No evidence for fetal microchimerism in the skin of patients with pemphigoid gestationis

ARTICLE

Auteur(s) : Maria Clara D’Alessio¹, Cinzia Mazzanti², Nicoletta Di Simone¹, Salvatore Mancuso¹, Giovanni Reddiconto³, Mariagrazia Garzia³, Giuseppe Leone³, Tommaso Gobello², Alessandro Caruso¹

¹Instituto di Ginecologia ed Ostetricia, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy
²Istituto Dermopatico dell’Immacolata, IDI-IRCCS, via dei Monti di Creta 104, 00167 Roma, Italy
³Instituto di Ematologia, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy

Pemphigoid gestationis (PG), previously termed herpes gestationis, is a rare autoimmune bullous disease associated with pregnancy [1]. The disease appears most commonly during the second or third trimester and usually recurs in subsequent pregnancies. PG is characterised by circulating autoantibodies targeting BP180 (also known as collagen XVII), a 180-kDa hemidesmosomal transmembrane protein component required for dermal-epidermal adhesion [2]. PG antibodies predominantly belong to the complement-fixing IgG1 subclass, thus explaining the constant detection of C3 deposits along the cutaneous basement membrane zone in PG skin. BP180 is also expressed in the first trimester in term syncytial and cytotrophoblastic cells of placenta and in epithelial cells of amniotic membrane [3]. Although the exact pathogenetic mechanisms of PG remain to be determined, literature data suggest that an abnormal expression of HLA class II molecules of paternal haplotype may be involved in triggering the production of autoantibodies against placental BP180 and then the autoantibodies cross react with the skin [4].

Pregnancy could be considered the most frequent physiological cause of microchimerism, due to bi-directional exchanges of cells between the fetus and the mother. The female predilection for most autoimmune diseases and the increased rates of some of these after pregnancy raises questions about the long-term effects of pregnancy. Chronic graft-versus-host disease (cGvHD) resulting from stem cell transplantation has clinical similarities with some autoimmune diseases. These observations, together with the trafficking of fetal cells during pregnancy and their persistency in maternal tissues and blood for decades, have suggested a possible role of fetal microchimerism in the pathogenesis of autoimmune diseases, the so-called “bad microchimerism” hypothesis [5]. The fetal cells could be involved in the generation of a graft-versus-host-like response in women and the subsequent maternal immune response to these foreign cells would contribute to post-partum autoimmune disease pathogenesis. However, other studies demonstrated an absence of fetal microchimerism in autoimmune disorders such as Sjogren’s syndrome [6] and primary biliary cirrhosis [7]. These conflicting data led to two different hypotheses about fetal microchimerism. One supports that fetal microchimerism is an innocent bystander and has no impact on maternal health. The alternative theory, the “good microchimerism hypothesis”, suggests that fetal cells provide a rejuvenating source of fetal progenitor cells that could participate in maternal tissue repair processes. Microchimerism might have adverse, neutral or beneficial effects for the host depending upon other factors, such as HLA genes and HLA relationships among cells.

We investigated the presence of fetal microchimerism in PG in order to evaluate if fetal cells could participate in disease pathogenesis. We used fluorescence in situ hybridization (FISH) of cells in lesional skin biopsy specimens with centromere X- and Y-chromosome specific DNA probes. To confirm the data and evaluate the exact mother-fetus origin of the cells, we employed PCR amplification of the amelogenin sex-specific locus and several polymorphic short tandem repeat (STR) markers distributed throughout the human genome. Eight patients with PG (diagnosed by direct and indirect immunofluorescence assays) and 8 male patients with psoriasis as positive controls were studied. PG patients were primiparous women or pluriparous with a male child in the index pregnancy, but with no male child in previous pregnancies (table 1), with an obstetrical history negative for miscarriage; they had clinical onset of the disease during the pregnancy and in all of them the disease regressed from 1 week to 4 months after delivery.
Table 1 Demographic characteristics of patients enrolled in the study

No nucleated cells containing Y chromosomes were detected in the epidermis and dermis of skin sections from PG patients, and no male DNA of fetal origin could be found by PCR of the sex-specific amelogenin locus and of other nine STR loci (figure 1). These results do not provide evidence for fetal microchimerism in the skin of PG. In agreement with our findings, data from literature showed that fetal microchimerism is also not involved in other skin diseases, such as lichen sclerosus of the vulva [8], oral lichen planus [9], or cutaneous lesions of lupus erythematosus [10]. We cannot exclude that the negative results could be in part ascribed in our patients to insufficient skin lesions to recruit cells to areas of tissue damage or to a predominant HLA genotyping, less frequently correlated to microchimerism. Thus, our study does not definitely rule out the presence of microchimerism in PG. However, these results, obtained with sensitive and widely used techniques, suggest that fetal microchimerism does not play a relevant role in PG pathogenesis.

Acknowledgments

References

2 Diaz LA, Ratrie III H, Saunders WS, Futamura S, Squiquera HL, Anhalt GJ. Isolation of a human epidermal cDNA corresponding to the 180-Kd autoantigen recognized by bullous pemphigoid and herpes gestationis sera. J Clin Invest 1990; 86: 1088-94.

3 Huilaja L, Hurskainem T, Autio-Harmainen H, et al. Pemphigoid gestationis autoantigen, transmembrane collagen XVII, promotes the migration of cytotrophoblastic cells of placenta and is a structural component of fetal membranes. Matrix Biol 2008; 27: 190-200.

4 Kelly SE, Black MM, Fleming S. Pemphigoid gestationis: A unique mechanism of initiation of an autoimmune response by MHC class II molecules? J Pathol 1989; 158: 81-2.

5 Johnson KL, Bianchi DW. Fetal cells in maternal tissue following pregnancy: what are the consequences? Hum Reprod Up 2004; 10: 497-502.

6 Toda I, Kuwana M, Tsubota K, Kawakami Y. Lack of evidence for an increased microchimerism in the circulation of patients with Sjogren’s syndrome. Ann Rheum Dis 2001; 60: 248-53.

7 Rubbia-Brandt L, Philippeaux MM, Chavez S, Mentha G, Borisch B and Hadengue A. Fish for Y chromosome in women with primary biliary cirrhosis: lack of evidence for leukocyte microchimerism. Hepatology 1999; 30: 821-2.

8 Bauer M, Weger W, Orescovic I, et al. Fetal microchimerism is not involved in the pathogenesis of lichen sclerosus of the vulva. Prenat Diagn 2006; 26: 175-8.

9 Weger W, Bauer M, Odell E, et al. Role of microchimerism in the pathogenesis of oral lichen planus. Experimental Dermatology 2006; 15: 125-9.

10 Khosrotehrani K, Mery L, Aractingi S, Bianchi DW, Johson KL. Absence of fetal cell microchimerism in cutaneous lesions of lupus erythematosus. Ann Rheum Dis 2005; 64: 159-60.