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Mast cells and innate immunity: master troupes of the avian immune system

Published online by Cambridge University Press:  03 August 2017

Z.U. REHMAN ,
C. MENG ,
S. UMAR ,
K.M. MAHROSE ,
C. DING  and
M. MUNIR
Z.U. REHMAN
Affiliation:
Shanghai Veterinary Research Institute (SHVRI), Chinese Academy of Agricultural Sciences (CAAS), Shanghai, China Faculty of Veterinary and Animal Sciences, PMAS Arid Agriculture University, Rawalpindi, Pakistan
C. MENG
Affiliation:
Shanghai Veterinary Research Institute (SHVRI), Chinese Academy of Agricultural Sciences (CAAS), Shanghai, China
S. UMAR
Affiliation:
Faculty of Veterinary and Animal Sciences, PMAS Arid Agriculture University, Rawalpindi, Pakistan
K.M. MAHROSE
Affiliation:
Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
C. DING*
Affiliation:
Shanghai Veterinary Research Institute (SHVRI), Chinese Academy of Agricultural Sciences (CAAS), Shanghai, China
M. MUNIR
Affiliation:
Avian Innate Immunity and Host Genetic Diversity, Avian Viral Diseases Programme, The Pirbright Institute, Surrey, GU24 0NF, United Kingdom
*
Corresponding author: shoveldeen@shvri.ac.cn
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Abstract

Mast cells (MCs) are granulated cells of haematopoietic lineage and constitute a major sensory arm of the immune system. MCs dually guard hosts and regulate immune responses against invading pathogens. This property of the MCs is attributed to their adaptability to detect stress signals and pathogens, and the production of signal specific mediators to engage immune cells for clearance of infectious agents. Pathogen-specific signals establish basis for the initiation of adoptive immune responses. These immune regulatory roles of MCs have opened avenues to engage different MCs activators which culminate in effective passive immunisation. The molecular mechanisms and dynamics of functionalities of MCs in host defences have been extensively characterised in mammals and rodents, and research on MCs in avian species is emerging. This review surveys the development, morphology and distribution of MCs in different tissues of the poultry and highlight areas that can be exploited for disease control and prevention.

Keywords

mast cellimmune systemvirusbacteriaparasitepoultry
Type
Reviews
Information
World's Poultry Science Journal , Volume 73 , Issue 3 , September 2017 , pp. 621 - 632
Copyright
Copyright © World's Poultry Science Association 2017 

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References

ABRAHAM, S.N. and ST JOHN, A.L. (2010) Mast cell-orchestrated immunity to pathogens. Nature Reviews Immunology 10: 440-452.Google Scholar
ANTHONY, R.M., RUTITZKY, L.I., URBAN, J.F., STADECKER, M.J. and GAUSE, W.C. (2007) Protective immune mechanisms in helminth infection. Nature Reviews Immunology 7: 975-987.Google Scholar
ASHINA, K., TSUBOSAKA, Y., NAKAMURA, T., OMORI, K., KOBAYASHI, K., HORI, M., OZAKI, H. and MURATA, T. (2015) Histamine induces vascular hyperpermeability by increasing blood flow and endothelial barrier disruption in vivo. PLoS ONE 10: e0132367.Google Scholar
BANUELOS-CABRERA, I., VALLE-DORADO, M.G., ALDANA, B.I., OROZCO-SUAREZ, S.A. and ROCHA, L. (2014) Role of histaminergic system in blood-brain barrier dysfunction associated with neurological disorders. Archives of Medical Research 45: 677-686.Google Scholar
