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Isolator and other neonatal piglet models in developmental immunology and identification of virulence factors*

Published online by Cambridge University Press:  10 February 2009

J. E. Butler*
Affiliation:
Department of Microbiology, University of Iowa College of Medicine, Iowa City, IA 52242-1109, USA

Abstract

The postnatal period is a ‘critical window’, a time when innate and passive immunity protect the newborn mammal while its own adaptive immune system is developing. Neonatal piglets, especially those reared in isolators, provide valuable tools for studying immunological development during this period, since environmental factors that cause ambiguity in studies with conventional animals are controlled by the experimenter. However, these models have limited value unless the swine immune system is first characterized and the necessary immunological reagents developed. Characterization has revealed numerous features of the swine immune system that did not fit mouse paradigms but may be more generally true for most mammals. These include fetal class switch recombination that is uncoupled from somatic hypermutation, the relative importance of the molecular mechanisms used to develop the antibody repertoire, the role of gut lymphoid tissue in that process, and the limited heavy chain repertoire but diverse IgG subclass repertoire. Knowledge gained from studies of adaptive immunity in isolator-reared neonatal pigs suggests that isolator piglets can be valuable in identification of virulence factors that are often masked in studies using conventional animals.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2009

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Footnotes

*

Based on the American Association of Veterinary Immunologists’ (AAVI) Award talk at the Conference of Research Workers in Animal Diseases Annual Meeting, Chicago, IL, 2 December 2007.

References

Albina, E, Piriou, L, Hutet, E, Cariolet, R and Hospitalier, R (1998). Immune responses in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). Veterinary Immunology and Immunopathology 61: 4966.Google Scholar
Allan, GM and Ellis, JA (2000). Porcine circoviruses: a review. Journal of Veterinary Diagnostic Investigation 12: 314.Google Scholar
Bailey, M, Miller, BG, Telemo, E, Stokes, CR and Bourne, FJ (1994). Altered immune responses to proteins fed after neonatal exposure of piglets to the antigen. International Archives of Allergy and Immunology 103: 183187.Google Scholar
Barratt, MEJ, Strachan, PJ and Porter, P (1978). Antibody mechanisms implicated in digestive disturbances following ingestion of soya proteins in claves and piglets. Clinical and Experimental Immunology 31: 305312.Google Scholar
Bautista, EM and Molitor, TW (1997). Cell-mediated immunity to porcine reproductive and respiratory syndrome virus in swine. Viral Immunology 10: 8394.Google Scholar
Becker, RS and Knight, KL (1990). Somatic diversification of immunoglobulin heavy chain VDJ genes: evidence for somatic gene conversion in rabbits. Cell 63: 987997.Google Scholar
Benfield, DA, Nelson, E, Collins, JE, Harris, L, Goyal, D, Robison, W, Christianson, T, Morrison, RB, Gorcyca, D and Chladek, D (1992). Characterization of swine infertility and respiratory syndrome (SIRS) virus (isolate ATCC VR-2332). Journal of Veterinary Diagnostic Investigation 4: 127133.Google Scholar
Blutt, SE, Crawford, SE, Warfield, KL, Lewis, DE, Estes, MK and Conner, ME (2004). The VP7 outer capsid protein of rotavirus induces polyclonal B-cell activation. Journal of Virology 78: 69746981.Google Scholar
Bradley, DS, Broen, JJ and Cafruny, WA (1991). Infection of SCID mice with lactate dehydrogenase-elevating virus stimulates B cell activation. Viral Immunology 4: 5970.Google Scholar
Butler, JE (1974). Immunoglobulins of the mammary secretions. In: Larson, BL and Smith, V (eds) Lactation, A Comprehensive Treatise. Vol. III. New York: Academic Press, pp. 217255.Google Scholar
Butler, JE (2006). Preface: why I agreed to do this. Antibody repertoire development. Developmental and Comparative Immunology 30: 117.Google Scholar
