Villitis of unknown etiology

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Villitis of unknown etiology
Other namesChronic villitis
Villitis of unknown etiology - very high mag.jpg
Micrograph of villitis of unknown etiology. H&E stain.
Specialty Pathology, gynecology

Villitis of unknown etiology (VUE), also known as chronic villitis, is a placental injury. VUE is an inflammatory condition involving the chorionic villi (placental villi). VUE is a recurrent condition and can be associated with intrauterine growth restriction (IUGR). IUGR involves the poor growth of the foetus, stillbirth, miscarriage, and premature delivery. [1] [2] VUE recurs in about 1/3 of subsequent pregnancies. [3]

Contents

VUE is a common lesion characterised by inflammation in the placental chorionic villi. VUE is also characterised by the transfer of maternal lymphocytes across the placenta. [2]

VUE is diagnosed in 7–10% placentas in pregnancies. Roughly 80% of the VUE cases are in term placentas (greater than 37 weeks of pregnancy). A case of VUE in a placenta less than 32 weeks old should be screened for infectious villitis. [1]

Pathogenesis

Inflammatory cells of maternal origin could access the foetal villous stoma in multiple ways:

The villous trophoblast barrier could be damaged. In the third trimester, syncytial knots (nucleated clusters formed in the syncytiotrophoblast) break off [4] and are shed from the foetal placental villi. The shedding can strip the villous stroma. The barrier could breakdown either by upstream foetal thrombosis or ischemic damage from maternal infarction. The necrosis of syncytiotrophoblasts could arise as a result of the activation of coagulation components, complement system or platelets by antibodies or antiphospholipids. [5]

Syncytiotrophoblasts can be made to exhibit adhesion molecules (intracellular adhesion molecule 1, E-selectin) in VUE, although in normal conditions adhesion molecules are not expressed. [6]

Maternal lymphocytes can enter the foetal stroma by passing the villous trophoblastic barrier via the anchoring villi. The anchoring villi lose their layer of continuous epithelial syncytiotrophoblast as the villi mature into invasive intermediate trophoblasts through the developmental course of the placenta. A trophic factor, IL-15, for CD8+ memory T-cells is expressed by decidual stromal cells. The trafficking of maternal lymphocytes responding to an antigen in the chronic deciduitis could activate and enter via the decidua. [7] [8]

VUE is a T-cell mediated, CD8+ dominating inflammatory reaction. VUE develops in the foetal fibrovasculature stroma of the placenta villi usually towards the end of pregnancy (term placentas). [1] The lymphocytes in VUE are of maternal origin. VUE is a host-derived inflammatory response happening within a donor allograft tissue. The non-T-cell component of the inflammatory infiltrate originates both from the maternal and placental side. Majority of the antigen-presenting cells were Hofbauer cells (macrophages) were of foetal origin. [9] [10] Perivillous monocyte-macrophages and histiocytic giant cells were of maternal origin. [11] Foetal macrophages in VUE proliferate and are activated as a result of the up-regulation of MHC class 2 antigen expression. [12] [13] [14] Examination of a male placenta with VUE demonstrated that 11.2% of the intravillous CD3+ lymphocytes were foetal, and 88.8% were maternal. Macrophages, intervillous lymphocytes, multinucleated giant cells were maternal; 10.5% of intravillous CD68+ cells and 96.4% of perivillous CD68+ cells were maternal. Lymphocytes were predominantly maternal T-cells. [11] Maternal cells can enter the placental villi and the foetus as well. [15]

Diagnosis

VUE can be of 2 types, low grade chronic villitis or high grade chronic villitis. Low grade chronic villitis involves less than 10 villi containing lymphocytes. Low grade chronic villitis can be either focal or multifocal. Focal has involved villi on only one glass slide, while multifocal has involved villi on at least two slides. High grade chronic villitis has more than 10 inflamed villi per focus. High grade chronic villitis is differentiated into diffuse and patchy. The term patchy is used if less than 30% of distal villi are involved. The term diffuse is used if more than 30% of distal villi are involved. [ citation needed ]

VUE has 2 prominent distinct patterns. Approximately 50% of the cases only involve the distal villi (mature intermediate and terminal villi) and do not involve the proximal stem villi, the anchoring villi embedded in the basal plate, and the chorionic plate. The second most common pattern (roughly 30% of VUE cases) involves the proximal stem villi (and possibly the chorionic plate) and the distal villi usually. This type of VUE is linked with foetal vascular obtrusive lesions (Obliterative Foetal Vasculopathy). [1] [16]

