THE IMMUNE SYSTEM OF BIRDS AND MAMMALS: COMPARATIVE CHARACTERISTICS
DOI:
https://doi.org/10.37000/abbsl.2022.104.06Keywords:
bird, mammals, immune system, similarities and differencesAbstract
This review summarises the current state of knowledge of the chicken's immune response, highlighting differences in the bird compared to mammals. Birds and mammals evolved from a common reptilian-like ancestor over 200 million years ago, so there has been ample opportunity for parallel evolution in the development of their immune systems. The avian immune system operates on the same general principles as the mammalian immune system. Antigenic stimulation initiates an immune response that involves cellular cooperation most notably between macrophages, B lymphocytes and T lymphocytes. Macrophages process the antigen and present the antigen to the lymphocytes. B lymphocytes, the principal cells that mediate humoral immunity, transform into plasma cells and produce antibodies. T lymphocytes, most important for cellular immunity, differentiate into functionally diverse subpopulations. Among the avian species, the immune system of the chicken has been studied most extensively. There are many similarities between the general immune mechanisms of mammals and chickens. There are also important differences. Our knowledge of the avian immune system and the avian immune response to disease and vaccination still lags behind that of better studied biomedical model systems, such as the human and mouse, progress has been dramatic. Thanks to the chicken genome sequence, we now have far greater understanding of the genes and molecules available to the avian immune response and, therefore, access to the tools required to enable us to understand the biology of that response in far greater detail than previously. In broad terms, the immune systems and responses of mammals and birds are similar. However, when one looks at the organs, cells, and molecules of the immune response in birds, one begins to understand that mammals and birds achieve the same overall responses often in quite different ways and, in many respects (but not all), the avian immune response is different. Birds rely on gene conversion to generate an antibody repertoire, and the major histocompatability complex is some 20-fold smaller than that of mammals. Birds respond to antigenic stimulation by generating antibodies as well as cellular immunity. There are three principal classes of antibodies in birds i.e., IgM, IgG (also called IgY) and IgA. Antibody diversity is achieved by gene conversion. T cells are the main effector cells of cellular immunity. Recently, genes of several avian cytokines have been cloned and expressed. In order to develop novel solutions to avian disease problems, including novel vaccines and/or vaccine adjuvants, and the identification of disease resistance genes which can feed into conventional breeding programmes, it is necessary to gain a more thorough understanding of the avian immune response and how pathogens can subvert that response. Studies of avian vaccinology provide important insights as well as pioneering developments, such as embryonic vaccination. Avian immunology is a growing field of study that offers exciting prospects and still has much to contribute to mainstream immunology.
References
Balázs Felföldi, Gergely Imre, Botond Igyártó, Judit Iván, Rudolf Mihalik, Erzsébet Lackó, Imre Oláh, and Attila Magyar. In ovo vitelline duct ligation results in transient changes of bursal microenvironments. Immunology. 2005 Oct; 116(2): 267–275. doi: 10.1111/j.1365-2567.2005.02221.x.
Ballou AL, Ali RA, Mendoza MA, et al. Development of the chick microbiome: how early exposure influences future microbial diversity. Front Vet Sci 2016; 3:2https://doi.org/10.3389/fvets.2016.00002
Boehm T, Bleul CC: The evolutionary history of lymphoid organs, Nat Immunol 8:131–135, 2007.
Boyd, R. and Wick, G. (1980) Killer cells in the chicken: a microcytotoxicity assay using antigen-coated erythrocytes as targets. Journal of Immunological Methods 35: 233–247.
Brownlie , R. , Zhu , J. , Allan , B. , Mutwiri , G.K. , Babiuk , L.A. , Potter , A. & Griebel , P. 2009 . Chicken TLR21 acts as a functional homologue to mammalian TLR9 in the recognition of CpG oligodeoxynucleotides . Molecular Immunology 46 , 3163 3170 . doi: 10.1016/j.molimm.2009.06.002
Casteleyn C, Doom M, Lambrechts E, Van den Broeck W, Simoens P, Cornillie P Locations of gut-associated lymphoid tissue in the 3-month-old chicken: a review.