Butler, JE and Kehrle, ME (2005). Immunocytes and immunoglobulins in milk. In: Mestecky, J, Lamm, ME, Strober, W, McGhee, JR, Mayer, L and Bienenstock, J (eds) Mucosal Immunology. 3rd edn. New York: Academic Press, pp. 17631793.Google Scholar
Butler, JE and Wertz, N (2006). Antibody repertoire development in fetal and neonatal pigs. XVII. IgG subclass transcription in newborns revisited with emphasis on new IgG3. Journal of Immunology 177: 54805489.Google Scholar
Butler, JE and Sinkora, M (2007). The isolator piglet: A model for studying the development of adaptive immunity. Immunologic Research 39: 3351.Google Scholar
Butler, JE, Sun, J and Navarro, P (1996). The swine immunoglobulin heavy chain locus has a single JH and no identifiable IgD. International Immunology 8: 18971904.CrossRefGoogle Scholar
Butler, JE, Weber, M, Sinkora, M, Sun, J, Ford, SJ and Christenson, R (2000a). Antibody repertoire development in fetal and neonatal piglets. II. Characterization of heavy chain CDR3 diversity in the developing fetus. Journal of Immunology 165: 69997011.Google Scholar
Butler, JE, Sun, J, Weber, P and Francis, D (2000b). Antibody repertoire development in fetal and neonatal piglets. III. Colonization of the gastrointestinal tracts results in preferential diversification of the pre-immune mucosal B-cell repertoire. Immunology 100: 119130.CrossRefGoogle Scholar
Butler, JE, Sun, J, Weber, P, Ford, SP, Rehakova, Z, Sinkora, J and Lager, K (2001). Antibody repertoire development in fetal and neonatal piglets. IV. Switch recombination, primarily in fetal thymus occurs independent of environmental antigen and is only weakly associated with repertoire diversification. Journal of Immunology 167: 32393249.CrossRefGoogle ScholarPubMed
Butler, JE, Weber, P, Sinkora, M, Baker, D, Schoenherr, A, Mayer, B and Francis, D (2002). Antibody repertoire development in fetal and neonatal piglets. VIII. Colonization is required for newborn piglets to make serum antibodies to T-dependent and type 2 T-independent antigens. Journal of Immunology 169: 68226830.CrossRefGoogle ScholarPubMed
Butler, JE, Wertz, N, Wang, H, Sun, J, Chardon, P, Piumi, F and Wells, K (2004). Antibody repertoire in fetal and neonatal pigs. VII. Characterization of the pre-immune kappa light chain repertoire. Journal of Immunology 173: 67946805.CrossRefGoogle Scholar
Butler, JE, Wertz, N, Sun, J and Sacco, R (2005a). Characterization of the porcine V b repertoire in thymocytes versus peripheral T-cells. Immunology 114: 84193.Google Scholar
Butler, JE, Wertz, N, Sun, J, Wang, H, Lemke, C, Chardon, P, Puimi, F and Wells, K (2005b). The pre-immune variable kappa repertoire of swine is selectively generated from certain subfamilies of V k 2 and one J k gene. Veterinary Immunology and Immunopathology 108: 127137.Google Scholar
Butler, JE, Francis, D, Freeling, J, Weber, P, Sun, J and Krieg, AM (2005c). Antibody repertoire development in fetal and neonatal piglets. IX. Three PAMPs act synergistically to allow germfree piglets to respond to TI-2 and TD antigens. Journal of Immunology 175: 67726785.Google Scholar
Butler, JE, Sinkora, M, Wertz, N, Holtmeier, W and Lemke, CD (2006a). Development of the neonatal B- and T-cell repertoire in swine: implications for comparative and veterinary immunology. Veterinary Research 37: 417441.CrossRefGoogle ScholarPubMed
Butler, JE, Weber, P and Wertz, N (2006b). Antibody repertoire development in fetal and neonatal pigs. XIII. “Hybrid VH genes” and the pre-immune repertoire re-visited. Journal of Immunology 177: 54595470.Google Scholar
Butler, JE, Lemke, CD, Weber, P, Sinkora, M and Lager, KD (2007). Antibody repertoire development in fetal and neonatal piglets. XIX. Undiversified B cells with hydrophobic HCDR3s preferentially proliferate in PRRS. Journal of Immunology 178: 63206331.Google Scholar
Butler, JE, Lager, KM, Splichal, I, Francis, D, Kacskovics, I, Sinkora, M, Wertz, N, Sun, J, Zhao, Y, Brown, WR, DeWald, R, Dierks, S, Muyldermanns, S, Lunney, JK, McCray, PB, Rogers, CS, Welsh, MJ, Navarro, P, Klobasa, F, Habe, F and Ramsoondar, J (2008a). The piglet as a model for studying the development of adaptive immunity. Veterinary Immunology and Immunopathology (in press).Google Scholar
