multiple transcription factors in 5'-flanking region of human polymeric Ig receptor control its basal expression.American Journal of Phsiology.Gastrointestinal and Liver Physiology.2002;283:G415-G425
13.Blanch VJ,Piskurich JF,Kaetzel CS.Cutting edge:coordinate regulation of IFN regulatory factor-1 and the polymeric Ig receptor by proinflammatory cytokines.The Journal of Immunology.1999;162:1232-1235.
14.Pine R.Convergence of TNFalpha and IFNgamma signalling pathways through synergistic induction of IRF-l/ISGF-2 is mediated by a composite GAS/kappaB promoter element.Nucleic Acids Research.1997;25:4346-4354.
15.Ackermann LW,Denning GM.Nuclear factor-KB contrubutes to interleukin-4 and interferon-dependent polymeric immunoglobulin receptor expression in human intestinal epithelial cells.Immunology.2004;111:75-85.
16.Schjerven H,Brandtzaeg P,Johansen FE.A novel NF-KB/Rel site in intron 1 cooperates with proximal promoter elements to mediate TNF-a induced transcription of the human polymeric Ig receptor.The Journal of Immunology.2001;167:6412-6420.
17.Schjerven H,Tran TN,Brandtzaeg P,et al.De novo synthesized RelB mediates TNF-induced up-regulation of the human polymeric Ig receptor.The Journal of Immunology.2004;173:1849-1857.
18.Bruno MEC,Kaetzel CS.Long-term exposure of the HT-29 human intestinal epithelial cell line to TNF causes sustained up-regulation of the polymeric Ig receptor and proinflammatory genes through transcriptional and posttranscriptional mechanisms.The Journal of Immunology.2005;174:7278-7284.
19.Ackermann LW,Wollenweber LA,Denning GM.IL-4 and IFN-γ increase steady state levels of polymeric Ig receptor mRNA in human airway and intestinal epithelial cells.The Journal of Immunology.1999;162:5112-5118.
20.Loman S,Jansen HM,Out TA,et al.Interleukin-4 and interferon-γ synergistically increase secretory component gene expression,but are additive in stimulating secretory immunoglobulin A release by Calu-3 airway epithelial cells.Immunology.1999;96:537-543.
21.Schjerven H,Brandtzaeg P,Johansen FE.Mechanism of IL-4-mediated up-regulation of the polymeric Ig receptor:role of STAT6 in cell type-specific delayed transcriptional response.The Journal of Immunology.2000;165:3898-3906.
22.Bjercke S,Brandtzaeg P.Glandular distribution of immunoglobulins,J chain,secretory component, and HLA-DR in the human endometrium throughout the menstrual cycle.Human Reproduction.1993;8:1420-1425.
23.Kaushic C,Richardson JM,Wira CR.Regulation of polymeric immunoglobulin:A receptor messenger ribonucleic acid expression in rodent uteri:effect of sex hormones.Endocrinology.1995;136:2836-2844.
24.Claessens F,et al.Selective DNA binding by the androgen receptor as a mechanism for hormone-specific gene regulation.The Journal of Steroid Biochemistry and Molecular Biology.2001;76:23-30.
25.Yu-Lee L.Stimulation of interferon regulatory factor-1 by prolactin.Lupus.2001;10:691-699.
26.Chapman RS,et al.A novel role for IRF-1 as a suppressor of apoptosis.Oncogene.2000;19:6386-6391.
27.Kvale D,Brandtzaeg P.Constitutive and cytokine induced expression of HLA molecules,secretory component,and intercellular adhesion molecule-1 is modulated by butyrate in the colonic epithelial cell line HT-29.Gut.1995;36:737-742.
28.Fernandez MI,Pedron T,Tournebize R,et al.Anti-inflammatory role for intracellular dimeric immunoglobulin A by neutralization of lipopolysaccharide in epithelial cells.Immunity.2003;18:739-749.
