High level of thymus and activation-regulated chemokine in blister fluid and sera of patients with bullous pemphigoid.
BACKGROUND
Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by eosinophilia and high serum IgE levels. The accumulated evidence suggests that various cytokines are involved in the lesional skin of patients with BP. Recently, thymus and activation-regulated chemokine (TARC/CCL17), a CC chemokine, was identified as a selective chemoattractant for CC chemokine receptor 4 (CCR4)-expressing cells.


OBJECTIVE
In this study, we examined the involvement of TARC in patients with BP.


METHODS
We determined the fluid and serum TARC levels in patients with BP by enzyme-linked immunosorbent assay and compared the serum TARC levels with the eosinophil numbers in peripheral blood. We also compared the serum TARC levels in five patients with BP before and after they were treated. Moreover, we examined TARC, CCR4 and CXC chemokine receptor 3 (CXCR3) expression in the lesional skin of patients with BP by immunohistochemical procedures. Furthermore, we measured CCR4 positivity in CD4+ CD45RO+ cells of peripheral blood mononuclear cells (PBMCs) in patients with BP and healthy control subjects.


RESULTS
The fluid TARC levels in patients with BP were significantly higher than those in blisters from burn patients or suction blisters of healthy control subjects. The serum TARC levels in patients with BP were also significantly higher than those in pemphigus vulgaris (PV) patients and healthy control subjects, and decreased after the treatment. The serum TARC levels in patients with BP significantly correlated with the eosinophil numbers in peripheral blood (r = 0.72, P < 0.002). Immunohistochemistry showed a strong reactivity of TARC in the epidermal keratinocytes (KCs) of BP. Moreover, both CCR4 and CXCR3 were expressed on the dermal infiltrating CD4+ T cells mainly beneath the bullae of patients with BP. Fluorescence-activated cell sorting analysis showed a higher percentage of CCR4 positivity in CD4+ CD45RO+ cells of PBMCs in patients with BP than that in healthy control subjects, while there was no significant difference of CXCR3 positivity in CD4+ CD45RO+ cells of PBMCs between patients with BP and healthy control subjects.


CONCLUSIONS
These findings strongly suggest that TARC may be one of the important chemokines that are involved in the pathogenesis of BP.
Kakinuma
T
T
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. kakinumat-der@h.u-tokyo.ac.jp
Wakugawa
M
M
Nakamura
K
K
Hino
H
H
Matsushima
K
K
Tamaki
K
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001768:Blister / Q000097:blood / Q000378:metabolism*; D002056:Burns / Q000378:metabolism; D015704:CD4 Antigens / Q000097:blood; D016022:Case-Control Studies; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000032:analysis* / Q000097:blood; D004804:Eosinophils; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D010391:Pemphigoid, Bullous / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D010392:Pemphigus / Q000097:blood; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000032:analysis; D014157:Transcription Factors / Q000032:analysis
C106230:CCL17 protein, human; C515354:CCR4 protein, human; D015704:CD4 Antigens; C515187:CXCR3 protein, human; D054414:Chemokine CCL17; D019742:Chemokines, CC; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D014157:Transcription Factors