BISCHOFF, S.C. (2009) Physiological and pathophysiological functions of intestinal mast cells. Seminars in Immunopathology 31: 185-205.CrossRefGoogle ScholarPubMed
BOESIGER, J., TSAI, M., MAURER, M., YAMAGUCHI, M., BROWN, L.F., CLAFFEY, K.P., DVORAK, H.F. and GALLI, S.J. (1998) Mast cells can secrete vascular permeability factor/ vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin e-dependent upregulation of fc epsilon receptor i expression. Journal of Experimental Medicine 188: 1135-1145.CrossRefGoogle ScholarPubMed
CALDWELL, D.J., DANFORTH, H.D., MORRIS, B.C., AMEISS, K.A. and MCELROY, A.P. (2004) Participation of the intestinal epithelium and mast cells in local mucosal immune responses in commercial poultry. Poultry Science 83: 591-599.Google Scholar
CARLSON, H. and HACKING, M. (1972) Distribution of mast cells in chicken, turkey, pheasant, and quail, and their differentiation from basophils. Avian Diseases 16: 574-577.Google Scholar
CARON, G., DELNESTE, Y., ROELANDTS, E., DUEZ, C., HERBAULT, N., MAGISTRELLI, G., BONNEFOY, J.Y., PESTEL, J. and JEANNIN, P. (2001) Histamine induces cd86 expression and chemokine production by human immature dendritic cells. Journal of Immunology 166: 6000-6006.CrossRefGoogle ScholarPubMed
COLLINS, C.B., MCGRATH, J., BAIRD, A.W. and CAMPION, D.P. (2007) Effect of mast cell degranulation on chicken ileal ion transport in vitro. Poultry Science 86: 843-849.Google Scholar
CRIVELLATO, E., BELTRAMI, C.A., MALLARDI, F. and RIBATTI, D. (2003) Paul Ehrlich's doctoral thesis: A milestone in the study of mast cells. British Journal of Haematology 123: 19-21.CrossRefGoogle Scholar
DAHLIN, J.S. and HALLGREN, J. (2015) Mast cell progenitors: Origin, development and migration to tissues. Molecular Immunology 63: 9-17.Google Scholar
DARMAWIA, , BALQISA, U., HAMBALA, M., TIURIAB, R., >FRENGKIA, and PRIOSOERYANTO, B.P. (2013) Mucosal mast cells response in the jejunum of ascaridia galli-infected laying hens. Media Peternakan 36: 113-119.CrossRefGoogle Scholar
DEBRUIN, E.J., GOLD, M., LO, B.C., SNYDER, K., CAIT, A., LASIC, N., LOPEZ, M., MCNAGNY, K.M. and HUGHES, M.R. (2015) Mast cells in human health and disease. Methods in Molecular Biology 1220: 93-119.Google Scholar
DEMEURE, C.E., BRAHIMI, K., HACINI, F., MARCHAND, F., PERONET, R., HUERRE, M., ST-MEZARD, P., NICOLAS, J.F., BREY, P., DELESPESSE, G. and MECHERI, S. (2005) Anopheles mosquito bites activate cutaneous mast cells leading to a local inflammatory response and lymph node hyperplasia. Journal of Immunology 174: 3932-3940.Google Scholar
EBERT, S., BECKER, M., LEMMERMANN, N.A., BUTTNER, J.K., MICHEL, A., TAUBE, C., PODLECH, J., BOHM, V., FREITAG, K., THOMAS, D., HOLTAPPELS, R., REDDEHASE, M.J. and STASSEN, M. (2014) Mast cells expedite control of pulmonary murine cytomegalovirus infection by enhancing the recruitment of protective cd8 t cells to the lungs. PLoS Pathogens 10: e1004100.Google Scholar
EHRLICH, P. (1878) Beiträge für theorie und praxis der histologischen färbung (Leipzig.).Google Scholar
FERDUSHY, T., NEJSUM, P., ROEPSTORFF, A., THAMSBORG, S.M. and KYVSGAARD, N.C. (2012) Ascaridia galli in chickens: Intestinal localization and comparison of methods to isolate the larvae within the first week of infection. Parasitology Research 111: 2273-2279.Google Scholar
GALLI, S.J., GRIMBALDESTON, M. and TSAI, M. (2008) Immunomodulatory mast cells: Negative, as well as positive, regulators of immunity. Nature Reviews Immunology 8: 478-486.Google Scholar