VUE does not have specific clinical signs and symptoms suggesting diagnosis; but an analysis of the inflammatory filtrate can aid in diagnosis. [1] The composition of inflammatory infiltrate in VUE on a cellular level is primarily macrophages and lymphocytes. The relative proportions of cells vary case by case. The lymphocytes present in VUE are predominantly CD8+ T-cells then CD4. There is usually a ratio of 0.1 to 0.5 for CD4/CD8. [17] [18] The macrophages present are mainly Mac387-, followed by CD68 and HAM56+. Class 2 major histocompatibility complex (MHC) antigens on macrophages are up-regulated at sites of VUE. Neutrophils should not be present at sites of VUE. VUE is a condition involving inflammation and not infection. High numbers of neutrophils are present in infectious villitis and not VUE. [1] [14]

Histopathology

Histomorphologically, VUE is characterized by a lymphocytic infiltrate of the chorionic villi without a demonstrable cause. Plasma cells should be absent; the presence of plasma cells suggests an infective etiology, e.g. CMV infection.[ citation needed ]

Differential diagnosis

VUE is often confused with infectious villitis. They can be differentiated by the following characteristics: There are no signs of infection in either the mother or the infant with VUE. Infectious villi there is both maternal and foetal infection. VUE is more common than infectious villitis; Infectious villitis is present in approximately 1–4 births per 1000 births. VUE is present in approximately 76–136 births per 1000 births. VUE occurs in the term placenta, in the late third trimester of pregnancy. Infectious villitis occurs at the early-third to late-second trimester of the pregnancy. Infectious villitis involves a greater part of the placenta (umbilical cord, chorionic plate, membranes) compared to VUE (terminal and stem villi). Histologically VUE is characterised with more lymphocytes present than infectious villitis. Recurrence of infectious villitis is rare. VUE has a 10% to 15% recurrence rate. [1]

Prevention

There are no known prevention methods for VUE, but it is predicted that it could be due to infection by Treponema pallidum , Toxoplasma gondi , and cytomegalovirus. [1]

Epidemiology

In New Zealand VUE is more common in Caucasians than in Maori and Asian ancestry. Obese women are more likely to develop VUE; this could be due to obese women having larger placentas, thus having a greater number of villous macrophages which could increase the efficiency of antigen presentation resulting in VUE. [19]

See also

Related Research Articles

<span class="mw-page-title-main">Placenta</span> Organ that connects the fetus to the uterine wall

The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate maternal and fetal circulations, and is an important endocrine organ, producing hormones that regulate both maternal and fetal physiology during pregnancy. The placenta connects to the fetus via the umbilical cord, and on the opposite aspect to the maternal uterus in a species-dependent manner. In humans, a thin layer of maternal decidual (endometrial) tissue comes away with the placenta when it is expelled from the uterus following birth. Placentas are a defining characteristic of placental mammals, but are also found in marsupials and some non-mammals with varying levels of development.

<span class="mw-page-title-main">Chorion</span> Outermost fetal membrane around the embryo in amniotes

The chorion is the outermost fetal membrane around the embryo in mammals, birds and reptiles (amniotes). It develops from an outer fold on the surface of the yolk sac, which lies outside the zona pellucida, known as the vitelline membrane in other animals. In insects it is developed by the follicle cells while the egg is in the ovary.

<span class="mw-page-title-main">Chorionic villus sampling</span> Type of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus

Chorionic villus sampling (CVS), sometimes called "chorionic villous sampling", is a form of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus and testing it for chromosomal abnormalities, usually with FISH or PCR. CVS usually takes place at 10–12 weeks' gestation, earlier than amniocentesis or percutaneous umbilical cord blood sampling. It is the preferred technique before 15 weeks.

<span class="mw-page-title-main">Trophoblast</span> Early embryonic structure that gives rise to the placenta

The trophoblast is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the placenta. They form during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg to become extraembryonic structures that do not directly contribute to the embryo. After gastrulation, the trophoblast is contiguous with the ectoderm of the embryo and is referred to as the trophectoderm. After the first differentiation, the cells in the human embryo lose their totipotency and are no longer totipotent stem cells because they cannot form a trophoblast. They are now pluripotent stem cells.

Antepartum bleeding, also known as antepartum haemorrhage (APH) or prepartum hemorrhage, is genital bleeding during pregnancy after the 28th week of pregnancy up to delivery.

<span class="mw-page-title-main">Decidua</span> Part of uterus modified in pregnancy

The decidua is the modified mucosal lining of the uterus that forms every month, in preparation for pregnancy. It is shed off each month when there is no fertilised egg to support. The decidua is under the influence of progesterone. Endometrial cells become highly characteristic. The decidua forms the maternal part of the placenta and remains for the duration of the pregnancy. After birth the decidua is shed together with the placenta.

<span class="mw-page-title-main">Syncytiotrophoblast</span> Embryonic cell of the placental surface

Syncytiotrophoblast is the epithelial covering of the highly vascular embryonic placental villi, which invades the wall of the uterus to establish nutrient circulation between the embryo and the mother. It is a multi-nucleate, terminally differentiated syncytium, extending to 13 cm.

