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While many of the infertility cases are due to known causes, idiopathic infertility is reported in 30% of the infertile couples. In such cases, 18% of the infertile males carry antisperm antibodies (ASAs). Such data are lacking in livestock, wherein 20\u201330% of the animals are being culled due to low fertility. In males, the blood\u2013testis barrier (BTB) and biomolecules in the semen provide an immuno\u2010tolerant microenvironment for spermatozoa as they traverse the immunologic milieu of both the male and female reproductive tracts. For example, insults from environmental contaminants, infections and inflammatory conditions are likely to impact the immune privilege state of the testis and fertility. The female mucosal immune system can recognize allogenic spermatozoa\u2010specific proteins affecting sperm kinematics and sperm\u2010zona binding leading to immune infertility. Elucidating the functions and pathways of the immune regulatory molecules associated with fertilization are prerequisites for understanding their impact on fertility. An insight into biomolecules associated with spermatozoal immune tolerance may generate inputs to develop diagnostic tools and modulate fertility. High\u2010throughput sequencing technologies coupled with bioinformatics analyses provides a path forward to define the array of molecules influencing pregnancy outcome. This review discusses the seminal immune regulatory molecules from their origin in the testis until they traverse the uterine environment enabling fertilization and embryonic development. Well\u2010designed experiments and the identification of biomarkers may provide a pathway to understand the finer details of reproductive immunology that will afford personalized therapies.<\/jats:p>","DOI":"10.1002\/mrd.23263","type":"journal-article","created":{"date-parts":[[2019,9,13]],"date-time":"2019-09-13T13:34:05Z","timestamp":1568381645000},"page":"1485-1504","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Immune regulatory molecules as modifiers of semen and fertility: A review"],"prefix":"10.1002","volume":"86","author":[{"given":"S. Siddalingappa","family":"Archana","sequence":"first","affiliation":[{"name":"Reproductive Physiology Laboratory, Animal Physiology Division ICAR\u2010National Institute of Animal Nutrition and Physiology  Bengaluru India"},{"name":"Department of Biochemistry Jain University  Bengaluru India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5516-238X","authenticated-orcid":false,"given":"Sellappan","family":"Selvaraju","sequence":"additional","affiliation":[{"name":"Reproductive Physiology Laboratory, Animal Physiology Division ICAR\u2010National Institute of Animal Nutrition and Physiology  Bengaluru India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. 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