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Villitis
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            The terminology for villitis was established by Altshuler and Russel with some exceptions[1]. Their category of diffuse villitis described primarily as villous edema and immaturity is not usually considerd villitis. Acute villitis is also not usually considered villitis as much as a rare component of chorioamnionitis, since its etiology and significance is different from the chronic villitides. Reparative villitis and granulomatous villitis are descriptive variants of lympho-histiocytic villitis. The presence of plasma cells is considered atypical of lympho-histiocytic villitis, and should be named plasma cell villitis. Most villitis is of unknown etiology, unless a specific congenital falls into the category of  lympho-histiocytic villitis.In some cases, the extent of villitis in a stem villous area is such that the lesion can be seen as gross pallor, and an estimate of the extent can also be made from cut placental sections. In most cases, the villitis is found only after microscopic sectioning. Knox and Fox proposed a simple grading system for the extent of villitis. [2]. Grade 1: 1-2 foci inflammation in 4 slides, with each focus with only a few villi involvedGrade 2: up to 6 foci, with up to 20 villi/focusGrade 3: multiple foci, up to ½ of a low power fieldGrade 4: large areas of most sections Empirically they found that 4 sections were required to have a reliable sample. A simpler but similar system was proposed by Russell: low: no more than 1 focus per low power field, moderate: frequent foci up to 25% of the field, and severe: more than 25%[3].
            The description of the extent of villitis is more complex than such simple quantification. Villitis may be extensive in the distribution of single villous stem, but not be distributed to other villous stem areas. Villitis may be scattered in the parenchyma, or it may be in the confined to the basal villi. The latter are embedded in the basal plate and often are denuded of syncytiotrophoblast. Their anatomy may expose fetal (and hence paternal) HLA antigens to more direct contact with maternal lymphocytes.
   
The types of cells most commonly found in villitis are T lymphocytes and activated macrophages [4, 5]. In a study of in situ hybridization of three male infant placentas, the T cells in villitis were maternal[6]. Villitis of the basal villi has the same inflammatory cells as other villitis [7]. Hofbrauer macrophages are part of the normal villous cell population and are not per se evidence of inflammation. Hofbrauer cell activation has been demonstrated by expression of DR surface antigens in syphilitic infection[8]. Plasma cells suggest antigen presentation in the villi and are characteristically found in CMV villitis in which the viral antigen is present in the villi. B cells have not been prominent in the more common lympho-histiocytic villitis. Neutrophils may be present in small numbers. Multi-nucleated macrophage giant cells may be found without evidence of a specific granulomatous infection.
 
            Villitis usually shows marked loss of capillary vessels although overt thrombi are rare. Immuno-histologic studies are consistent with up regulation of thrombotic regulators in villitis suggesting a similarity to the mechanism of allograft rejection[5]. Altshuler and Russel proposed progression of villitis to avascular villi [1]. In CMV villitis, hemosiderin macrophages occur in involved villi. Villitis may be accompanied by varying amounts of chronic inflammatory cells in the intervillous space (intervillositis), and of intervillous fibrin or fibrinoid deposition. A study using curettage could not find a correlation of decidual inflammation (parietal or basal) with villitis[9].
            Villitis is present in a substantial number of human placentas, usually more than 10%. The actual percentage varies, perhaps because of differences in definition, in sampling of the placenta, and in geographic location[2]. Several studies have identified a correlation of extensive villitis with intrauterine growth retardation[10-13]. One study found a normal ponderal index in the growth restricted fetuses, suggesting an early onset of the effects of the villitis[10]. Another study found a correlation of villitis with pregnancy induced hypertension in infants less than 26 weeks of gestation.
 