Butler, JE, Wertz, N, Deschacht, N and Kacskovics, I (2008b). Porcine IgG: Structure, genetics and evolution. Immunogenetics doi:10.1007/00251-008-03369Google ScholarPubMed
Butler, JE, Weber, P, Wertz, N and Lager, KM (2008c). Porcine reproductive and respiratory syndrome virus (PRRSV) subverts normal development of adaptive immunity by proliferation of germline-encoded B cells with hydrophobic HCDR3s. Journal of Immunology 180: 23472356.Google Scholar
Cafruny, WA and Hovinen, DE (1988). Infection of mice with lactate dehydrogenase-elevating virus leads to stimulation of autoantibodies. Journal of General Virology 69: 723729.CrossRefGoogle ScholarPubMed
Cafruny, WA and Plagemann, PGW (1982). Immune response to lactate dehydrogenase elevating virus: isolation of infectious virus-immunoglobulin complexes and quantitation of specific anti-viral immunoglobulin G response in wild-type and nude mice. Infection and Immunity 37: 10011006.CrossRefGoogle Scholar
Cheung, AK, Lager, KM, Kohutyuk, OI, Vincent, AL, Henry, SC, Baker, RB, Rowland, RR and Dunham, AG (2007). Detection of two porcine circovirus type 2 genotypic groups in United States swine herds. Archives of Virology 152: 10351044.Google Scholar
Chianini, F, Majo, N, Segales, J, Dominguez, J and Domingo, M (2003). Immunohistochemical characterization of PCV2 associated lesions in lymphoid and non-lymphoid tissues of pigs with natural post weaning multisystemic wasting syndrome (PMWS). Veterinary Immunology and Immunopathology 94: 6375.Google Scholar
Collins, JE, Bergeland, ME, Bouley, D, Ducommun, AL, Francis, DH and Yeske, P (1989). Diarrhea associated with Clostridium perfringens type A enterotoxin in neonatal pigs. Journal of Veterinary Diagnostic Investigation 1: 351353.Google Scholar
Conzelmann, KK, Visser, N, Van Woensel, P and Thiel, HJ (1993). Molecular characterization of porcine reproductive and respiratory syndrome virus, a member of the arterivirus group. Virology 193: 329339.CrossRefGoogle ScholarPubMed
Coutelier, J-P, Coulie, PG, Wauters, P, Heremans, H and van der Logt, JT (1990). In vivo polyclonal B-lymphocyte activation elicited by murine viruses. Journal of Virology 64: 53835388.Google Scholar
Cukrowska, B, Sinkora, J, Mandel, L, Splichal, I, Bianchi, ATJ, Kovaru, F and Tlaskalova-Hogenova, H (1996). Thymic B cells of pig fetuses and germ free pigs spontaneously produce IgM, IgG and IgA: detection of ELISPOT method. Immunology 87: 487494.Google Scholar
Deenick, EK, Hasbold, J and Hodgkins, PD (1999). Switching to IgG3, IgG2b and IgA is division linked and independent revealing a stochastic framework for describing differentiation. Journal of Immunology 163: 47074717.Google Scholar
Dighiero, GP, Lymberi, P, Holmberg, D, Lundquist, I, Coutinho, A and Avrameas, S (1985). High frequency of natural autoantibodies in normal mice. Journal of Immunology 134: 765771.Google Scholar
Ducluzeau, R (1993). Installation, equilibre et role de la flore microbienne du nouveau-ne. Annals Pediatriques 4: 1322.Google Scholar
Durandy, A (2003). Activation-induced cytidine deaminase: A dual role in class switch recombination and somatic hypermutation. European Journal of Immunology 33: 20692073.Google Scholar
Eguchi-Ogawa, TN, Wertz, T, Sun, X-Z, Uenishi, H, Piumi, F, Chardon, P and Butler, JE (2009). Antibody Repertoire development in fetal and neonatal piglets. XI. The relationship between VH gene usage and the genomic organization of VH heavy chain locus (pending).Google Scholar
Elliott, DE, Setiawan, T, Metwali, A, Blum, A, Urban, JF Jr and Weinstock, JW (2004). Heligmosomoides polygyrus inhibits established colitis in IL-10 deficient mice. European Journal of Immunology 34: 26902698.Google Scholar
Fey, H and Margadant, A (1961). Hypogammaglobulinemia bei der Colisepsis des Kalbes. Pathology and Microbiology 24: 970976.Google Scholar
Francis, DH, Collins, JE and Duimstra, JR (1986). Infection of gnotobiotic pigs with an Escherichia coli O157:H7 strain associated with an outbreak of hemorrhagic colitis. Infection and Immunity 51: 953956.Google Scholar
