Microchimerism and Skin Disease: True-True Unrelated?

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cells that can form cells of all lineages: Microchimerism and Skin Disease: ectodermal, mesenchymal and endo- dermal (Grove et al., 2004). True-True Unrelated? Many studies support the concept of Anita C. Gilliam1 transdifferentiation — the reprogram- ming of stem cells to differentiate into Microchimerism, the stable presence of foreign cells in an individual, may result multiple different cell types appropri- from trafficking during pregnancy or from organ or hematopoietic transplan- ate to their local environments (Alonso tation, and has been hypothesized to cause autoimmunity and certain skin and Fuchs, 2003). Thus the mater- diseases. Yet microchimeric cells are found in normal individuals and may be nal–fetal exchange via the placenta, important to tissue repair. Thus microchimerism may be common, and find- coupled with the enormous potential ing microchimeric cells in diseased as well as normal tissue may be a “true-true of stem cells to produce a variety of unrelated” situation. cell types, might produce a microchi- Journal of Investigative Dermatology (2006) 126, 239–241. doi:10.1038/sj.jid.5700061 merism of not only hematopoietic cells but also cells of all possible lineages, including skin cells. Microchimerism and Cell Trafficking ferentiated cells such as fetal nucleated During Pregnancy erythrocytes or placental trophoblasts Microchimerism and Transplantation The word ‘chimera’ comes from a in maternal blood are a useful marker The study of microchimerism in trans- mythological animal that is a com- of placental health. When an increased plantation biology allows manipula- bination of lion, goat and snake. In number of nucleated erythrocytes and tion of the variables and has led to modern biology, ‘microchimerism’ is trophoblasts are present in maternal some remarkable findings. Recipients the stable presence of low numbers circulation, abnormal placental bar- of transplanted hematopoietic cells of foreign cells in an individual. For rier function such as in preeclampsia remain chimeric for donor and recipi- instance, approximately 8% of identi- or fetal aneuploidy can also be present ent immune cells for a long time after cal twins are chimeric for each other’s (Bianchi, 2000). These differentiated transplantation. Because bone mar- leukocytes because of a shared blood cells do not survive long in maternal row stem cells are diverse and plastic, supply in utero. In single pregnancies, circulation. However, fetal stem and other tissues also become chimeric for the placenta allows passage of mater- progenitor cells can proliferate, differ- donor and recipient after bone marrow nal and fetal cells in both directions, entiate and travel to various maternal transplantation. Bone marrow-derived which explains how fetal and maternal tissues. Cord blood is an important cells can contribute to tissue repair microchimerism can occur after preg- source of fetal stem cells, which are (skeletal muscle, cardiac muscle, liver, nancy. Cord blood samples collected known to have a mobile and plastic lung, kidney, central nervous system). for transplantation contain up to 20% phenotype, and it is the likely source of Bone marrow-derived Y chromosome- maternal cells by in situ hybridiza- cells in maternal microchimerism. Fetal positive keratin-positive cells can be tion and up to 40% maternal cells by hematopoietic stem cells, and presum- found in skin of female recipients of PCR (Lo et al., 1996). These foreign ably their progeny T and B lympho- bone marrow transplanted from male cells can persist in both mother and cytes, monocytes and NK cells, have donors (Grove et al., 2004). child, giving rise to microchimerism. been demonstrated in maternal circula- Microchimerism also occurs in recip- Bianchi et al. reported that CD34+ and tion and tissue. Similarly, maternal stem ients of solid organ transplants (lung, CD34+CD38+ fetal cells were present cells can survive and proliferate in the liver and kidney). Starzl and colleagues in maternal circulation up to 27 years tissues of offspring because of the two- proposed that organ engraftment is a after pregnancy (Bianchi et al., 1996). way traffic of cells via the placenta. form of partial tolerance that is depen- This microchimerism is more likely dent on leukocyte chimerism generated when the fetus is HLA compatible Stem Cells by ‘passenger leukocytes’ and stem with the mother. Fetal microchimerism Multiple types of stem cells have been cells in solid organ grafts (Starzl, 2004). is not as well characterized but is an identified, and the list of stem cells in In these situations, the microchimerism intriguing new area of investigation. adult individuals continues to expand. studied is of leukocytes, transmitted What types of cells are seen in Adult bone marrow contains hemato- to the recipient via transplantation of microchimerism due to maternal–fetal poietic stem cells, mesenchymal stem passenger leukocytes in a solid organ exchange via the placenta? Highly dif- cells and multipotent adult progenitor such as intestine, lung, liver or kidney. Anderson and Matzinger studied 1Department of Dermatology, Case/University Hospitals of Cleveland, Cleveland, Ohio, USA microchimerism produced by passen- Correspondence: Dr. Anita C. Gilliam, Department of Dermatology, Case/University Hospitals of ger leukocytes in skin grafts in mice and Cleveland, 11100 Euclid Ave, Cleveland, Ohio 44106-5028, USA. Email: [email protected] found that the outcomes varied depend-

ing mainly on the recipients’ immuno- to conflicting data. For instance, other A new paradigm — the presence of logical maturity and on the antigenic autoimmune diseases with female pre- cells other than leukocytes in micro- differences. They concluded that donor dominance and a later onset do not chimerism as a possible factor in skin cells could be either tolerogenic or have demonstrable microchimerism disease — is explored in the article immunogenic, depending on the condi- (Sjögren syndrome, primary biliary by Khosrotehrani et al. in this issue tions (Anderson and Matzinger, 2001). cirrhosis). Also, microchimerism can (2006). The authors identified mater- Therefore, the rules for the sequelae of be shown in normal individuals and nally derived cytokeratin-positive cells microchimerism due to transplantation in non-autoimmune diseases such as in archival paraffin-embedded sections in humans are complex and are still infectious hepatitis and cervical can- of the skin of 11 of 12 male children being defined. cer (Johnson and Bianchi, 2004). A with pityriasis lichenoides by fluores- case control study of individuals with cent in situ hybridization with X and Microchimerism and Autoimmunity a variety of connective tissue diseases Y chromosome-specific probes. These What are the consequences of micro- led to the conclusion that microchime- maternally derived cells were also chimerism? It has been proposed that rism was common in all individuals, present in biopsies of skin from male microchimerism may lead to auto- including normal ones (Gannage et control subjects without skin disease, immune disease in some individuals al., 2002). Bianchi, who first reported but with a lower frequency (4 of 7) and with a permissive genetic makeup. microchimerism in humans, concludes density (approximately 20-fold lower Autoimmune diseases in recipients that multiple factors may determine in pityriasis lichenoides patients than of transplanted hematopoietic cells whether microchimerism is a cause of in normal subjects). are well known. These include graft- disease: presence of foreign cells not The search for foreign cells in skin versus-host disease, which can only in blood but also in diseased tis- disorders has produced conflicting be lupus-like or scleroderma-like, sue; tissue type; disease type; history data. Inherent in these experiments are Sjögren’s syndrome, primary biliary of pregnancy; and immune status are the technical difficulties of fluorescent cirrhosis, myositis, myasthenia gravis, all important (Johnson and Bianchi, in situ hybridization or PCR analysis in hyper- and hypothyroidism and auto- 2004). To date, the connection between archived specimens. Background can immune cytopenias (thrombocytope- microchimerism and disease has not be high and interpretation difficult. nia, leukopenia, neutropenia). Disease yet been definitively made. In fact, it Often the sequences of interest are in transplant recipients resembles that has also been suggested that fetal cells also found in normal control subjects. in individuals with the correspond- may provide a renewable source of For instance, women with lichen scle- ing primary autoimmune diseases. stem cells that can help with repair of rosis with and without squamous-cell The dysregulation of tolerance in the maternal tissues, a positive rather than carcinoma, vulvar