GALLI, S.J., NAKAE, S. and TSAI, M. (2005) Mast cells in the development of adaptive immune responses. Nature Immunology 6: 135-142.Google Scholar
GORDON, J.R. and GALLI, S.J. (1990) Mast cells as a source of both preformed and immunologically inducible tnf-alpha/cachectin. Nature 346: 274-276.Google Scholar
GUPTA, S.K. and GILBERT, A.B. (1988) Mast cells in the ovary of gallus gallus domesticus. British Poultry Science 29: 245-249.Google Scholar
HOU, P., LIU, L., LI, Y-F., WANG, H-H. and WANG, G-Q. (2009) Histochemical and ultrastructural effects on mast cells of jejunums in the chicken of selenium deficiency on the daily food. China Animal Husbandry and Veterinary Medicine 7: 014.Google Scholar
HRABIA, A., RZAĄSA, J., PACZOSKA-ELIASIEWICZ, H. and SLOMCZYŃSKA, M. (2001) Presence of histamine and mast cells in chicken oviduct. Folia Biologica 49: 265-271.Google Scholar
HU, Y., JIN, Y., HAN, D., ZHANG, G., CAO, S., XIE, J., XUE, J., LI, Y., MENG, D., FAN, X., SUN, L.Q. and WANG, M. (2012) Mast cell-induced lung injury in mice infected with h5n1 influenza virus. Journal of Virology 86: 3347-3356.Google Scholar
JUN-FENG, G., JIN-GUO, L., DENG-HUI, G. and HONG-YAN, Y. (2011) Observation of developing mast cells in immune organs of chick embryos. Guizhou Agricultural Sciences 39: 145-147.Google Scholar
KARACA, T., YÖRÜK, M. and USLU, S. (2006) Age-related changes in the number of mast cells in the avian lymphoid organs. Anatomia Histologia Embryologia 35: 375-379.CrossRefGoogle ScholarPubMed
KAWAKAMI, T. and GALLI, S.J. (2002) Regulation of mast-cell and basophil function and survival by ige. Nature Reviews Immunology 2: 773-786.Google Scholar
KUNDER, C.A., JOHN, A.L.S., LI, G., LEONG, K.W., BERWIN, B., STAATS, H.F. and ABRAHAM, S.N. (2009) Mast cell–derived particles deliver peripheral signals to remote lymph nodes. Journal of Experimental Medicine 206: 2455-2467.CrossRefGoogle ScholarPubMed
LI, J-G. (2008) Quantitative study on mast cells in the lungs of chickens. Journal of Anhui Agricultural Sciences 36: 5449-5450.Google Scholar
LI, J-G., GAO, D.-H., YAO, H.-Y., OU, D.-Y., JIANG, X.-M. and GUO, J.-F. (2011) Observation on mast cells in different days old chicken embryo's lungs. Guizhou Agricultural Sciences 39: 151-153.Google Scholar
LIU, Y-W., LIU, N., LIU, L-Q., LIN, Y., LIU, J-C. and FAN, C-Y. (2011) Effect of heat stress on mast cell number and histamine content in small intestine of broilers. Progress in Veterinary Medicine 32: 129-132.Google Scholar
LIU, Y.H., PIAO, X.S., OU, D.Y., CAO, Y.H., HUANG, D.S. and LI, D.F. (2006) Effects of particle size and physical form of diets on mast cell numbers, histamine, and stem cell factor concentration in the small intestine of broiler chickens. Poultry Science 85: 2149-2155.Google Scholar
LU, L-F., LIND, E.F., GONDEK, D.C., BENNETT, K.A., GLEESON, M.W., PINO-LAGOS, K., SCOTT, Z.A., COYLE, A.J., REED, J.L. and VAN SNICK, J. (2006) Mast cells are essential intermediaries in regulatory t-cell tolerance. Nature 442: 997-1002.Google Scholar
LUNA-OLIVARES, L.A., KYVSGAARD, N.C., FERDUSHY, T., NEJSUM, P., THAMSBORG, S.M., ROEPSTORFF, A. and IBURG, T.M. (2015) The jejunal cellular responses in chickens infected with a single dose of ascaridia galli eggs. Parasitology Research 114: 2507-2515.Google Scholar
MALAVIYA, R., GAO, Z., THANKAVEL, K., VAN DER MERWE, P.A. and ABRAHAM, S.N. (1999) The mast cell tumor necrosis factor α response to fimh-expressing escherichia coli is mediated by the glycosylphosphatidylinositol-anchored molecule cd48. Proceedings of the National Academy of Sciences 96: 8110-8115.Google Scholar