29.Pal K,Kaetzel CS,Brundage K,et al.Regulation of polymeric immunoglobulin receptor (pIgR)expression by reovirus.The Journal of General Virology.2005;86:2347-2357.
30.Brandtzaeg P,Johansen FE.Confusion about the polymeric Ig receptor.Trends in Immunology.2001;22:545-546.
31.Walter Hunziker,Jean-Pierre Kraehenbuhl.Epithelial transcytosis of immunoglobulins.Journal of Mammary Gland Biology and Neoplasia.1998;3 (3):287-302.
32.Hamburger AE,West AP Jr,Bjorkman PJ.Crystal structure of a polymeric immunoglobulin binding fragment of the human polymeric immunoglobulin receptor.Structure.2004;12:1925-1935.
33.Braathen R,Sorensen V,Brandtzaeg P,et al.The carboxy-terminal domains of IgA and IgM direct isotype-specific polymerization and interaction with the polymeric immunoglobulin receptor.Journal of Biological Chemistry.2002;277:42755-42762.
34.Johansen FE,Braathen R,Brandtzaeg P.Role fo J chain in secretory immunoglobulin formation.Scandinavian Journal of Immunology.2000;52:240-248.
35.Hendrickson BA,et al.Altered hepatic transport of immunoglobulin A in mice lacking the J chain.The Journal of Experimental Medicine.1995;182:1905-1911.
36.Hendrickson BA,et al.Lack of association of secretory component with IgA in J chain-deficient mice.The Journal of Immunology.1996;157:750-754.
37.Lycke N,Erlandsson L,Ekman L,et al.Lack of J chain inhibits the transport of gut IgA and abrogates the development of intestinal antitoxic protection.The Journal of Immunology.1999;163:913-919.
38.Gan Y-J,Chodosh J,Morgan A,et al.Epithelial cell polarization is a determinant in the infectious outcome of immunoglobulin A-mediated entry by Epstein-Barr virus,the Journal of Virology.1997;71:519-526.
39.Yan H,Lamm ME,Bjorling E,et al.Multiple functions of immunoglobulin A in mucosal defense against viruses:an in vitro measles virus model.The Journal of Virology.2002;76:10972-10979.
40.Zhang JR,et al.The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells.Cell.2000;102:827-837.
41.Raul Rojas,Gerard Apodaca.Immunoglobulin Transport across polarized epithelial cells.Nature reviews.Molecular cell biology.2002;3:1-12.
42.Elm C,et al.Ectodomains 3 and 4 of human polymeric immunoglobulin receotor (hpIgR)mediate invasion of Streptococcus pneumoniae into the epithelium.Journal of Biological Chemistry.2004;279:6269-6304.
43.Eiffert H,et al.Determination of the molecular structure of the human free secretory component.Biological Chemistry Hoppe-Seyler.1991;372:119-128.
44.Hughes GJ,Reason AJ,Savoy L,et al.Carbohydrate moieties in human secretory component.Biochim Biophys Acta.1999;1434:86-93
45.Phalipon A,Corthesy B.Novel function of the polymeric Ig receptor:well beyond transport of immunoglobulin.Tends in Immunology.2003;24:55-58.
46.Mostov K,Su T,ter Beest M.Polarized epithelial membrane traffic:conservation and plasticity.Nature.Cell Biology.2003;5:287-293.
47.Eiffert H,et al.The primary structure of the human free secretory component and the arragement of the disulfide bonds.Hoppe-Seyler's Zeitschrift fur Physiologische Chemie.1984;365:1489-1495.
48.Musil LS,Baenzger JU.Cleavage of membrane secretory component to soluble secretory component occurs on the cell surface of rat hepatocyte monolayers.The Journal of Cell Biology.1987;104:1725-1733.
49.Musil LS,Baenziger JU.Proteolytic processing of rat liver membrane secretory component.Cleavage activity is localized to bile canalicular membranes.Journal of Biological Chemistry.1988;263:15799-15808.