.Avian Pathol. 2010 Jun;39(3):143-50. doi: 10.1080/03079451003786105.PMID: 20544418 Review
Chan, M.M., Chen, C.H. and Cooper, M.D. (1988) Identification of avian homologues of mammalian CD4 and CD8 antigens. Journal of Immunology 140: 2133.
Chen, H.L., Li, D.F., Chang, B.Y., Gong, L.M., Piao, X.S., Yi, G.F. and Zhang, J.X. (2003b) Effects of lentinan on broiler splenocyte proliferation, interleukin-2 production, and signal transduction. Poultry Science 82: 760–766.
Cormican , P. , Lloyd , A.T. , Downing , T. , Connell , S.J. , Bradley , D. & O'Farrelly , C. 2009 . The avian Toll-Like receptor pathway—subtle differences amidst general conformity . Developmental and Comparative Immunology 33 , 967 973 . doi: 10.1016/j.dci.2009.04.001
del Cacho , E. , Gallego , M. , Lillehoj , H.S. , López-Bernard , F. & Sánchez-Acedo , C. 2009 . Avian follicular and interdigitating dendritic cells: isolation and morphologic, phenotypic, and functional analyses . Veterinary Immunology and Immunopathology 129 , 66 75 . doi: 10.1016/j.vetimm.2008.12.015.
Davison F. The importance of the avian immune system and its unique features // Avian Immunology. – Elsevier Ltd., 2008. – P. 2-19.
Farnell , M.B. , Crippen , T.L. , He , H. , Swaggerty , C.L. & Kogut , M.H. 2003a . Oxidative burst mediated by toll like receptors (TLR) and CD14 on avian heterophils stimulated with bacterial toll agonists . Developmental and Comparative Immunology 27 , 423 429 . doi: 10.1016/S0145-305X(02)00115-5
Farnell , M.B. , He , H. & Kogut , M.H. 2003b . Differential activation of signal transduction pathways mediating oxidative burst by chicken heterophils in response to stimulation with lipopolysaccharide and lipoteichoic acid . Inflammation 27 , 225 231 . doi: 10.1023/A:1025088514676.
Fife , M.S. , Salmon , N. , Hocking , P. & Kaiser , P. 2009 . Fine mapping of the chicken salmonellosis resistance locus (SAL1) . Animal Genetics 40 , 871 877 . doi: 10.1111/j.1365-2052.2009.01930.x
Fukui , A. , Inoue , N. , Matsumoto , M. , Nomura , M. , Yamada , K. , Matsuda , Y. , et al. . 2001 . Molecular cloning and functional characterization of chicken toll-like receptors. A single chicken toll covers multiple molecular patterns . Journal of Biological Chemistry 276 , 47143 47149 . doi: 10.1074/jbc.M103902200.
Fussell, L.W. (1998) Poultry industry strategies for control of immunosuppressive diseases. Poultry Science 77: 1193-1196.CrossRefGoogle ScholarPubMed.
Gadde U, Rathinam T, Lillehoj HS. Passive immunization with hyperimmune egg-yolk IgY as prophylaxis and therapy for poultry diseases-a review. Anim Health Res Rev 2015; 16:163–76. https://doi.org/10.1017/S1466252315000195.
Garceau, V., Smith, J., Paton, I.R., Davey, M., Fares, M.A.Sester, D.P. 2010. Avian colony-stimulating factor 1 (CSF-1), interleukin-34 (IL-34), and CSF-1 receptor genes and gene products. Journal of Leukocyte Biology, 87: 753–764.
Gibson, M.S., Kaiser, P. and Fife, M. 2009. Identification of chicken granulocyte colony stimulating factor (G-CSF/CSF3); the previously described myelomonocytic growth factor is actually CSF3. Journal of Interferon and Cytokine Research, 29: 339–344.
Goldsby, R.A., Kindt, T., Osborne, B. and Kuby, J. (2003) Immunology, 5th edition, New York, W.H. Freeman.
Gómez Del Moral M, Fonfría J, Varas A, Jiménez E, Moreno J, Zapata A G. Appearance and development of lymphoid cells in the chicken (Gallus gallus) caecal tonsil. Anat Rec . 1998 Feb;250(2):182-9. doi: 10.1002/(SICI)1097-0185(199802)250:2<182::AID-AR8>3.0.CO;2-5.