           Villitis has been found in cases of hematogenous fetal infection. The most common of these infections in the United States is CMV infection. The characteristic villitis demonstrates plasma cells and hemosiderin macrophages[14]. Diagnostic inclusions may also be present, usually not in the areas of inflammation. Immuno-histochemistry or in situ hybridization for CMV are more sensitive placental tests. Some positive placentas by these techniques may demonstrate only a lympho-histiocytic villitis[15-17]. Other infections have also been associated with lympho-histiocytic villitis including toxoplasmosis, syphilis, varicella and enterovirus[18-23].  In one study, villitis did not correlate with cord blood IgM[24]. The significance of plasma cells and giant cells has been emphasized in some of the articles on infectious villitis, but the predictive power of these cells for infection is unproven, except in the typical CMV villitis. The incidence of fetal infection with lympho-histiocytic villitis, and the incidence of lympho-histiocytic villitis with specific infections remain unknown.Villitis may reoccur in subsequent pregnancies. Based on 10 patients with recurrent villitis, Redline and Abramowsky found that recurrent cases at a .05 P level had increased incidence of fetal loss, maternal infection with gonorrhea, obesity, and autoimmune disease compared to nonrecurrent cases[25] . They also noted two patterns of disease. Six patients with basal villitis and decidual plasma cells were unmarried, of lower economic status and had sexually transmitted disease. Four patients with more intervillositis and fibrinoid had a higher economic status, obesity, and spontaneous abortions. Redline also reported repetitive villitis of bacterial origin in mothers with an extrauterine source (tubo-ovarian abscess or utero-gastrointestinal fistula)[26]. A case reported by Russell may be similar as the mother had micro-abscesses and had a successful pregnancy with heavy antibiotics[27]. A study of villitis in twins found asymmetry of involvement of villitis between twins (both presence and quantity) unrelated to birthweight[28]. One case was monochorionic. There is a single case report of neonatal alloimmune thrombocytopenia with HLA alloimmunization. The placenta showed microthrombi and hemorrhagic endovasculosis suggesting platelet aggregation in the placenta. There was also villitis, which the authors suggested might correlate with the anti-paternal HLA antibodies[29].
 
          
In proven infection, such as CMV villitis, there is a scattered pattern of villous involvement, which is similar to that seen with lymphohistiocytic villitis.  Based on this analogy, a reasonable hypothesis is that lympho-histiocytic villitis of unknown etiology is due to infection by blood borne organisms such as asymptomatic bacteremia from dental manipulation or mild viral infection. Random seeding of viremia could explain the asymmetric villitis between monozygotic twins. Infection can produce symmetric growth retardation from fetal cell damage, for example in rubella. Some infections might produce villitis but it would not have been detected because no perinatal symptoms would have indicated the need for placental examination, for example the less severe CMV infections that result in deafness. If some villitis is due to infection, these cases may have elevated cord blood IgM or evidence of B or plasma cells in the inflammatory infiltrate.The vast majority of cases of villitis do not have a detected infection. A plausible alternative hypothesis is that the villitis is the result of maternal T cell rejection. If the syncytiotrophoblast is breached by some injury, circulating maternal T would be exposed to cells with paternal allogenic HLA antigens, and rejection would ensue. Labarre and colleagues have shown by immuno-staining that the same factors are elevated in villitis as in graft rejection[5]. They also point out that graft rejection initiates mediators of thrombosis and results in vascular injury similar to that in villitis. The presence of antibodies to paternal HLA in cord blood could be an alternative marker of such rejection. One hypothetical significance of maternal T-lymphocyte infiltration of the placental villi of unknown etiology is that these T-cells in the fetus may lead to autoimmune disease in the child. This is based on the observation that microchimerism, that is small numbers of T-cells in another individual, may orchestrate T-cell mediated cell injury that mimics autoimmune disease[30-38]. From the point of view of these foreign T-cells, this “autoimmune response” is an alloimmune rejection of the host tissue. This mechanism appears to explain maternal scleroderma and post partum thyroiditis due to fetal cells entering the mother[39-41]. Juvenile dermatomyositis is the best documented disease that appears to be due to maternal cells that have entered the fetus[30, 42, 43]. Other diseases have been proposed but not proven, and other likely candidates such as biliary atresia have not been studied.
 
