Current topicThe immunological basis of villitis of unknown etiology – Review
Introduction
Villitis of unknown etiology (VUE) is one of the most common, inflammatory placental lesions [1], [2]. Albeit visualized at any gestation, its incidence is higher at term [2]. Histologically, VUE is characterized by an “inflammatory cell infiltrate”, containing Höfbauer cells (placental macrophages) and T-cell lymphocytes within the placental villi, in the absence of an infective etiology [3]. The placental pathology was first recognized in the 1960's by Gershon and Strauss [4], but not until 1975 was VUE defined and differentiated pathologically from placental lesions of a known infective source [5]. Even today, VUE remains a placental enigma and its importance is significantly under recognized due in part to a lack of awareness amongst clinicians. This review will describe our current understanding of VUE, its clinical consequences, and the most current hypotheses regarding its true underlying etiology.
Section snippets
Background
VUE is a solely histopathological diagnosis which can further be classified according to distinct patterns of trophoblast villous involvement (Fig. 1b–d). The predominant diagnostic feature of VUE is simply an inflammatory cell infiltrate, characterized by mononuclear cells and areas of destructive fibrinoid necrosis, within the substance of the chorionic villi in the absence of an identifiable infectious agent [5], [6], [7], [8], [9]. Unlike villitis of infectious origin, a cardinal feature is
Clinical implications of VUE
Normal pregnancy remains the most common outcome in association with VUE both at term and preterm [17], [18]. However, there is evidence to suggest VUE is not simply a “benign placental lesion”. VUE has been associated with a range of adverse pregnancy outcomes as summarized in Table 1; pre-term labor (PTL) [19], [20], [21], intra-uterine growth restriction (IUGR) and small for gestational age (SGA) [5], [7], [9], [17], [18], [20], [22], [23], [24], [25], [26], [27], spontaneous pregnancy loss
VUE pathogenesis – an unidentified microbial antigen?
Two main hypotheses currently exist regarding the underlying pathogenesis of VUE. The first is that a response to an unidentified underlying infection is responsible, with the nature of the potential organism, (i.e. bacterial or viral) undetermined. Infections are certainly a well-defined cause of chronic villitis including; varicella [32], Toxoplasmosis [32], rubella, herpes simplex virus and Cytomegalovirus (Reviewed in Altshuler 1975, and Boog 1996) [5], [8], [17]. Specifically considering
VUE pathogenesis – a failure of maternal–fetal tolerance?
Pregnancy presents a unique challenge for the maternal immune system with maternal–fetal tolerance essential for protecting the genetically foreign semi-allogeneic fetus [37]. The second hypothesis as to the etiology of VUE is that it has a primary immunological etiology, and is a manifestation of failed maternal–fetal tolerance [36]. Since 1993, when Redline R, et al. proposed a hypothesis akin to allograft rejection, the immunological basis of VUE has gained particular interest [36].
In
Immunological mechanisms in VUE
There have been many recent advances in our understanding of the mechanisms that enable normal maternal–fetal tolerance during pregnancy, many of which may be relevant for our understanding of the events initiating abnormal infiltration of lymphocytes into the placental villi [37], [43].
There are several stages immunologically during which normal physiological processes could be disrupted and contribute to the development of VUE. There may be abnormal exposure to fetal antigens or presentation
Conclusion
Despite recognition that VUE represents a common, under-diagnosed major placental inflammatory lesion, uncertainties regarding both its underlying pathogenesis and exact clinical implications persist. In part this is due to it being a retrospective diagnosis and the general lack of awareness amongst clinical obstetricians.
Despite promising advances, delineating the primary immune basis of VUE continues to be a challenge. There is however a growing consensus that VUE results from disruption of
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