Hanan Al-Khalaifah, A. Al-Nasser. Cytokines as Effective Elements of the Avian Immune System. Journal of Microbiology and Genetics. October 2018. https://gavinpublishers.com/articles/mini-review/Journal-of-Microbiology-and-Genetics-ISSN-2574-7371/cytokines-as-effective-elements-of-the-avian-immune-system.
Harmon, B.G. (1998) Avian heterophils in inflammation and disease resistance. Poultry Science 77: 972–977.
Higuchi , M. , Matsuo , A. , Shingai , M. , Shida , K. , Ishii , A. , Funami , K. , et al. . 2008 . Combinational recognition of bacterial lipoproteins and peptidoglycan by chicken Toll-like receptor 2 subfamily . Developmental and Comparative Immunology 32 , 147 155 . doi: 10.1016/j.dci.2007.05.003.
Hirakawa R, Nurjanah S, Furukawa K, et al. Heat stress causes immune abnormalities via massive damage to effect proliferation and differentiation of lymphocytes in broiler chickens. Front Vet Sci 2020; 7:46https://doi.org/10.3389/fvets.2020.00046
Hoerr, F.J. (2010) Clinical Aspects of Immunosuppression in Poultry. Avian Diseases 54: 2-15.CrossRefGoogle ScholarPubMed
Hudson, J.C., Hoerr, E.J., Parker, S.H. and Ewald, S.J. (2002) Quantitative measures of disease in broiler breeder chicks of different major histocompatibility complex genotypes after challenge with infectious bursal disease virus. Avian Diseases 46: 581-592.CrossRefGoogle ScholarPubMed
Hughes , S. , Poh , T.Y. , Bumstead , N. & Kaiser , P. 2007 . Re-evaluation of the chicken MIP family of chemokines and their receptors suggests that CCL5 is the prototypic MIP family chemokine, and that different species have developed different repertoires of both the CC chemokines and their receptors . Developmental and Comparative Immunology 31 , 72 86 . doi: 10.1016/j.dci.2006.04.003
Hung , L.H. , Li , H.P. , Lien , Y.Y. , Wu , M.L. & Chaung , H.C. 2010 . Adjuvant effects of chicken interleukin-18 in avian Newcastle disease vaccine . Vaccine 28 , 1148 1155 . doi: 10.1016/j.vaccine.2009.11.042
Igyarto , B.-Z. , Lacko , E. , Olah , I. & Magyar , A. 2006 . Characterization of chicken epidermal dendritic cells . Immunology 119 , 278 288 . doi: 10.1111/j.1365-2567.2006.02432.x
Igyarto , B.-Z. , Magyar , A. & Olah , I. 2007 . Origin of follicular dendritic cell in the chicken spleen . Cell and Tissue Research 327 , 83 92 . doi: 10.1007/s00441-006-0250-0
International Chicken Genome Sequencing Consortium . 2004 . Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution . Nature 432 , 695 716 . doi: 10.1038/nature03154.
International Chicken Polymorphism Map Consortium . 2004 . A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms . Nature , 432 , 717 722 . doi: 10.1038/nature03156.
Janardhana V, Broadway MM, Bruce MP, et al. Prebiotics modulate immune responses in the gut-associated lymphoid tissue of chickens. J Nutr 2009; 139:1404–9. https://doi.org/10.3945/jn.109.105007
Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Reddy DN. Role of the normal gut microbiota. World J Gastroenterol 2015; 21:8787–803. https://doi.org/10.3748/wjg.v21.i29.8787.
Jia Y, Si W, Hong Z, et al. Toll-like receptor 2-mediated induction of avian β-defensin 9 by Lactobacillus rhamnosus and its cellular components in chicken intestinal epithelial cells. Food Agric Immunol 2019; 30:398–417. https://doi.org/10.1080/09540105.2019.1593325.
Júnior A.F, dos Santos J.P., de Oliveira S.I., Martin I., Alves T.G.L., Rosado I.R. Gallus gallus domesticus: immune system and its potential
for generationof immunobiologics. Ciência Rural, Santa Maria, v.48:08, e20180250, 2018. http://dx.doi.org/10.1590/0103-8478cr20180250
Kabir SML. The role of probiotics in the poultry industry. Int J Mol Sci 2009; 10:3531–46. https://doi.org/10.3390/ijms10083531.