<span class="mw-page-title-main">Cytotrophoblast</span>

"Cytotrophoblast" is the name given to both the inner layer of the trophoblast or the cells that live there. It is interior to the syncytiotrophoblast and external to the wall of the blastocyst in a developing embryo.

<span class="mw-page-title-main">Chorionic villi</span>

Chorionic villi are villi that sprout from the chorion to provide maximal contact area with maternal blood.

Hofbauer cells are oval eosinophilic histiocytes with granules and vacuoles found in the placenta, which are of mesenchymal origin, in mesoderm of the chorionic villus, particularly numerous in early pregnancy.

<span class="mw-page-title-main">BYSL</span> Protein-coding gene in the species Homo sapiens

Bystin is a protein that in humans is encoded by the BYSL gene.

<span class="mw-page-title-main">Placental disease</span> Medical condition

A placental disease is any disease, disorder, or pathology of the placenta.

<span class="mw-page-title-main">Placentitis</span> Medical condition

Placentitis is an inflammation of the placenta. The main forms of placentitis are:

Immune tolerance in pregnancy or maternal immune tolerance is the immune tolerance shown towards the fetus and placenta during pregnancy. This tolerance counters the immune response that would normally result in the rejection of something foreign in the body, as can happen in cases of spontaneous abortion. It is studied within the field of reproductive immunology.

<span class="mw-page-title-main">Fetal membranes</span>

The fetal membranes are the four extraembryonic membranes, associated with the developing embryo, and fetus in humans and other mammals. They are the amnion, chorion, allantois, and yolk sac. The amnion and the chorion are the chorioamniotic membranes that make up the amniotic sac which surrounds and protects the embryo. The fetal membranes are four of six accessory organs developed by the conceptus that are not part of the embryo itself, the other two are the placenta, and the umbilical cord.

<span class="mw-page-title-main">Intermediate trophoblast</span>

Intermediate trophoblast is a distinct subtype of trophoblastic tissue that arises from the cytotrophoblast.

<span class="mw-page-title-main">Placental expulsion</span>

Placental expulsion occurs when the placenta comes out of the birth canal after childbirth. The period from just after the baby is expelled until just after the placenta is expelled is called the third stage of labor.

<span class="mw-page-title-main">Placental villous immaturity</span> Medical condition

Placental villous immaturity is chorionic villous development that is inappropriate for the gestational age.

Extravillous trophoblasts(EVTs), are one form of differentiated trophoblast cells of the placenta. They are invasive mesenchymal cells which function to establish critical tissue connection in the developing placental-uterine interface. EVTs derive from progenitor cytotrophoblasts (CYTs), as does the other main trophoblast subtype, syncytiotrophoblast (SYN). They are sometimes called intermediate trophoblast.

Massive perivillous fibrin deposition refers to excessive deposition of fibrous tissue around the chorionic villi of the placenta. It causes reduced growth of the foetus, and leads to miscarriage in nearly 1 in 3 pregnancies affected. There are typically no symptoms, and it is rarely detected before birth. The cause is unknown, but may be autoimmune. Diagnosis is based on the histology of the placenta. There are currently no known treatments. MPFD is very rare, but recurrence is around 18% in those affected.