Paget’s disease, and transplant recipient is thought to allow a negative outcome of microchime- normal vulvar skin who had male child- development of autoreactive T-cell rism. One hypothesis is that stem cells ren were no different when Y chromo- clones, leading to autoimmune dis- may migrate to sites of inflammation some sequences were evaluated by ease. Whether this results from micro- and differentiate into cells that partici- PCR in paraffin-embedded sections. chimerism or simply from immuno- pate in repair. Thus, finding microchi- In summary, microchimerism not compromise is not known. meric cells in diseased tissue does not only of leukocytes but also of other The best-studied example of necessarily mean they were responsible cell types may be a common event immune-cell microchimerism as a for the initial injury. in both normal and diseased tissues, possible factor in primary autoim- a "true-true unrelated" situation. Host mune disease is scleroderma, which Microchimerism and Skin Disease reaction to microchimerism as a cause has a peak incidence in women after In addition to scleroderma, other of skin disease has not yet been defini- the childbearing years. Women with examples of microchimerism and skin tively demonstrated. scleroderma are more likely than disease due to the two-way traffic matched control subjects to have had between mother and fetus have been CONFLICT OF INTEREST The author states no conflict of interest. an HLA-compatible fetus, and Y chro- proposed. For instance, it has been mosome-positive cells can be found in suggested that fetal cells in the mater- REFERENCES fibrotic maternal tissue of women with nal circulation produce the eruptions Adams KM, Nelson JL (2004) Microchimerism: scleroderma many years after delivery associated with pregnancy, such as an investigative frontier in autoimmunity and of a male baby (Artlett, 2005). Fetal pruritic urticarial papules and plaques. transplantation. JAMA 291:1127–31 microchimerism has been proposed Pemphigoid gestationis is thought to be Alonso L, Fuchs E (2003) Stem cells in the skin: as an explanation for scleroderma in an immune reaction to the father’s his- waste not, Wnt not. Genes Dev 17:1189–00. males and children. This hypothesis for tocompatibility antigens on fetal cells Anderson CC, Matzinger P (2001) Immunity or tolerance: opposite outcomes of microchimerism as a cause of sclero- in maternal tissue. Erythema toxicum microchimerism from skin grafts. Nat Med derma is still in debate (Adams and neonatorum, which occurs in the first 7:80–7 Nelson, 2004). few days postpartum, may be a mild Artlett CM (2005) Pathophysiology of fetal Studies on other autoimmune disor- graft-versus-host disease-like reaction microchimeric cells. Clin Chim Acta 360:1–8 ders and in normal individuals have led to maternal cells in the newborn. Bianchi DW (2000) Fetomaternal cell trafficking:

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a new cause of disease? Am J Med Genet 91: 10:497–502 et al., 2001). Injury to adult murine 22–8 Khosrotehrani K et al. (2006) Presence of chimeric skin, such as hair plucking, induces Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, maternally-derived keratinocytes in cutaneous re-expression of PPARα in the adult DeMaria MA (1996) Male fetal progenitor cells inflammatory diseases of children: the example interfollicular epidermis, and re-expres- persist in maternal blood for as long as 27 years of pityriasis lichenoides. J Invest Dermatol postpartum. Proc Natl Acad Sci USA 93:705–8 126:345–348 sion can also be observed in the edges Gannage M, Amoura Z, Lantz O, Piette JC, Lo YM et al. (1996) Two-way cell traffic between of full-thickness wounds. Conversely, Caillat-Zucman S (2002) Feto-maternal mother and fetus: biologic and clinical in PPARα-deficient mice, the early microchimerism in connective tissue diseases. implications. Blood 88:4390–5 phase of wound healing is delayed, Eur J Immunol 32:3405–13 Regauer S, Schwaiger P, Liegl B, Klintschar M and this delay is retained when the Grove JE, Bruscia E, Krause DS (2004) Plasticity of (2004) Fetal microchimerism is common deficiency is targeted to the epidermis bone marrow-derived stem cells. Stem Cells in normal and diseased vulvar skin. J Invest 22:487–500 Dermatol 122:1059–60 only and not to the dermis (Michalik α Johnson KL, Bianchi DW (2004) Fetal cells in Starzl TE (2004) Chimerism and tolerance in et al., 2005). In pups lacking PPAR , a maternal