MALAVIYA, R., IKEDA, T., ROSS, E. and ABRAHAM, S.N. (1996) Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through tnf-α. Nature 381: 77-80.Google Scholar
MARSHALL, J.S. (2004) Mast-cell responses to pathogens. Nature Reviews Immunology 4: 787-799.Google Scholar
MAURER, M., KOSTKA, S.L., SIEBENHAAR, F., MOELLE, K., METZ, M., KNOP, J. and VON STEBUT, E. (2006) Skin mast cells control t cell-dependent host defense in leishmania major infections. The FASEB journal 20: 2460-2467.Google Scholar
MCLACHLAN, J.B., SHELBURNE, C.P., HART, J.P., PIZZO, S.V., GOYAL, R., BROOKING-DIXON, R., STAATS, H.F. and ABRAHAM, S.N. (2008) Mast cell activators: A new class of highly effective vaccine adjuvants. Nature Medicine 14: 536-541.Google Scholar
MENG, D., HUO, C., WANG, M., XIAO, J., LIU, B., WEI, T., DONG, H., ZHANG, G., HU, Y. and SUN, L. (2016) Influenza a viruses replicate productively in mouse mastocytoma cells (p815) and trigger pro-inflammatory cytokine and chemokine production through tlr3 signaling pathway. Frontiers in Microbiology 7: 2130.Google Scholar
METCALFE, D.D., BARAM, D. and MEKORI, Y.A. (1997) Mast cells. Physiological Reviews 77: 1033-1079.Google Scholar
MORRIS, B.C., DANFORTH, H.D., CALDWELL, D.J., PIERSON, F.W. and MCELROY, A.P. (2004) Intestinal mucosal mast cell immune response and pathogenesis of two eimeria acervulina isolates in broiler chickens. Poultry Science 83: 1667-1674.Google Scholar
MUCHA, K.H. and HUFFMAN, J.E. (1991) Inflammatory cell stimulation and wound healing in sphaeridiotrema globulus experimentally infected mallard ducks (anas platyrhynchos). Journal of Wildlife Diseases 27: 428-434.Google Scholar
MUÑOZ, S., HERNÁNDEZ-PANDO, R., ABRAHAM, S.N. and ENCISO, J.A. (2003) Mast cell activation by mycobacterium tuberculosis: Mediator release and role of cd48. The Journal of Immunology 170: 5590-5596.Google Scholar
ORINSKA, Z., BULANOVA, E., BUDAGIAN, V., METZ, M., MAURER, M. and BULFONE-PAUS, S. (2005) Tlr3-induced activation of mast cells modulates cd8+ t-cell recruitment. Blood 106: 978-987.Google Scholar
OU, D-Y., GAO, D-H., WANG, K-G. and XU, L-R. (2003) Mast cells in the thymic medulla and jejunal mucosa of chickens infected experimentally with ascaridia galli. Chinese Journal of Veterinary Science 1: 017.Google Scholar
PARSHAD, R.K. and KATHPALIA, K. (1993) Distribution and characteristics of mast cells in the chick ovary. British Poultry Science 34: 65-71.Google Scholar
PAUL, W.E. (2013) Fundamental immunology (United States, Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, c2013.).Google Scholar
PETRONE, V.M., CONSTANTINO, C.F. and PRADAL-ROA, P. (2002) Identification and quantification of granulocytes in caecal mucosa and submucosa of chickens experimentally infected with eimeria tenella and salmonella enteritidis. British Poultry Science 43: 653-661.Google Scholar
QIAO, H., ANDRADE, M.V., LISBOA, F.A., MORGAN, K. and BEAVEN, M.A. (2006) Fcepsilonr1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107: 610-618.Google Scholar
RAO, K.N. and BROWN, M.A. (2008) Mast cells: Multifaceted immune cells with diverse roles in health and disease. Annals of the New York Academy of Sciences 1143: 83-104.Google Scholar
