Elsevier

Theriogenology

Volume 104, December 2017, Pages 62-71
Theriogenology

Mucosal immunity of the postpartum bovine genital tract

https://doi.org/10.1016/j.theriogenology.2017.08.010Get rights and content

Highlights

  • Complexity of the mucosal immune system in the postpartum bovine genital tract is highlighted.

  • Uterine involution is an inflammatory process that needs to be resolved in a timely manner for rebreeding to occur.

  • Role of the epithelial cells in bacterial sensing, non-specific immune response and immune regulation is discussed.

  • Neutrophil and macrophages are the first line of uterine immune defense against the infections.

  • Complex interactions between the innate immune cells and lymphocytes facilitate an immune response in a controlled manner.

  • Role of the genital tract microbiome in the pathogenesis and regulation of uterine inflammation is emphasized.

Abstract

In this review, mucosal immune defense mechanisms used to control infections in the bovine genital tract (vestibule, vagina, cervix, uterus and oviduct) during the postpartum period are reviewed. Knowledge gaps are highlighted to emphasize the need for further investigations. Physical barriers to the entry of microbes include vulvar sealing, vestibule-vaginal constriction, a narrow cervical opening and the mucosal epithelium along with the overlying mucus layer. Genital tract mucosal epithelial cells recognize damage-associated molecular patterns and pathogen-associated molecular patterns and respond by secreting antimicrobial peptides and cytokines to recruit and activate immune cells. Neutrophils and macrophages represent the first line of innate immune defenses recruited by cytokines to the site of inflammation. Macrophages, endometrial epithelial cells and dendritic cells interact with T-cells to elicit cellular responses and regulate antibody responses. Immune regulatory components such as M2-macrophages and regulatory T-cells, although less studied, may work in conjunction with epithelial cell regeneration to coordinate involution of the postpartum uterus and prepare the genital tract for the next pregnancy. A role for the vaginal and uterine microbiome in modulating uterine inflammation is an emerging research focus and further studies are required to integrate information on the nutritional and metabolic status of cows with innate immune responses and host-microbiome interactions. A greater understanding of these complex interactions is critical for developing more effective therapies for the prevention and treatment of uterine inflammation.

Introduction

The bovine female genital tubular system is functionally adapted to facilitate oocyte fertilization, nurture embryonic/fetal development, deliver a calf, and ensure a timely return to a pre-gravid state. Immunologically, the female genital system exhibits a large degree of flexibility from what is believed to be an immunotolerant state during pregnancy to the ability to mount active immune responses when encountering genital pathogens. The mechanisms of immunosuppression during bovine pregnancy have been extensively reviewed [1], [2], [3] and will not be covered in the present report. The current review will focus on knowledge of innate and acquired mucosal immune responses and their regulation during the postpartum period (up to 60 days in milk) in cattle.

The female genital tubular tract has several known physical barriers to minimize bacterial entry and colonization. These include vulvar sealing, vestibule-vaginal constriction, the cervix, cervico-vaginal mucus secretion, and the epithelial barrier, but until recently an in depth understanding of these and other protective mechanisms at a cellular and molecular level was lacking. Classically, mucosal sites such as the intestine, respiratory tract, and ocular mucosa are associated with organized sub-mucosal lymphoid tissue, collectively referred to as mucosal-associated lymphoid tissues (MALT), that is populated by both T- and B-lymphocytes [4]. The MALT constitutes a crucial inductive site for both antibody-dependent humoral (mainly immunoglobulin (Ig) A) and cellular immune responses against potential antigens. Isolated lymphoid aggregates (follicles) and isolated lymphoid infiltrations have been observed in the vestibule and throughout the rest of female genital tract of cattle, respectively [5]. Lymph fluid from the bovine uterus drains primarily to the internal iliac and sacral lymph nodes, which also function as important immune induction sites [6].

The following sections will focus on mucosal defense mechanisms of the bovine tubular genital tract during the postpartum period. Integration of epithelial cell function and immune mechanisms is crucial for maintaining the integrity of the mucosal barrier and this interaction will be emphasized. Where necessary, information from other species is incorporated to provide a comparative analysis of immune function and to highlight knowledge deficits that need to be addressed to better understand the function of the bovine postpartum uterus.

Section snippets

Genital tract inflammation during the postpartum period

Following delivery of a calf, the bovine genital tract undergoes an active inflammatory process to clear cellular debris from the placenta and respond to bacterial contamination. In healthy cows, uterine inflammation subsides by the fourth to fifth wk postpartum, however, genital tract (mainly uterus) reparation is not complete until the sixth to eighth wk postpartum [7]. Some cows will, however, exhibit either a systemic inflammatory response during the first two wk postpartum or will

Epithelial cells

The mucosal epithelial lining of the genital tract offers a physical defense mechanism against microbial attachment and invasion. The type of mucosal epithelium and the thickness of this layer varies with the anatomical location, responding to differing physiological needs (Fig. 1). A multilayered squamous epithelium in the vestibule and vagina [5] is important as these sites are the first to be challenged by bacteria from fecal, uterine and environmental origins. Extensive folding of the

Microflora

Bacterial contamination of the uterus from vaginal, fecal and environmental microflora occurs for two to three wk postpartum due to calving-associated relaxation of physical barriers, including an open cervix. Negative pressure events created by repeated uterine contraction and relaxation during this period enhances bacterial contamination by virtue of a vacuum effect. Regardless of circumstances, Gram-negative bacteria predominate in all bovine uteri during the first wk after calving and are

Conclusions

The bovine genital tract, like other mucosal surfaces, has an epithelium that can respond to PAMPs and DAMPs, eliciting local activation and recruitment of innate immune cells. Substantial knowledge has been acquired regarding the innate and acquired immune defense mechanisms present throughout the bovine genital tract (Table 1). For example, while the genital tract does not have specialized mucosa-associated lymphoid tissues, as seen in the gastro-intestinal and respiratory tracts, isolated

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