Fu, CJ, Jez, JM, Kerley, MS, Allee, GL and Krishnan, HB (2007). Identification, characterization, epitope mapping and three-dimensional modeling of the alpha subunit of beta-conglycinin of soybean, a potential allergen for young pigs. Journal of Agricultural and Food Chemistry 55: 40144020.CrossRefGoogle ScholarPubMed
Gagnon, CA, Trembling, D, Tijssen, P, Venne, M-H, Houde, A and Elahi, SM (2007). The emergence of a porcine circovirus 2b genotype (PCV-2b) in swine in Canada. Canadian Veterinary Journal 48: 811819.Google ScholarPubMed
Gay, CC, Anderson, N, Fisher, EW and McEwan, AD (1965). Gamma globulin levels and neonatal mortality in market calves. Veterinary Record 77: 148149.Google Scholar
Gay, CG and Richie, TL (eds) (2007). Advances in Immunology and Vaccine Delivery. US-EC Task Force Report. [Available online at http://ec.eu/research/biotechnology/ecus/index_en.html]Google Scholar
Goodman-Snitkoff, G, Mannano, RJ and McSharry, JJ (1981). The glycoprotein isolated from vesicular stomatitis virus is mitogenic for mouse B lymphocytes. Journal of Experimental Medicine 153: 14891502.Google Scholar
Guarner, F and Malagelada, J-R (2003). Gut flora in health and disease. Lancet 360: 512519.CrossRefGoogle Scholar
Gustafsson, BE and Laurell, CB (1959). Gammaglobulin production in germfree rats after bacterial contamination. Journal of Experimental Medicine 110: 675684.Google Scholar
Harvey, RB, Anderson, RC, Genovese, KJ, Callaway, TR and Nisbet, DJ (2005). Use of competitive exclusion to control enterotoxigenic strains of Escherichia coli in weaned pigs. Journal of Animal Science 83: E44E47.Google Scholar
Heimesaat, M, Bereswill, S, Fischer, A, Fuchs, D, Struck, D, Niebergall, J, Jahn, HK, Dunay, IR, Moter, A, Gescher, DM, Schumann, RR, Goebel, U and Liesnfeld, O (2006). Gram negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii. Journal of Immunology 177: 87858795.Google Scholar
Helm, RM, Furuta, G, Stanley, JS, Ye, J, Cockrell, G, Connaughton, C, Simpson, P, Bannon, GA and Burks, AW (2002). A neonatal swine model for peanut allergy. Journal of Allergy and Clinical Immunology 109: 136142.CrossRefGoogle ScholarPubMed
Holtmeier, W, Geisel, W, Bernert, K, Butler, JE, Sinkora, M, Rehakova, Z, Sinkora, J and Caspary, WF (2004). Prenatal development of the porcine TCR d repertoire: dominant expression of an invariant T cell receptor V d 3-J d 3 chain. European Journal of Immunology 34: 19411949.CrossRefGoogle Scholar
Honjo, T, Kinoshitoa, K and Muramatsu, M (2002). Molecular mechanism of class switch recombination; Linkage with somatic hypermutation. Annual Review of Immunology 20: 165196.CrossRefGoogle ScholarPubMed
Hsiao, FC, Lin, M, Tai, A, Chen, G and Huber, BT (2006). Cutting edge: Epstein-Barr virus transactivates the HERV-K18 superantigen by docking to the human complement receptor 2 (CD21) on primary B cells. Journal of Immunology 177: 20562060.CrossRefGoogle Scholar
Hu, B, Even, C and Plagemann, PGW (1992). Immune complexes bind ELISA plates not coated with antigen in mice infected with lactate dehydrogenase-elevating virus: Relationship to IgG2a and IgG2b specific polyclonal activation of B cells. Viral Immunology 5: 2738.CrossRefGoogle Scholar
Hunziker, L, Recher, M, Macpherson, AJ, Ciurea, A, Freigang, S, Hengartner, H and Zinkernagel, RM (2003). Hypergammaglobulinemia and autoantibody induction mechanisms in viral infections. Nature Immunology 4: 343349.CrossRefGoogle ScholarPubMed
Karupiah, G, Sacks, TE, Klinman, DM, Frederickson, TN, Hartley, JW, Chen, JH and Morse, HC (1998). Murine cytomegalovirus infection-induced polyclonal B cell activation is independent of CD4(+) T cells and CD40. Virology 240: 1226.CrossRefGoogle ScholarPubMed
Kim, YB, Bradley, G and Watson, DW (1966). Ontogeny of the immune response. II. Characterization of the 19 S g G and 7 S g G immunoglobulins in the true primary and secondary responses of piglets. Journal of Immunology 97: 189195.CrossRefGoogle Scholar
Klobasa, F, Werhahn, E and Butler, JE (1981). Regulation of humoral immunity in the piglet by immunoglobulins of maternal origin. Research in Veterinary Science 31: 195206.Google Scholar