REHMAN, Z.U., MENG, C., UMAR, S., MUNIR, M. and DING, C. (2016) Interaction of infectious bursal disease virus with the immune system of poultry. World's Poultry Science Journal 72: 805-820.Google Scholar
ROCHA-DE-SOUZA, C.M., BERENT-MAOZ, B., MANKUTA, D., MOSES, A.E. and LEVI-SCHAFFER, F. (2008) Human mast cell activation by staphylococcus aureus: Interleukin-8 and tumor necrosis factor alpha release and the role of toll-like receptor 2 and cd48 molecules. Infection and Immunity 76: 4489-4497.Google Scholar
ROSE, M.E., OGILVIE, B.M. and BRADLEY, J.W. (1980) Intestinal mast cell response in rats and chickens to coccidiosis, with some properties of chicken mast cells. International Archives of Allergy and Applied Immunology 63: 21-29.Google Scholar
SHELBURNE, C.P., NAKANO, H., ST JOHN, A.L., CHAN, C., MCLACHLAN, J.B., GUNN, M.D., STAATS, H.F. and ABRAHAM, S.N. (2009) Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues. Cell Host and Microbe 6: 331-342.Google Scholar
ST JOHN, A.L., RATHORE, A.P., YAP, H., NG, M.L., METCALFE, D.D., VASUDEVAN, S.G. and ABRAHAM, S.N. (2011) Immune surveillance by mast cells during dengue infection promotes natural killer (nk) and nkt-cell recruitment and viral clearance. Proceedings of the National Academy of Sciences of the United States of America 108: 9190-9195.Google Scholar
ST. JOHN, A.L. and ABRAHAM, S.N. (2013) Innate immunity and its regulation by mast cells. The Journal of Immunology 190: 4458-4463.Google Scholar
STENTON, G.R., VLIAGOFTIS, H. and BEFUS, A.D. (1998) Role of intestinal mast cells in modulating gastrointestinal pathophysiology. Annals of Allergy, Asthma & Immunology 81: 1-15.Google Scholar
SUN, Q., LI, W., SHE, R., WANG, D., HAN, D., LI, R., DING, Y. and YUE, Z. (2009) Evidence for a role of mast cells in the mucosal injury induced by newcastle disease virus. Poultry Science 88: 554-561.Google Scholar
SUN, Q., WANG, D., SHE, R., LI, W., LIU, S., HAN, D., WANG, Y. and DING, Y. (2008) Increased mast cell density during the infection with velogenic newcastle disease virus in chickens. Avian Pathology 37: 579-585.Google Scholar
SWAYNE, D.E. and WEISBRODE, S.E. (1990) Cutaneous mast cell tumor in a great horned owl (bubo virginianus). Veterinary Pathology 27: 124-126.Google Scholar
URB, M. and SHEPPARD, D.C. (2012) The role of mast cells in the defence against pathogens. PLoS Pathogens 8.Google Scholar
USLU, S. and YÖRÜK, M. (2013) Morfological and histometric studies on mast cell distribution and heterogeneity, present in the lower respiratory tract and in the lung of local duck (anas platyrhnchase) and goose (anser anser). Kafkas Üniversitesi Veteriner Fakültesi Dergisi 19: 475-482.Google Scholar
VALSALA, K.V., JARPLID, B. and HANSEN, H.J. (1986) Distribution and ultrastructure of mast cells in the duck. Avian Diseases 30: 653-657.Google Scholar
VAN GOOR, A., SLAWINSKA, A., SCHMIDT, C.J. and LAMONT, S.J. (2016) Distinct functional responses to stressors of bone marrow derived dendritic cells from diverse inbred chicken lines. Developmental and Comparative Immunology 63: 96-110.Google Scholar
VLIAGOFTIS, H. and BEFUS, A.D. (2005) Mast cells at mucosal frontiers. Current Molecular Medicine 5: 573-589.Google Scholar
WANG, D., JIA, X., SHE, R. and LIU, Y. (2012a) Acute hypersensitive-like injury in specific-pathogen-free chickens after infection with very virulent infectious bursal disease virus. Poultry Science 91: 334-339.Google Scholar