Kaiser P. Advances in avian immunology – prospects for disease control: a review. Avian Pathology. Vol 39, 2010. P.309-324. https://doi.org/10.1080/03079457.2010.508777
Kaiser , P. 2007 . The avian immune genome—a glass half-full or half-empty? Cytogenetic and Genome Research , 117 , 221 230. doi: 10.1159/000103183
Kaiser, P., Howell, J., Fife, M., Sadeyen, J.R., Salmon, N.Rothwell, L. 2008. Integrated immunogenomics in the chicken: deciphering the immune response to identify disease resistance genes. Developmental Biology (Basel), 132: 57–66.
Kaiser, P., Howell, J., Fife, M., Sadeyen, J.R., Salmon, N.Rothwell, L. 2009. Towards the selection of chickens resistant to Salmonella and Campylobacter infections. Bulletin et Mémoires de l'Académie Royale de Médecine de Belgique, 164: 17–25.
Kaiser , P. , Poh , T.Y. , Rothwell , L. , Avery , S. , Balu , S. , Pathania , U.S. , et al. . 2005 . A genomic analysis of chicken cytokines and chemokines . Journal of Interferon and Cytokine Research , 25 , 467 484 . doi: 10.1089/jir.2005.25.467.
Kaufman, J., Milne, S., Gobel, T.W., Walker, B.A., Jacob, J.P.Auffray, C. 1999. The chicken B locus is a minimal essential major histocompatibility complex. Nature, 401: 923–925.
Keesun Y., Inhwan C., Cheol-Heui Y. Immunosecurity: immunomodulants enhance immune responses in chickens. Animal Bioscience 2021; 34(3): 321-337. Special Issue. https://doi.org/10.5713/ab.20.0851
Kogut , M.H. , Iqbal , M. , He , H. , Philbin , V. , Kaiser , P. & Smith , A. 2005 . Expression and function of Toll-like receptors in chicken heterophils . Developmental and Comparative Immunology , 29 , 791 807 . doi: 10.1016/j.dci.2005.02.002.
Kogut , M.H. , Swaggerty , C. , He , H. , Pevzner , I. & Kaiser, P. 2006 . Toll-like receptor agonists stimulate differential functional activation and cytokine and chemokine gene expression in heterophils isolated from chickens with differential innate responses . Microbes and Infection , 8 , 1866 1874 . doi: 10.1016/j.micinf.2006.02.026.
Koskela K, Nieminen P, Kohonen P, Salminen H, Lassila O. Chicken B-cell-activating-factor: regulator of B-cell survival in the bursa of Fabricius. Scan J Immunol. 2004;59:449–57. [PubMed] [Google Scholar].
Kowalczyk K, Daiss J, Halpern J, Roth TF. Quantitation of maternal-fetal IgG transport in the chicken. Immunology. 1985;54:755–62. [PMC free article] [PubMed] [Google Scholar]
Kromer, G., Schauenstein, K. and Wick, G. (1984) Avian lymphokines: an improved method for chicken IL-2 production and assay. A con A-erythrocyte complex induces higher T cell proliferation and IL-2 production than does free mitogen. Journal of Immunological Methods 73: 273–281.
Lamont, S.J., Dekkers, J.C.M. and Zhou, H. (2014) Immunogenetics and the Mapping of Immunological Functions. Academic press, 2nd ed. 205-221.CrossRefGoogle Scholar.
Latorre JD, Hernandez-Velasco X, Bielke LR, et al. Evaluation of a Bacillus direct-fed microbial candidate on digesta viscosity, bacterial translocation, microbiota composition and bone mineralisation in broiler chickens fed on a rye-based diet. Br Poult Sci 2015; 56:723–32. https://doi.org/10.1080/00071668.2015.1101053.
Lee SH, Lillehoj HS, Park DW, et al. Protective effect of hyperimmune egg yolk IgY antibodies against Eimeria tenella and Eimeria maxima infections. Vet Parasitol 2009; 163:123–6. https://doi.org/10.1016/j.vetpar.2009.04.020
Lee S, La TM, Lee HJ, et al. Characterization of microbial communities in the chicken oviduct and the origin of chicken embryo gut microbiota. Sci Rep 2019; 9:6838https://doi.org/10.1038/s41598-019-43280-w.
