Lichen planus-type chronic graft-versus-host disease complicated by mucous membrane pemphigoid with positive anti-BP180/230 and scleroderma-related autoantibodies followed by reduced regulatory T cell frequency

ARTICLE

ejd.2011.1587

Auteur(s) : Takaaki Hanafusa¹, Hiroaki Azukizawa¹ azukizaw@derma.med.osaka-u.ac.jp, Megumi Nishioka¹, Atsushi Tanemura¹, Hiroyuki Murota¹, Hisao Yoshida², Emiko Sato², Yoshiko Hashii², Keiichi Ozono², Hiroshi Koga³, Takashi Hashimoto³, Ichiro Katayama¹

¹ Department of Dermatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita-shi, Osaka 565-0871, Japan

² Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan

³ Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology, Fukuoka, Japan

Chronic graft-versus-host disease (cGVHD) remains one of the most frequent complications of allogeneic hematopoietic stem cell transplantation. cGVHD often presents with clinical manifestations that resemble those of autoimmune diseases such as scleroderma [1]. Autoimmune bullous diseases are also associated with cGVHD via the production of circulating basement membrane zone antibodies, such as collagen VII, BP230, collagen XVII/BP180 or p200/laminin γ1 [2]. We report a lichen planus-type cGVHD complicated by mucous membrane pemphigoid with positive anti-BP180/230 and scleroderma-related autoantibodies followed by reduced regulatory T cell (Treg) frequency.

A 17-year-old Japanese man presented with recurrent oral aphtha and scaly erythemas on the trunk and extremities in October 2010. Peripheral blood stem cell transplantation (PBSCT) had been performed from human leukocyte antigen-identical unrelated donors 18 months before for his mixed lineage leukemia. One month after PBSCT, acute GVHD (aGVHD)-induced diarrhea developed and was improved by prednisolone (PSL), tacrolimus, and methotrexate (MTX). In October 2009, he presented with systemic scaly erythemas, diarrhea, and liver dysfunction (figure 1A). The histology of the erythema was compatible with lichen planus-like reaction (figure 1B). Therefore, he was diagnosed as lichen planus-type cGVHD, which was temporarily improved by the same medication. However, the recurrent oral aphtha and scaly erythemas exacerbated, and he was admitted to our hospital in February 2011. On admission, he presented with multiple erythemas with thick scales on the trunk and extremities, as well as severely painful oral ulcers (figure 1C). Laboratory findings were as follows (abnormal values are underlined): white blood cell count, 4.18×10³/μL (neutrophils: 56.0%; lymphocytes: 34.0%; monocytes: 10.0%; eosinophils: 0.0%, and basophils: 0.0%) C-reactive protein: 5.3 mg/L; creatinine: 0.49 mg/dL; aspartate aminotransferase: 32 U/L; alanine aminotransferase: 42 U/L; antinuclear antibody: 1:5120 (<1:40); anti-topoisomerase-1 (anti-Scl-70) antibody: 52.7 index (<16); anti-centromere antibody: 181.0 index (<10); anti-BP180 antibody: 59.5 index (<15); anti-BP230 antibody: 39.0 index (<9). The positive autoantibodies were all negative when cGVHD initially developed in October 2009. Indirect immunofluorescence assay with salt-split skin test demonstrated that serum IgG (×40) reacted to the epidermal side of the basement membrane zone of normal human skin. The patient serum also reacted with recombinant BP180-NC16A by immunoblot analysis. These results indicated that the intractable oral ulcers were anti-BP180/BP230 autoantibody-induced mucous membrane pemphigoid. PSL and MTX rapidly improved the skin erythemas (figure 1D). However, the oral ulcers remained severe. As previously reported for cGVHD [3], topical tacrolimus dramatically improved the oral lesions, and he has maintained complete remission. Once in remission, we evaluated the number of peripheral blood Tregs. Flow cytometric analysis demonstrated that the frequency of CD4⁺ CD25⁺ Foxp3⁺ Tregs, especially Foxp3^low CD45RA⁺ naïve Tregs [4], was lower than that of a healthy individual.

The pathogenesis of autoimmune disease development in cGVHD remains unclear, but there are two possible mechanisms. One is that Treg expansion is limited and its function is inhibited, attributable to the cytokine milieu of interleukin (IL)-6 elevation without IL-2 elevation in GVHD. Limited Treg expansion leads to the transition from acute to chronic GVHD, resulting in an increase of donor-derived CD4⁺ T cells, which may explain why autoimmunity occurs in some cGVHD patients [5]. Alternatively, the peripheral T-cell receptor repertoire is skewed and de novo T-cell generation is impaired, attributable to defects in regular thymopoiesis in GVHD [6]. In our case, peripheral blood Tregs were decreased during the clinical course, most likely leading to the breakdown of tolerance and production of multiple autoantibodies.

In conclusion, production of multiple autoantibodies in cGVHD provides useful information for the understanding of cGVHD-associated autoimmune disease development, especially the involvement of Tregs. Long-term observation of the T-cell repertoire, especially Tregs, is essential in cGVHD patients.

Disclosure

Financial support: none. Conflicts of interest: none.

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