          
The best documented experimental studies of transplacental passage of maternal T cells into the fetus were done using rat T cells already activated against a different strain of rat and then injected into the pregnant mother[44-46]. Depending on the dose, a percentage of the infant rats developed severe growth retardation and death due to engrafted maternal cells producing a systemic graft versus host reaction. No experiments looked at long term consequences of small numbers of maternal T cells engrafted, or of T-cells with stimulation to specific alloantigens. It seems likely that the smaller numbers of T-cells delivered naturally via the placenta are unlikely to cause severe graft versus host disease, but could still result in specific autoimmune syndromes. The histologic diagnosis of villitis is common, yet there are no clear guidelines for the further evaluation of the infant. Should a search be made for fetal infections based on the intensity or quality of the inflammation? Is villitis a possible marker for increased risk of early significant infections such as CMV? Alternatively, should concern  be raised that the child will have long term deleterious effects of persistent maternal T cell engraftment? Are there specific histologic features of the villitis or clinical histopathologic patterns of villitis that have diagnostic importance? Are small for gestational age infants with severe villitis at risk for any specific diseases in the future? Is recurrence of villitis in subsequent pregnancies a chance phenomenon or is there a subgroup of patients in which this is an important clinical pathologic entity? The information to answer these questions is not available.
 
                                       
References:
  
1.         Altshuler, G. and P. Russell, The human placental villitides: A review of chronic intrauterine infection. Curr Top Pathol, 1975. 60: p. 63-112.
2.         Knox, W.F. and H. Fox, Villitis of unknown aetiology: its incidence and significance in placentae from a British population. Placenta, 1984. 5(5): p. 395-402.

3.         Russell, P., Inflammatory lesions of the human placenta. III. The histopathology of villitis of unknown aetiology. Placenta, 1980. 1(3): p. 227-44.

4.         Altemani, A.M., Immunohistochemical study of the inflammatory infiltrate in villitis of unknown etiology. A qualitative and quantitative analysis. Pathol Res Pract, 1992. 188(3): p. 303-9.

5.         Labarrere, C.A., J.A. McIntyre, and W.P. Faulk, Immunohistologic evidence that villitis in human normal term placentas is an immunologic lesion. Am J Obstet Gynecol, 1990. 162: p. 515-522.

6.         Redline, R.W. and P. Patterson, Villitis of unknown etiology is associated with major infiltration of fetal tissue by maternal inflammatory cells [see comments]. Am J Pathol, 1993. 143(2): p. 473-9.

7.         Labarrere, C. and W. Faulk, Anchoring Villi in Human Placental Basal Plate - Lymphocytes; Macrophages and Coagulation. Placenta  12, 1991: p. 173-182.

8.         Greco, M.A., et al., Phenotype of villous stromal cells in placentas with cytomegalovirus, syphilis, and nonspecific villitis. Am J Pathol, 1992. 141(4): p. 835-42.

9.         Altemani, A.M., Decidual inflammation in villitis of unknown aetiology [letter]. Placenta, 1992. 13(1): p. 89-90.

10.       Althalbe, O. and C. Labarrere, Chronic villitis of unknown aetiology and intrauterine growth-retarded infants of normal and low ponderal index. Placenta, 1985. 6: p. 369-373.
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13.       Bjoro, K., Jr. and E. Myhre, The role of chronic non-specific inflammatory lesions of the placenta in intra-uterine growth retardation. Acta Pathol Microbiol Immunol Scand [A], 1984. 92(2): p. 133-7.

14.       Becroft, D.M.O., Prenatal cytomegalovirus infection: epidemiology, pathology, and pathogenesis. Persp Pediatr Pathol, 1981. 6: p. 203-235.

15.       Sachdev, R., et al., In situ hybridization analysis for cytomegalovirus in chronic villitis. Pediatr Pathol, 1990. 10(6): p. 909-17.

16.       Ozono, K., et al., Diagnosis of congenital cytomegalovirus infection by examination of placenta: application of polymerase chain reaction and in situ hybridization. Pediatr Pathol Lab Med, 1997. 17(2): p. 249-58.

17.       Muhlemann, K., et al., Cytomegalovirus infection of the human placenta: an immunocytochemical study. Hum Pathol, 1992. 23(11): p. 1234-7.

18.       Genest, D.R., et al., Diagnosis of congenital syphilis from placental examination: comparison of histopathology, Steiner stain, and polymerase chain reaction for Treponema pallidum DNA. Hum Pathol, 1996. 27(4): p. 366-72.

19.       Blanc, W.A., Pathology of the placenta and cord in ascending and in haematogenous infection. Ciba Found Symp, 1979. 77: p. 17-38.