Klobasa, F, Habe, F, Werhahn, E and Butler, JE (1985a). Changes in the concentration of serum IgG, IgA, and IgM of sows throughout the reproductive cycle. Veterinary Immunology Immunopathology 10: 341353.Google Scholar
Klobasa, F, Habe, F, Werhahn, E and Butler, JE (1985b). Influences of breed and gestation number on the concentration of serum IgG, IgA, and IgM of sows throughout the reproductive cycle. Veterinary Immunology Immunopathology 10: 355366.Google Scholar
Klobasa, F, Butler, JE, Werhahn, E and Habe, F (1986). Maternal-neonatal immunoregulation in swined II. Influence of multi-parity on de novo synthesis by piglets. Veterinary Immunology Immunopathology 11: 149159.Google Scholar
Klobasa, F, Butler, JE and Habe, F (1990). Maternal-neonatal immunoregulation: suppression of de novo immunoglobulin synthesis of IgG and IgA, but not IgM, in neonatal piglets by bovine colostrum, is lost upon storage. American Journal of Veterinary Science 51: 14071412.Google Scholar
Knight, KL and Becker, RS (1990). Molecular basis of allelic inheritance of rabbit immunoglobulin VH allotypes: implications for the generation of antibody diversity. Cell 60: 963979.Google Scholar
Kyte, J and Doolittle, RF (1982). A simple method for displaying the hydropathic character of a protein. Journal of Molecular Biology 157: 105132.Google Scholar
Leece, JG (1969). Rearing colostrum-free pigs in an automatic feeding device. Journal of Animal Science 2: 2733.Google Scholar
Lemcke, CD (2006). PRRSV infection of neonatal piglets induces immune dysregulation and modulation. PhD Thesis, University of Iowa.Google Scholar
Lemke, CD, Haynes, JS, Spaete, R, Adolphson, D, Vorwald, A, Lager, K and Butler, JE (2004). Lymphoid hyperplasia resulting in immune dysregulation is caused by PRRSV infection in pigs. Journal of Immunology 172: 19161925.Google Scholar
Lesser, TD, Amenuvor, JZ, Jensen, TK, Linecrona, RH, Boye, M and Moeller, K (2002). Culture-independent analysis of gut bacteria: the pig gastrointestinal tract microbiota revisited. Applied and Environmental Microbiology 68: 673690.Google Scholar
Levenson, SM, Mason, RP, Huber, TE, Malm, OL, Horowitz, RE and Einheber, A (1959). Germfree animals in surgical research. Annals of Surgery 150, 713730.Google Scholar
Li, X, Hu, B, Harty, J, Even, C and Plagemann, PGW (1990). Polyclonal B cell activation of IgG2a and IgG2b production by infection of mice with lactate dehydrogenase-elevating virus is partly dependent on CD4+ lymphocytes. Viral Immunology 3: 273287.Google Scholar
Liebler-Tenorio, EM and Pabst, R (2006). MALT structure and function in farm animals. Veterinary Research 37: 257280.Google Scholar
Loemba, HD, Mounir, S, Mardassi, H, Archambault, D and Dea, S (1996). Kinetics of humoral immune response to the major structural proteins of the porcine reproductive and respiratory syndrome virus. Archives of Virology 141: 751761.Google Scholar
Lopez, OJ, Fuertes, L, Domenech, N, Alvarez, B, Ezquerra, A, Pominquea, J, Castro, JM and Alovso, F (1999). Analysis of cellular immune response in pigs recovered from porcine reproductive and respiratory syndrome infection. Virus Research 64: 3342.Google Scholar
Maina, JN and van Gils, P (2001). Morphometric characterization of the airway and vascular systems of the lung of the domestic pig, Sus scrofa: comparison of the airway, arterial and venous systems. Comparative Biochemistry and Physiology. Part A, Molecular and Integrative Physiology 130: 781798.Google Scholar
Maldonado, MA, Kakkanaiah, V, MacDonald, GC, Chen, F, Reap, EA, Balish, E, Jennette, JC, Madalo, MP, Kotzin, BL and Eisenberg, RA (1999). The role of environmental antigens in the spontaneous development of autoimmunity in MRL-lpr mice. Journal of Immunology 162: 63226330.Google Scholar
Marchalonis, JJ, Schluter, SF, Bernstein, RM, Shanxiang, S and Edmundson, AB (1996). Phylogenetic emergence and molecular evolution of the immunoglobulin family. Advances in Immunology 70: 417506.Google Scholar
Marchalonis, JJ, Adelman, MK, Schluter, SF and Ramsland, PA (2006). The antibody repertoire in evolution: chance, selection and continuity. Developmental and Comparative Immunology 30: 223247.Google Scholar