References

  1. 1 2 3 4 5 6 7 8 Redline, RW. (Oct 2007). "Villitis of unknown etiology: noninfectious chronic villitis in the placenta". Hum Pathol. 38 (10): 1439–46. doi:10.1016/j.humpath.2007.05.025. PMID   17889674.
  2. 1 2 Tamblyn J, Lissauer D, Powell R, Cox P, Kilby M (2013). "The immunological basis of villitis of unknown etiology – Review". Placenta. 34 (10): 846–55. doi:10.1016/j.placenta.2013.07.002. PMID   23891153.
  3. ↑ Feeley L, Mooney EE (2010). "Villitis of unknown aetiology: correlation of recurrence with clinical outcome". J Obstet Gynaecol. 30 (5): 476–9. doi:10.3109/01443611003802339. PMID   20604650. S2CID   11473529.
  4. ↑ Webster, Samuel (2016). Embryology at a glance (Second ed.). Chichester. p. 27. ISBN   9781118910801.
  5. ↑ Nelson DM, Crouch EC, Curran EM, Farmer DR (1990). "Trophoblast interaction with fibrin matrix. Epithelialization of perivillous fibrin deposits as a mechanism for villous repair in the human placenta". The American Journal of Pathology. 136 (4): 855–65. PMC   1877640 . PMID   2327472.
  6. ↑ Labarrere C, Ortiz M, Sosa M, Campana G, Wernicke M, Baldridge L, Terry C, DiCarlo H (2005). "Syncytiotrophoblast intercellular adhesion molecule-1 expression in placental villitis of unknown cause". American Journal of Obstetrics and Gynecology. 193 (2): 483–488. doi:10.1016/j.ajog.2004.12.090. PMID   16098874.
  7. ↑ Ashkar A, Black G, Wei Q, He H, Liang L, Head J, Croy B (1992). "Assessment of Requirements for IL-15 and IFN Regulatory Factors in Uterine NK Cell Differentiation and Function During Pregnancy". The Journal of Immunology. 188 (3): 2937–2944. doi: 10.4049/jimmunol.171.6.2937 . PMID   12960317.
  8. ↑ Liu K, Catalfamo M, Li Y, Henkart P, Weng N (2002). "IL-15 mimics T cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in CD8+ memory T cells". Proceedings of the National Academy of Sciences. 99 (9): 6192–6197. Bibcode:2002PNAS...99.6192L. doi: 10.1073/pnas.092675799 . PMC   122925 . PMID   11972069.
  9. ↑ Labarrere C, Faulk W (1995). "Maternal Cells in Chorionic Villi From Placentae of Normal and Abnormal Human Pregnancies". American Journal of Reproductive Immunology. 33 (1): 54–59. doi:10.1111/j.1600-0897.1995.tb01138.x. PMID   7619234. S2CID   20984951.
  10. ↑ Redline RW, Patterson P (1993). "Villitis of unknown etiology is associated with major infiltration of fetal tissue by maternal inflammatory cells". The American Journal of Pathology. 143 (2): 473–9. PMC   1887041 . PMID   8342596.
  11. 1 2 Myerson D, Parkin R, Benirschke K, Tschetter C, Hyde S (2006). "The Pathogenesis of Villitis of Unknown Etiology: Analysis with a New Conjoint Immunohistochemistry-in Situ Hybridization Procedure to Identify Specific Maternal and Fetal Cells". Pediatric and Developmental Pathology. 9 (4): 257–265. doi:10.2350/08-05-0103.1. PMID   16944988. S2CID   9712882.
  12. ↑ Altemani A (1992). "Immunohistochemical Study of the Inflammatory Infiltrate in Villitis of Unknown Etiology". Pathology – Research and Practice. 188 (3): 303–309. doi:10.1016/S0344-0338(11)81208-2. PMID   1625994.
  13. ↑ Kim M, Nien J, Kim C, Kim Y, Kim G, Goncalves L, Oh S, Chaiworapongsa T, Mazor M, Romero R (2004). "Villitis of unknown etiology as a placental counterpart of transplantation rejection: The demonstration of cd8+ T lymphocyte and NK cell infiltration in this lesion". American Journal of Obstetrics and Gynecology. 191 (6): S87. doi: 10.1016/j.ajog.2004.10.194 .
  14. 1 2 Labarrere C, Faulk W (1990). "MHC Class II Reactivity of Human Villous Trophoblast in Chronic Inflammation of Unestablished Etiology". American Journal of Obstetrics and Gynecology. 50 (5): 812–816. doi: 10.1097/00007890-199011000-00014 . PMID   2238057.
  15. ↑ Nelson JL (2002). "Microchimerism: incidental byproduct of pregnancy or active participant in human health?". Trends in Molecular Medicine. 8 (3): 109–113. doi:10.1016/s1471-4914(01)02269-9. PMID   11879770.
  16. ↑ Redline R, Ariel I, Baergen R, deSa D, Kraus F, Roberts D, Sander C (2004). "Fetal Vascular Obstructive Lesions: Nosology and Reproducibility of Placental Reaction Patterns". Pediatric and Developmental Pathology. 7 (5): 443–52. doi:10.1007/s10024-004-2020-x. PMID   15547768. S2CID   103062.
  17. ↑ Brito H, Juliano P, Altemani C, Altemani A (2005). "Is the immunohistochemical study of the inflammatory infiltrate helpful in distinguishing villitis of unknown etiology from non-specific infection villitis?". Placenta. 26 (10): 839–841. doi:10.1016/j.placenta.2004.10.012. PMID   16169075.
  18. ↑ Kapur P, Rakheja D, Gomez A, Sheffield J, Sanchez P, Rogers B (2004). "Characterization of Inflammation in Syphilitic Villitis and in Villitis of Unknown Etiology". Pediatric and Developmental Pathology. 7 (4): 453–458. doi:10.1007/s10024-004-2124-3. PMID   15547769. S2CID   25895302.
  19. ↑ Becroft D, Thompson J, Mitchell E (2005). "Placental villitis of unknown origin: Epidemiologic associations". American Journal of Obstetrics and Gynecology. 192 (1): 264–271. doi:10.1016/j.ajog.2004.06.062. PMID   15672035.
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