CXCR3 <-> ligand-mediated skin inflammation in cutaneous lichenoid graft-versus-host disease.
BACKGROUND
Lichenoid graft-versus-host disease (liGVHD) histologically shares several common features with other lichenoid dermatoses, such as cutaneous lupus erythematosus and lichen planus (LP), which collectively show a junctional infiltrate of cytotoxic lymphocytes with liquefaction of the basal layer ("interface dermatitis"). Because recent studies have shown a role for type I interferon (IFN)-associated inflammation, including lymphocyte recruitment via CXCR3 <-> ligand interaction in cutaneous lupus erythematosus and LP, we hypothesized that similar mechanisms might also be involved in liGVHD.


METHODS
Ten representative lesional skin biopsies taken from patients with different subsets of chronic cutaneous graft versus host disease (GvDH) were recovered from the authors' archives. Eight LP specimens and 5 punch biopsies taken from healthy skin were analyzed for control purposes. Immunohistochemistry was performed to characterize the lesional infiltrate (CD3, CD4, CD8, CD20, CD56, or CD68), to analyze type I IFN signaling (MxA), and to investigate expression of the IFN-inducible chemokines CXCL9 and CXCL10 and their ligand CXCR3. In situ hybridization was performed to visualize IFNalpha expression on the mRNA level.


RESULTS
Our analyses revealed striking similarities between the inflammatory pattern seen in LP and liGVHD. Both disorders presented with a predominantly T-cellular inflammation with CD8(+) lymphocytes affecting the basal epidermal layer. The majority of lesional lymphocytes expressed the chemokine receptor CXCR3. The corresponding chemokines CXCL9 and CXCL10 were found in the epidermis and within the inflammatory infiltrate. Analyses of MxA and IFNalpha mRNA expression supported a role for type I IFNs in these conditions.


CONCLUSIONS
This study was limited by the number of well characterized cases in our archives. In situ hybridization was realizable only in single cases.


CONCLUSIONS
Our results support the hypothesis that CXCR3 <-> ligand-mediated lymphocyte recruitment is involved in cutaneous liGVHD. The fact that CXCL10 was seen in precisely those areas with extensive liquefaction of the basal epidermis supports a role of this chemokine for the development of the typical histologic "interface" pattern.
Wenzel
Joerg
J
Department of Dermatology at the Universitie of Bonn, Bonn, Germany. joerg.wenzel@ukb.uni-bonn.de
Lucas
Svenja
S
Zahn
Sabine
S
Mikus
Sandra
S
Metze
Dieter
D
Ständer
Sonja
S
von Stebut
Esther
E
Hillen
Uwe
U
Bieber
Thomas
T
Tüting
Thomas
T
D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D002908:Chronic Disease; D003872:Dermatitis / Q000209:etiology* / Q000473:pathology; D004817:Epidermis / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006086:Graft vs Host Disease / Q000150:complications / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D007370:Interferon Type I / Q000378:metabolism; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D008010:Lichen Planus / Q000473:pathology; D017512:Lichenoid Eruptions / Q000150:complications / Q000378:metabolism*; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism*; D012871:Skin Diseases / Q000150:complications / Q000378:metabolism*; D013601:T-Lymphocytes / Q000473:pathology
C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D007370:Interferon Type I; D016898:Interferon-alpha; D008024:Ligands; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019204:GTP-Binding Proteins