Matzinger, P (2002). The danger model: a renewed sense of self. Science 296: 301305.Google Scholar
McAleer, J, Weber, P, Sun, J and Butler, JE (2005). Antibody repertoire development in fetal and neonatal piglets. XI. The thymic B cell repertoire develops independently from that in blood and mesenteric lymph nodes. Immunology 114: 171183.CrossRefGoogle ScholarPubMed
McKee, ML, Melton-Celsa, AR, Moxley, RA, Francis, DH and O'Brien, AD (1995). Enterohemorrhagic Escherichia coli O157:H7 requires intimin to colonize the gnotobiotic pig intestine and to adhere to HEp-2 Cells. Infection and Immunity 62: 37393744.Google Scholar
Meyer, RC, Bohl, EH and Kohler, EM (1964). Procurement and maintenance of germfree swine for microbiological investigations. Applied Microbiology 12: 295300.Google Scholar
Mulupuri, P, Zimmerman, JJ, Hermans, J, Johson, CR, Cano, JP, Yu, W, Dee, SA and Murtaugh, MP (2008). Antigen-specific B cell responses to porcine reproductive and respiratory syndrome virus infection. Journal of Virology 82: 358370.Google Scholar
Neumann, EJ, Kliebenstein, JB, Johnson, CD, Mabry, JW, Bush, EJ, Seitzinger, AH, Green, AL and Zimmerman, JJ (2005). Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States. Journal of the American Veterinary Medical Association 227: 385392.Google Scholar
Nguyen, TV, Yuan, L, Azevedo, MSP, Jeong, K-I, Gonzalez, A-M and Saif, LJ (2007). Transfer of maternal cytokines to suckling piglets: in vivo and in vitro models with implications for immunomodulation of neonatal immunity. Veterinary Immunology and Immunopathology 117: 236248.Google Scholar
Nisbet, DJ, Corrier, DE and Stanker, LH (1999). Competitive exclusion culture for swine. United States Patent Office, U.S. Patent No. 5,951,977. 14 September 1999.Google Scholar
O'Hara, AM and Shanahan, F (2006). The gut flora as a forgotten organ. EMBO Report 7: 688693.Google Scholar
Ochsenbein, AF and Zinkernagel, R (2000). Natural antibodies and complement link innate and acquired immunity. Immunology Today 1: 624630.Google Scholar
Ohwaki, M, Yasutake, N, Yasui, H and Ogura, R (1976). Comparative study on humoral immune responses in germfree and conventional mice. Immunology 32: 4348.Google Scholar
Pabst, R and Binns, RM (1994). The immune system of the respiratory tract in pigs. Veterinary Immunology and Immunopathology 43: 151156.CrossRefGoogle ScholarPubMed
Pabst, R, Geist, M, Rothkotter, HJ and Fritz, FJ (1988). Postnatal development and lymphocyte production of jejunal and ileal Peyers patches in normal and gnotobiotic pig. Immunology 64: 539544.Google Scholar
Padlan, EA (1994). Anatomy of the antibody molecule. Molecular Immunology 31: 169217.Google Scholar
Plagemann, PGW and Moenning, V (1992). Lactate dehydrogenase elevating virus, equine arteritis virus and Simian hemorrhagic fever virus, a new group of positive strand RNA viruses. Advances in Viral Research 41: 99192.CrossRefGoogle ScholarPubMed
Raaphorst, FM, Raman, CS, Nall, BT and Teale, JM (1997). Molecular mechanisms governing reading frame choice of immunoglobulin diversity genes. Immunology Today 18: 3743.Google Scholar
Rapacz, J, Hasler-Rapacz, J, Taylor, KM, Checovich, WJ and Attie, AD (1986). Liproprotein mutations in pigs are associated with elvated plasma cholesterol and atheroschlerosis. Science 234: 15731577.Google Scholar
Reeds, P and Odle, J (1996). Pigs as models for nutrient functional interaction. In: Tumbleson, ME and Schook, LB (eds) Advances in Swine Biomedical Research. Vol. 2. New York: Plenum Press, pp. 709712.Google Scholar
Rogers, C, Stoltz, DA, Meyerholz, DK, Ostedgaard, LS, Rokhlina, T, Taft, JPJ, Rogan, MP, Pezzulo, AA, Karp, PH, Itani, OA, Kabel, AC, Wohlford-Lenane, CL, Davis, GJ, Hanfland, RA, Smityh, TL, Samuel, M, Wax, D, Murphy, CN, Rieke, A, Whitworht, K, Uc, A, Starner, TD, Brogden, KA, Shilyansky, J, MvCray, PB, Zabner, J, Prather, RS and Welsh, MJ (2008). Dirsuption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321: 18371841.Google Scholar
Rook, GA and Stanford, JL (1998). Give us this day our daily germs. Immunology Today 19: 113116.Google Scholar