WANG, D., LIU, Y., SHE, R., XU, J., LIU, L., XIONG, J., YANG, Y., SUN, Q. and PENG, K. (2009a) Reduced mucosal injury of spf chickens by mast cell stabilization after infection with very virulent infectious bursal disease virus. Veterinary Immunology and Immunopathology 131: 229-237.Google Scholar
WANG, D., MA, W., SHE, R., SUN, Q., LIU, Y., HU, Y., LIU, L., YANG, Y. and PENG, K. (2009b) Effects of swine gut antimicrobial peptides on the intestinal mucosal immunity in specific-pathogen-free chickens. Poultry Science 88: 967-974.Google Scholar
WANG, D., XIONG, J., SHE, R., LIU, L., ZHANG, Y., LUO, D., LI, W., HU, Y., WANG, Y., ZHANG, Q. and SUN, Q. (2008) Mast cell mediated inflammatory response in chickens after infection with very virulent infectious bursal disease virus. Veterinary Immunology and Immunopathology 124: 19-28.Google Scholar
WANG, Q., ZENG, L., WANG, C., LIN, H., JIA, H. and ZHANG, W. (2012b) Effect of lactobacilli on the mucosal immune function in duodenum of young broiler. Journal of Animal and Veterinary Advances 11: 3843-3848.Google Scholar
WANG, Y-H., WANG, C-L. and ZHANG, W-Y. (2005) Effect of cold stress on the numbers of mast cells of spleen and thymus in royal chickens Journal of Heilongjiang August First Land Reclamation University 4: 014.Google Scholar
WELLER, C.L., COLLINGTON, S.J., BROWN, J.K., MILLER, H.R., AL-KASHI, A., CLARK, P., JOSE, P.J., HARTNELL, A. and WILLIAMS, T.J. (2005) Leukotriene b4, an activation product of mast cells, is a chemoattractant for their progenitors. Journal of Experimental Medicine 201: 1961-1971.Google Scholar
WERNERSSON, S. and PEJLER, G. (2014) Mast cell secretory granules: Armed for battle. Nature Reviews Immunology 14: 478-494.Google Scholar
WIGHT, P. (1970) Mast cells of gallus domesticus. I. Distribution and ultrastructure. Acta Anatomica 75: 100-113.Google Scholar
WOODBURY, R.G., MILLER, H.R., HUNTLEY, J.F., NEWLANDS, G.F., PALLISER, A.C. and WAKELIN, D. (1984) Mucosal mast cells are functionally active during spontaneous expulsion of intestinal nematode infections in rat. Nature 312: 450-452.Google Scholar
XIAOWEN, Z., QINGHUA, Y., XIAOFEI, Z. and QIAN, Y. (2009) Co-administration of inactivated avian influenza virus with cpg or ril-2 strongly enhances the local immune response after intranasal immunization in chicken. Vaccine 27: 5628-5632.Google Scholar
YANG, P., YU, Z., GANDAHI, J.A., BIAN, X., WU, L., LIU, Y., ZHANG, L., ZHANG, Q. and CHEN, Q. (2012) The identification of c-kit-positive cells in the intestine of chicken. Poultry Science 91: 2264-2269.Google Scholar
YILDIZ, M., AYDEMİR, I., KUM, Ş. and EREN, Ü. (2016) The distribution and heterogeneity of mast cells in the cecum of quail (coturnix coturnix japonica). Kafkas Universitesi Veteriner Fakultesi Dergisi 22: 197-202.Google Scholar
ZARNEGAR, B., MENDEZ-ENRIQUEZ, E., WESTIN, A., SODERBERG, C., DAHLIN, J.S., GRONVIK, K.O. and HALLGREN, J. (2017) Influenza infection in mice induces accumulation of lung mast cells through the recruitment and maturation of mast cell progenitors. Frontiers in Immunology 8: 310.CrossRefGoogle ScholarPubMed
ZHANG, H., PENG, S-S., GE, T-T., ZHONG, S-W. and ZHOU, Z-H. (2014) Distribution of mast cells in stomach and small intestine of yugan black-bone fowl. Chinese Journal of Veterinary Science 7: 021.Google Scholar
ZHANG, X., ZHANG, X. and YANG, Q. (2007) Effect of compound mucosal immune adjuvant on mucosal and systemic immune responses in chicken orally vaccinated with attenuated newcastle-disease vaccine. Vaccine 25: 3254-3262.Google Scholar