Li XY, Jin LJ, McAllister TA, et al. Chitosan-alginate microcapsules for oral delivery of egg yolk immunoglobulin (IgY). J Agric Food Chem 2007; 55:2911–7. https://doi.org/10.1021/jf062900q.
Litman GW, Rast JP, Fugmann SD: The origins of vertebrate adaptive immunity, Nat Rev Immunol 10:543–553, 2010.
Lynn , D.J. , Higgs , R. , Lloyd , A.T. , O'Farrelly , C. , Hervé-Grépinet , V. , Nys , Y. , et al. . 2007 . Avian beta-defensin nomenclature: a community proposed update . Immunology Letters , 110 , 86 89 . doi: 10.1016/j.imlet.2007.03.007.
Madej JP, Bednarczyk M. Effect of in ovo-delivered prebiotics and synbiotics on the morphology and specific immune cell composition in the gut-associated lymphoid tissue. Poult Sci 2016; 95:19–29. https://doi.org/10.3382/ps/pev291
Philbin , V.J. , Iqbal , M. , Boyd , Y. , Goodchild , M.J. , Beal , R.K. , Bumstead , N. , et al. . 2005 . Identification and characterization of a functional, alternatively spliced Toll-like receptor 7 (TLR7) and genomic disruption of TLR8 in chickens . Immunology , 114 , 507 521 . doi: 10.1111/j.1365-2567.2005.02125.x.
Poli, G., Zanella, A., Dall'ara, P. and Bonizzi, L. (2000) Avian immunology: the old and the new. [Italian]. Selezione Veterinaria 8/9: 535–560.
Qureshi, M.A. (2003) Avian macrophage and immune response: an overview. Poultry Science 82: 691–698.
Reese S., Dalamani G., Kaspers B. The avian lung-associated immune system: a review. Veterinary Research, BioMed Central, 2006, 37 (3), pp.311-324. https://hal.archives-ouvertes.fr/hal-00903026.
Roach , J.C. , Glusman , G. , Rowen , L. , Kaur , A. , Purcell, M.K. , Smith , K.D. , et al. . 2005 . The evolution of vertebrate Toll-like receptors . Proceedings of the National Academy of Sciences USA , 102 , 9577 9582 . doi: 10.1073/pnas.0502272102.
Schaffner T, Mueller J, Hess MW, Cottier H, Sordat B, Ropke C. The bursa of Fabricius: a central organ providing contact between the lymphoid system and intestinal content. Cell Immunol. 1974;13:304–12. [PubMed] [Google Scholar].
Sharma J.M. (1997) The structure and function of the avian immune system. Acta Veterinaria Hungarica, 01 Jan 1997, 45(3):229-238. https://europepmc.org/article/med/9276985
Shini, S., Huff, G.R., Shini, A. and Kaiser, P. (2010) Understanding stress-induced immunosuppression: Exploration of cytokine and chemokine gene profiles in chicken peripheral leukocytes. Poultry Science 89: 841-851.CrossRefGoogle ScholarPubMed.
Sornplang P, Leelavatcharamas V, Soikum C. Heterophil phagocytic activity stimulated by Lactobacillus salivarius L61 and L55 supplementation in broilers with Salmonella infection. Asian-Australas J Anim Sci 2015; 28:1657–61. https://doi.org/10.5713/ajas.15.0359.
Sorvari R, Sorvari TE. Bursa Fabricii as a peripheral lymphoid organ. Immunology. 1977;32:499–505. [PubMed] [Google Scholar]
Staines K., Young J. R., Butter C. Expression of chicken DEC205 reflects the unique structure and function of the avian immune system. January 2013. Volume 8. Issue 1. doi:10.1371/journal.pone.0051799.
Stefaniak T, Madej JP, Graczyk S, et al. Selected prebiotics and synbiotics administered in ovo can modify innate immunity in chicken broilers. BMC Vet Res 2019; 15:105https://doi.org/10.1186/s12917-019-1850-8.
Suresh G, Das RK, Kaur Brar SK, et al. Alternatives to antibiotics in poultry feed: molecular perspectives. Crit Rev Microbiol 2018; 44:318–35. https://doi.org/10.1080/1040841X.2017.1373062.
