The Journal of Experimental Medicine
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A correction to this article has been published: J. Exp. Med. 194 (6) 871-872
Published online 27 August 2001. doi:10.1084/jem.194.5.615
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© The Rockefeller University Press, 0022-1007/2001/9/615/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 5, September 3, 2001 615-628

Original Article

Overexpression of CD40 Ligand in Murine Epidermis Results in Chronic Skin Inflammation and Systemic Autoimmunity

Annette Mehlinga, Karin Losera, Georg Vargaa, Dieter Metzea, Thomas A. Lugera, Thomas Schwarza, Stephan Grabbea, and Stefan Beisserta
a Ludwig Boltzmann Institute for Cell Biology, Department of Dermatology and Immunology of the Skin, University of Münster, D-49149 Münster, Germany

Correspondence to: Stefan Beissert, Dept. of Dermatology, University of Münster, Von Esmarch Strasse 58, D-48149 Münster, Germany. Tel:49-251-835-6582 Fax:49-251-835-8579 E-mail:beisser{at}uni-muenster.de.

CD40–CD40 ligand (L) interactions play a pivotal role in immune-mediated inflammatory responses via the activation of antigen-presenting cells (APCs). To investigate the effects of continuous activation of resident tissue APCs, in this case the Langerhans cells (LCs) of the skin, CD40L expression was targeted to the basal keratinocytes of the epidermis of mice using the keratin-14 promoter. Approximately 80% of the transgenic (Tg) mice spontaneously developed dermatitis on the ears, face, tail, and/or paws. Compared with littermates, Tgs had a >90% decrease in epidermal LCs yet increased numbers within the dermis suggestive of enhanced emigration of CD40-activated LCs. Tgs also displayed massive regional lymphadenopathy with increased numbers of dendritic cells and B cells. Moreover, a decrease in IgM and an increase in IgG1/IgG2a/IgG2b/IgE serum concentrations was detectable. Screening for autoantibodies revealed the presence of antinuclear antibodies and anti-dsDNA antibodies implicative of systemic autoimmunity. Accordingly, renal Ig deposits, proteinuria, and lung fibrosis were observed. Adoptive transfer of T cells from Tgs to nonTg recipients evoked the development of skin lesions similar to those found in the Tgs. Dermatitis also developed in B cell–deficient CD40L Tg mice. These findings suggest that in situ activation of LCs by CD40L in the skin not only leads to chronic inflammatory dermatitis but also to systemic mixed-connective-tissue-like autoimmune disorders, possibly by breaking immune tolerance against the skin.

Key Words: Langerhans cell, autoantibody, transgenic mice, mixed connective tissue disease, migration


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