Rott, O, Charreire, J, Mignon-Godefray, K and Cash, E (1995). B cells superstimulatory influenza virus activates peritoneal B cells. Journal of Immunology 155: 134142.Google Scholar
Rowland, RRR, Even, C, Anderson, GW, Chen, Z, Hu, B and Plagemann, PGW (1994). Neonatal infection of mice with lactate dehydrogenase-elevating virus results in suppression of humoral anti-viral immune response but does not alter the course of viremia or the polyclonal activation of B cells and immune complex formation. Journal of General Virology 75: 10711081.CrossRefGoogle ScholarPubMed
Rupa, P, Hamilton, K, Cirinna, M and Wilkie, BN (2007). A neonatal swine model of allergy induced by the major food allergen chicken ovomucoid (Gal d 1). International Archives of Allergy and Immunology 146: 1118.Google Scholar
Saalmueller, A, Reddehase, MJ, Buehriing, HJ, Jonjic, S and Koszinowski, UH (1987). Simultaneous expression of CD4 and CD8 antigens by a substantial proportion of resting porcine T lymphocytes. European Journal of Immunology 9: 12971301.Google Scholar
Sachs, D, Sykes, M, Robson, SC and Cooper, DK (2001). Xenotransplantation. Advances in Immunology 79: 129223.Google Scholar
Scalzo, AA and Anders, EM (1985). Influence viruses as lymphocyte mitogens. II. Role of I-E molecules in B cell mitogenesis by influenzae A viruses of the H2 and H6 subtypes. Journal of Immunology 135: 35243529.Google Scholar
Shen, HM, Tanaka, A, Bozek, G, Nicolae, D and Storb, U (2006). Somatic hypermutation and class switch recombination in Msh6−/− Ung−/− double knockout mice. Journal of Immunology 177: 53865392.Google Scholar
Silverman, GJ, Nayak, JV and La Cava, A (1997). B cell superantigens: molecular and cellular implications. International Review of Immunology 14: 259290.Google Scholar
Sinkora, M, Sun, J and Butler, JE (2000). Antibody repertoire development in fetal and neonatal piglets. V. VDJ gene chimeras resembling gene conversion products are generated at high frequency by PCR in vitro. Molecular Immunology 37: 10251034.Google Scholar
Sinkora, M, Sun, J, Sinkorova, J, Christenson, RK, Ford, SP and Butler, JE (2003). Antibody repertoire development in fetal and neonatal piglets. VI. B cell lymphogenesis occurs in multiple sites with differences in the frequency of in-frame rearrangements. Journal of Immunology 170: 17811788.Google Scholar
Smith, A, Madden, KB, Au Yeung, KJ, Zhao, A, Elfrey, J, Finkelman, F, Levander, O, Shea-Donohue, T and Urban, JF Jr (2005). Deficiencies in selenium and or vitamin E lowers the resistance of mice to Heligmosomoides polygyrus infections. Journal of Nutrition 135: 830836.Google Scholar
Stevenson, PG and Doherty, PC (1999). Non-specific B cell activation following murine gammaherpesvirus infection is CD4 independent in vitro but CD4 dependent in vivo. Journal of Virology 73: 10751079.Google Scholar
Sudo, N, Sawamura, SA, Tanaka, K, Aiba, Y, Kudo, C and Koga, Y (1997). The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance. Journal of Immunology 159: 17391745.Google Scholar
Summers, RW, Elliott, DE, Qadir, K, Urban, JF Jr, Thompson, R and Weinstock, JW (2003). Trichuiris sius seems to be safe and possibly effective in the treatment of inflammatory bowel disease. American Journal of Gastroenterology 89: 20342041.Google Scholar
Sun, J, Kacskovics, I, Brown, WR and Butler, JE (1994). Expressed swine VH genes belong to a small VH gene family homologous to human VH III. Journal of Immunology 153: 56185627.Google Scholar
Tapiainen, T, Ylitalo, S, Eorola, E and Uhari, M (2006). Dynamics of gut colonization and source of intestinal flora in healthy newborn infants. Acta Pathologica, Microbiologica et Immunologica Scandinavica 114: 812817.Google Scholar
Thacker, EL (2006). Lung inflammatory responses. Veterinary Research 37: 469486.Google Scholar
Thorbecke, GJ (1959). Some histological and functional aspects of lymphoid tissue in germfree animals. I. Morphological studies. Annals of the New York Academy of Sciences 78: 237246.Google Scholar
Tong, G-Z, Tian, Z-J, Zhou, Y-J, Hao, X-F, An, T-Q, Wei, T-C, Qui, H-J and Cai, X-H (2007). PRRS in China. Proceedings of the International PRRS Symposium, Chicago, 30 November–1 December.Google Scholar