50.Solari R,Schaerer E,Tallichet C,et al.Cellular location of the cleavage event of the polymeric immunoglobulin receptor and fate of its anchoring domain in the rat hepatocyte.Biochemical Journal.1989;257:759-768.
51.Breitfeld PP,Harris JM,Mostov KE,et al.Postendocytotic sorting of the ligand for the polymeric immunoglobulin receptor in Madin-Dardy canine kidney cells.Journal of Cell Biology.1989;109:475-486.
52.Sztul E,Colombo M,Stahl P,et al.Control of protein traffic between distinct plasma membrane domains.Requirement for a novel 108,000 protein in the fusion of transcytotic vesicles with the apical plasma membrane.Journal of Biological Chemistry.1993;268:1876-1885.
53.Pilette C,Ouadrhiri Y,Dimanche F,et al.Secretory component is cleaved by neutrophil serine proteinases but its epithelial production is increased by neutrophils through NF-kB and p38 mitogen-activated protein kinase-dependent mechanisms.American Journal of Respiratory Cell and Molecular Biology.2003;28:485-498.
54.Chintalacharuvu KR,Piskurich JF,Lamm ME,et al.Cell polarity regulates the release of secretory component,the epithelial receptor for polymeric immunoglobulins,from the surface of HT-29 colon carcinoma cells.Journal of Cellular Physiology.1991;148:35-47
55.Deitcher DL,Neutra MR,Mostov KE.Functional expression of the polymeric immunoglobulin receptor from cloned cDNA in fibroblasts.Journal of Cell Biology.1986;102:811-919.
56.Asano M,et al.Multiple cleavage sites for polymeric immunoglobulin receptor.Immunology.2004;112:583-589.
57.Hirunsatit R,et al.Polymeric immunoglobulin receptor polymorphisms and risk of nasopharyngeal cancer.BMC Genet 2003;4:3.
58.Obara W,et al.Association of single-nucleotide polymorphisms in the polymeric immunoglobulin receptor gene with immunoglobulin A nephropathy (IgAN)in Japanese patients.Journal of human genetics.2003;48:293-299.
59.Renegar KB,Jackson GD,Mestecky J.In vitro comparison of the biologic activities of monoclonal monomelic IgA,polymeric IgA,and secretory IgA.The Journal of Immunology.1998;160:1219-1223.
60.Lindh E.Increased resistance of immunoglobulin A dimmers to proteolytic degradation after binding of secretory component.The Journal of Immunology.1975;1975:284-286.
61.Mestecky J,Lue C,Russell MW.Selective transport of IgA.Cellular and molecular aspects.Gastroenterology Clinics of North America.1991;20:441-471.
62.Uren TK,Johansen FE,Wijburg OL,Koentgen F,Brandtzaeg P,Strugnell RA.Role of the polymeric Ig receptor in mucosal B cell homeostasis.The Journal of Immumolog.2003;170:2531-2539.
63.Sun K,Johansen FE,Eckmann L,Metzger DM.An important role for polymeric Ig receptor-mediated transport of IgA in protection against Streptococcus pneumoniae nasopharyngeal carriage.The Journal of Immumolog.2004;173:4576-4581.
64.Kaetzel CS.Polymeric Ig receptor:defender of the fort or Trojan horse? Current Biology.2001;11:R35-R38.
65.Dallas SD,Rolfe RD.Binding of Clostridium difficile toxin A to human milk secretory component.Journal of Medical Microbiology.1998;47:879-888.
66.de Oliveira IR,de Araujo AN,Bao SN,Giugliano LG Binding of lactoferrin and free secretory component to enterotoxigenic Escherichia coli.FEMS Microbiology Letters.2001;203:29-33.
67.Marshall LJ,Perks B,Ferkol T,Shute JK.IL-8 released constitutively by primary bronchial epithelial cells in culture forms an inactive complex with secretory component.The Journal of Immunology.2001;167:2816-2823.