Chronic histiocytic intervillositis: A breakdown in immune tolerance comparable to allograft rejection?

Abstract

Chronic histiocytic intervillositis (CHI) is a pregnancy disorder characterized by infiltration of maternal macrophages into the intervillous space of the human placenta, often with accompanying perivillous fibrin deposition. CHI is associated strongly with foetal growth restriction and increased risk of miscarriage and stillbirth. Although rare, affecting 6 in every 10 000 pregnancies beyond 12 weeks' gestation, the rate of recurrence is high at 25%-100%. To date, diagnosis of CHI can only be made post-delivery upon examination of the placenta due to a lack of diagnostic biomarkers, and criteria vary across publications. No treatment options have shown proven efficacy, and CHI remains a serious obstetric conundrum. Although its underlying aetiology is unclear, due to the presence of maternal macrophages and the reported increased incidence in women with autoimmune disease, CHI is hypothesized to be an inappropriate immune response to the semi-allogeneic foetus. Given this lack of understanding, treatment approaches remain experimental with limited rationale. However, there is recent evidence that immunosuppression and antithrombotic therapies may be effective in preventing recurrence of associated adverse pregnancy outcomes. With similarities noted between the pathological features of CHI and acute rejection of solid organ transplants, further investigation of this hypothesis may provide a basis for tackling CHI and other immune-related placental conditions. This review will explore parallels between CHI and allograft rejection and identify areas requiring further confirmation and exploitation of this comparison.

Keywords: HLA; graft rejection; macrophages; miscarriage; placenta; pregnancy; stillbirth.

FIGURE 1

Histological characteristics of a placenta affected by chronic histiocytic intervillositis (CHI) compared with that of a healthy control pregnancy. Immunohistochemical staining demonstrates infiltration of maternal CD68⁺ macrophages (M) into the intervillous space (IVS) of the placenta in CHI, surrounding foetal villi (V). Fibrin (F) shown by haematoxylin and eosin (H&E) staining as a shade of dark pink is present to a degree within the healthy term placenta, though is considerably increased in cases of CHI. Scale bars = 50μm

FIGURE 2

Suggested pathophysiology of chronic histiocytic intervillositis (CHI) of the placenta. Maternal monocytes, predominantly CD68 + M2‐like macrophages, infiltrate the intervillous space of the placenta, in association with increased fibrin deposition. ⁶⁷ CD4+ and CD8 + T cells are also increased within maternal blood surrounding the foetal villi, though they constitute a much smaller proportion of the infiltrate. ¹¹ In addition to T cells directed towards paternal antigens, anti‐HLA antibodies have been identified in women affected by CHI and are hypothesized to interact with antigens expressed on the placenta. ¹² In some cases of CHI, deposition of the complement protein C4d, usually associated with an antibody‐mediated immune response and macrophage recruitment, is increased along the surface of the syncytiotrophoblast. ⁶³ Increased intercellular adhesion molecule‐1 (ICAM‐1) expression by syncytiotrophoblast is also hypothesized as a contributory factor in macrophage recruitment. ⁷⁵ Expression of CD39, an ectonucleotidase responsible for hydrolysis of damage‐associated molecular patterns (DAMPs), is decreased in CHI in areas of dense cellular infiltration, suggesting it may also be involved in the maternal inflammatory response. ⁷⁷ The mechanism of fibrin deposition in CHI is unclear, though it is often present as a non‐specific response to placental damage. ¹¹¹ Macrophages in CHI have been found to express complement receptor CR4, which outside of CHI is capable of mediating monocyte adhesion to fibrinogen, though remains unexplored in this context. ⁶⁷ Certain cases of CHI demonstrate increased toll‐like receptor 1 (TLR1) expression, suggesting a possible bacterial component, though this is not always evident. ⁸¹ Figure created with BioRender.com

FIGURE 3

Immunohistochemical staining of complement cascade split product C4d in a healthy placenta and a case of chronic histiocytic intervillositis (CHI), compared with a biopsy of a kidney with confirmed antibody‐mediated rejection (AMR). In some cases of CHI, C4d is present along the apical membrane of the syncytiotrophoblast, similar to deposition within the vessels (Ve) of a rejected kidney allograft. Within placentas affected by CHI, terminal villi are often entrapped within deposits of fibrin (F). IVS = intervillous space, V = villi. Scale bars = 100μm