Tonnelle, C, Cuisinier, AM, Gauthhier, L, Guelpa-Fonlupt, V, Milili, M, Schiff, C and Fougereau, M (1995). Fetal versus adult pre-B or B cells: the human VH repertoire. Annals of the New York Academy of Sciences 764: 231241.Google Scholar
Travnicek, J, Mandel, L, Lanc, A and Ruzicka, R (1966). The breeding of microbe-free piglets. Ceskoslovenska Fysiologie 15: 240244.Google Scholar
Uenishi, H, Hiraiwa, H, Yamamoto, R, Yasue, H, Takagaki, Y, Shiina, T, Kikkawa, E, Inoko, H and Awata, T (2003). Genomic structure around joining segments and constant regions of swine T-cell receptor a/b (TRA/TRD) locus. Immunology 109: 515526.Google Scholar
Uhr, G (1993). Vergleichende Untersuchungen am Darmtrakt des Wild- und Hausschweines unter besonderer Berucksichtigung des Darmschleimhautimmunsystems. Habilitation Thesis, Veterinary School, Hannover.Google Scholar
Urban, JF Jr, Steenhard, NR, Solano-Aquilar, GI, Dawson, HD, Iweala, OI, Nagler, CR, Noland, GS, Kumar, N, Anthony, RM, Shea-Donohue, T, Weinstock, J and Gause, WC (2007). Infection with parasitic nematodes confounds vaccination efficacy. Veterinary Parasitology 148: 1420.Google Scholar
Viau, M, Cholly, B, Bjorck, L and Zouali, M (2004). Down-modulation of the antigen receptor by a superantigen in human B cells. Immunology Letters 92: 9196.Google Scholar
Walker, R and Buckley, M (2006). Probiotic microbes: the scientific basis. American Academy of Sciences Colloquium Report. American Academy of Microbiology.Google Scholar
Weller, S, Faili, A, Garcia, C, Braun, MC, Le Deist, FF, de Saint Basile, GG, Hermine, O, Fischer, A, Reynaud, C and Weill, J-C (2001). CD4–CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans. Proceedings of the National Academy of Sciences, USA 98: 11661170.Google Scholar
Werhahn, E, Klobasa, F and Butler, JE (1981). Investigation of some factors which influence the absorption of IgG by the neonatal piglet. Veterinary Immunology Immunopathology 2: 3551.Google Scholar
Wilson, M, Bengten, E, Miller, NW, Clem, LW, Du Pasquier, L and Warr, GW (1997). A novel chimeric Ig heavy chain from a teleost fish shares similarities to IgD. Proceedings of the National Academy of Sciences, USA 94: 45934597.Google Scholar
Yazdanbaksh, M, Kremsner, PG and van Ree, R (2002). Allergy, parasites and the hygiene hypothesis. Science 296: 490494.Google Scholar
Yuan, S, Lu, J, Zhang, J, Li, X, Sun, Z and Liu, W (2007). Molecular characterization of a highly pathogenic strain of PRRSV associated with porcine high fever syndrome in China. Proceedings of the International PRRS Symposium, Chicago. Poster No. 70.Google Scholar
Zhao, Y, Pan-Hammarstrom, Q, Kacskovics, I and Hammarstrom, L (2003). The porcine Ig d gene: unique chimeric splicing of the first constant region domain in its heavy chain transcripts. Journal of Immunology 171: 13121318.Google Scholar
Zhao, Y, Pan-Hammarstrom, Q, Yu, S, Wertz, N, Zhang, X, Li, N, Butler, JE and Hammarstrom, L (2006). Identification of IgF, a hinge-region containing Ig class and IgD in Xenopus tropicalis. Proceedings of the National Academy of Sciences, USA 103: 1208712092.Google Scholar
Zitterkopf, NL, Jones, QA, Bradley, DS, Durick, K, Rowland, RR, Plagemann, PG and Cafruny, WA (2003). Hydrophobic IgG-containing immune complexes in the plasma of autoimmune MRL/lpr mice, lactate dehydrogenase-elevating virus infected mice and pigs: association with transforming growth factor-b and pH dependent amplification. Viral Immunology 16: 511523.Google Scholar
Zoentendal, EG, Akkermans, AD and De Vos, WM (1998). Temperature gradient gel electrophoresis analysis of 16S rRNA from human fecal samples reveals stable and host-specific communities of active bacteria. Applied and Environmental Microbiology 64: 38543859.Google Scholar
Zouali, M (1995). B cell superantigens: implications for selection of the human antibody repertoire. Immunology Today 16: 399405.Google Scholar
Zuckermann, FA and Husmann, RJ (1996). Functional and phenotypic analysis of porcine peripheral blood CD4/CD8 double-positive T cells. Immunology 87: 500512.Google Scholar