Swaggerty , C.L. , Ferro , P.J. , Pevzner , I.Y. & Kogut , M.H. 2005 Heterophils are associated with resistance to systemic Salmonella enteritidis infection in genetically distinct lines of chickens . FEMS Immunology and Medical Microbiology 43 149 154 doi: 10.1016/j.femsim.2004.07.013.
Swaggerty , C.L. , Kogut , M.H. , Ferro , P.J. , Rothwell , L. , Pevzner , I.Y. & Kaiser , P. 2004 Differential cytokine mRNA expression in heterophils isolated from Salmonella-resistant and -susceptible chickens . Immunology 113 139 148 doi: 10.1111/j.1365-2567.2004.01939.x .
Swaggerty , C.L. , Pevzner , I.Y. , Lowry , V.K. , Farnell , M.B. & Kogut , M.H. 2003b Functional comparison of heterophils isolated from commercial broilerchickens . AvianPathology 32 95 102 doi: 10.1080/0307945021000070769.
Temperley , N.D. , Berlin , S. , Paton , I.R. , Griffin , D.K. & Burt , D.W. 2008 Evolution of the chicken Toll-like receptor gene family: a story of gene gain and gene loss . BMC Genomics 9 62 doi: 10.1186/1471-2164-9-62.
Tizard I.R. Avian Immune Responses: A Brief Review. Avian Diseases Vol. 23, No. 2 (Apr. - Jun., 1979), p. 290-298.
Tizard I.R. Veterinary immunology. – 9th ed. – Elsevier, 2013. – 615p.
Umar S., Munir M.T., Ahsan U., Raza I., Chowdhury M.R., Ahmed Z. and Shah M.A.A. Immunosuppressive interactions of viral diseases in poultry. World’s Poultry Science Journal. Vol. 73. Issue 1. March 2017. P. 121-135. https://doi.org/10.1017/S0043933916000829.
Umar, S., Ullah, S., Yaqoob, M., Shah, M.A.A. and Ducatez, M. (2014) Chicken infectious anaemia, an immunosuppressive disease of poultry birds. World's Poultry Science Journal 70: 759-766.CrossRefGoogle Scholar.
Umar, S., Arif, M., Shah, M.A.A., Munir, M.T., Ahmed, S. and Khan, M.I. (2015b) Application of Avian cytokines as immuno-modulating agents. World's Poultry Science Journal 71: 643-654.CrossRefGoogle Scholar.
Verwoolde MB, van den Biggelaar RHGA, van Baal J, Jansen CA, Lammers A. Training of primary chicken monocytes results in enhanced pro-inflammatory responses. Vet Sci 2020; 7:115https://doi.org/10.3390/vetsci7030115
Warren, W.C. , Clayton, D.F. , Ellegren, H. , Arnold, A.P. , Hillier, L.W. , Künstner , A. , et al. . 2010 The genome of a songbird . Nature 464 , 757 762 . doi: 10.1038/nature08819.
Wu , Z. , Rothwell , L. , Young , J. , Kaufman , J. , Butter , C. , & Kaiser , P. 2010 Generation and characterisation of chicken bone marrow-derived dendritic cells . Immunology 129, 133 145 . doi: 10.1111/j.1365-2567.2009.03129.x.
Xu Y, Li X, Jin L, et al. Application of chicken egg yolk immunoglobulins in the control of terrestrial and aquatic animal diseases: a review. Biotechnol Adv 2011; 29:860–8. https://doi.org/10.1016/j.biotechadv.2011.07.003.
Yasuda M, Tanaka S, Arakawa H, Taura Y, Yokomizo Y, Ekino S. A comparative study of gut-associated lymphoid tissue in calf and chicken. Anat Rec. 2002;266:207–17. [PubMed] [Google Scholar]
Zekarias, B., Terhuurne, A.A., Landman, W.J., Rebel, J.M., Pol, J.M. and Gruys, E. (2002) Immunological basis of differences in disease resistance in the chicken. Veterinary Research 33: 109-125.CrossRefGoogle ScholarPubMed
Гарагуля Г. І., Матковська С. Г. Гарагуля А. М., Стасюк В. О. Фагоцитарна активність клітин крові перепелів за імунної стимуляції. Аграрний вісник Причорномор'я. Одеса, 2019. № 93. С. 143–150.
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