20.       Benirschke, K., et al., Villitis of known origin: varicella and toxoplasma. Placenta, 1999. 20(5-6): p. 395-9.

21.       Popek, E., Granulomatous Villitis Due to Toxoplasma-Gondii. Pediatric Pathology, 1991. 12: p. 281-288.

22.       Qureshi, F. and S.M. Jacques, Maternal varicella during pregnancy: correlation of maternal history and fetal outcome with placental histopathology. Hum Pathol, 1996. 27(2): p. 191-5.

23.       Garcia, A.G.P., et al., Enterovirus associated placental morphology: a light; viroogical; electron microscopic and immunologic study. placenta, 1991. 12: p. 533-547.

24.       Altemani, A.M., A. Fassoni, and S. Marba, Cord IgM levels in placentas with villitis of unknown etiology. J Perinat Med, 1989. 17(6): p. 465-8.

25.       Redline, R. and C. Abramowsky, Clinical and pathologic aspects of recurrent placental villitis. Hum Pathol, 1985. 16: p. 727-31.

26.       Redline, R., Recurrent villitis of bacterial etiology. Pediatr Pathol Lab Med, 1996. 16: p. 995-1001.

27.       Russell, P., K. Atkinson, and L. Krishnan, Recurrent reproductive failure due to severe placental villitis of unknown etiology. J Reprod Med, 1980. 24(2): p. 93-8.

28.       Jacques, S. and F. Qureshi, Chronic villitis of unknown etiology in twin gestations. Pediatr Pathol, 1994. 14: p. 575-84.

29.       De Tar, M.W., et al., Neonatal alloimmune thrombocytopenia with HLA alloimmunization: case report with immunohematologic and placental findings. Pediatr Dev Pathol, 2002. 5(2): p. 200-5.

30.       Kowalzick, L., et al., Chronic graft-versus-host-disease-like dermopathy in a child with CD4+ cell microchimerism. Dermatology, 2005. 210(1): p. 68-71.

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32.       Nelson, J.L., Microchimerism and human autoimmune diseases. Lupus, 2002. 11(10): p. 651-4.

33.       Nelson, J.L., Microchimerism: incidental byproduct of pregnancy or active participant in human health? Trends Mol Med, 2002. 8(3): p. 109-13.

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35.       Reed, A.M., Microchimerism in children with rheumatic disorders: what does it mean? Curr Rheumatol Rep, 2003. 5(6): p. 458-62.

36.       Rossi, G., Nature of stem cell involved in fetomaternal microchimerism. Lancet, 2004. 364(9449): p. 1936.

37.       Sarkar, K. and F.W. Miller, Possible roles and determinants of microchimerism in autoimmune and other disorders. Autoimmun Rev, 2004. 3(6): p. 454-63.

38.       Stevens, A.M., et al., Maternal and sibling microchimerism in twins and triplets discordant for neonatal lupus syndrome-congenital heart block. Rheumatology (Oxford), 2005. 44(2): p. 187-91.

39.       Artlett, C.M., J.B. Smith, and S.A. Jimenez, Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Eng J Med, 1998. 338: p. 1186-91.

40.       Klintschar, M., et al., Evidence of fetal microchimerism in Hashimoto's thyroiditis. J Clin Endocrinol Metab, 2001. 86(6): p. 2494-8.

41.       Imaizumi, M., et al., Intrathyroidal fetal microchimerism in pregnancy and postpartum. Endocrinology, 2002. 143(1): p. 247-53.

42.       Reed, A.M., et al., Chimerism in children with juvenile dermatomyositis. Lancet, 2000. 356(9248): p. 2156-7.

43.       Reed, A.M., et al., Does HLA-dependent chimerism underlie the pathogenesis of juvenile dermatomyositis? J Immunol, 2004. 172(8): p. 5041-6.

44.       Beer, A.E. and R.E. Billingham, Maternally acquired runt disease. Science, 1973. 179(70): p. 240-3.

45.       Beer, A.E., R.E. Billingham, and S.L. Yang, Maternally induced transplantation immunity, tolerance, and runt disease in rats. J Exp Med, 1972. 135(4): p. 808-26.

46.       Billingham, R.E., et al., Quantitative studies on the induction of tolerance of homologous tissues and on runt disease in the rat. Ann N Y Acad Sci, 1960. 87: p. 457-71.