tissue following pregnancy: what transplantation. Proc Natl Acad Sci USA delay in stratum corneum formation is are the consequences? Hum Reprod Update 101(Suppl 2):14607–614 observed between day 18.5 of epidermal development and birth (Schmuth et al., 2002), whereas in PPARα-deficient adults, only a modest decrease in the See related article on page 374 expression of involucrin, loricrin, and filaggrin persists. This indicates that (P)PARsing Epidermal Development other mediators can compensate for the absence of PPARα; that is, there is 1 1 Sandrine Dubrac and Matthias Schmuth redundancy (Komuves et al., 2000). In this issue, Gonzalez et al. (2006) Overexpression of PPAR-α, a developmental transcription factor important in report on the skin phenotype of trans- epidermal embryogenesis, in basal keratinocytes causes epidermal thinning genic mice constitutively overexpress- when activated constitutively during development, but not if activated in adults; ing PPARα in the epidermis. These mice and lack of PPAR-α transiently delays stratum corneum formation within a win- die within 2 days after birth, presum- dow late in epidermal development (day 18.5 to birth). In contrast, pharmaco- ably because of abnormal development logic activation of PPAR-α inhibits proliferation and induces differentiation in of the tongue and mammary gland epi- mouse epidermis regardless of developmental stage. Thus, PPAR-α is an impor- thelia; overexpression of PPARα also tant regulator of epidermal homeostasis. results in epidermal thinning and sparse Journal of Investigative Dermatology (2006) 126, 241–242. doi:10.1038/sj.jid.5700137 fur in these animals, which could contribute to the lethality. Importantly, cor- responding to the transient effects of Nuclear hormone receptors are tran- ligands. Since Issemann and Green PPARα deficiency on developing epi- scription factors that regulate the cloned mouse PPARα in 1990 and Sher dermis, PPARα overexpression exerts expression of target genes by binding to et al. cloned its human homologue in its effects only during a developmental regulatory DNA sequences and interact- 1993 (Issemann and Green, 1990; Sher window; that is, after birth it does not ing with co-regulatory protein complex- et al., 1993), several groups have gener- cause the abnormalities. es. A large molecular family of these ated mouse models of PPARα deficiency. Consequences of a gain of PPARα receptors has been identified by homo- Such animals displayed abnormal lipid function have previously been stud- logy searches. Soon after the sequences and xenobiotic metabolism in the liver, ied using pharmacologic activators. In became available, individual receptors heart, muscle, and kidney, indicating explants of developing rat epidermis, the were characterized for their tissue distri- a role of PPARα in fatty acid oxidation expression of proteins required for epi- bution, ligand identity, patterns of target and detoxification of xenobiotic com- dermal differentiation (filaggrin, loricrin, gene activation, and interaction with pounds. Although PPARα was originally involucrin) was stimulated by the PPARα co-regulatory proteins. To better under- evaluated for its systemic activities, its agonist farnesol (Hanley et al., 1997). In stand their physiological roles, individ- expression was soon also noted in skin. contrast to the VP16PPAR-α bitransgen- ual receptors were tested in genetic ani- PPARα is present in both epidermis ic mice reported here (Gonzales et al., mal models of loss and gain of function. and dermis beginning at day 13.5 of 2006), there was a concomitant induc- In this fashion, peroxisome proli- development. Yet shortly after birth it tion of the granular layer. These differ- ferator-activated receptor-α (PPARα) was becomes undetectable in the interfol- ences could be explained by differences found to be a nuclear hormone recep- licular epidermis, although expression between in vitro and in vivo experimen- tor that is activated by fatty acid-derived persists in the hair follicles (Michalik tal systems and by differences in the tim- ing of the PPARα signal. Nevertheless, 1Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria in adult mice, pharmacologic activation α Correspondence: Dr Sandrine Dubrac, Department of Dermatology, Innsbruck Medical University, of PPAR induces epidermal differentia- Anichstraße 35, A6020 Innsbruck, Austria. Email: [email protected] tion, inhibits proliferation, and increases