Hair Loss, Allergy and Hypersensitivity
Alopecia areata (AA) is an autoimmune disease of the hair follicles [1–3] that can be transferred by skin transplants as well as by CD4+ plus CD8+ T cells [4–7]. It has been shown that induction of AA is accompanied by major histocompatibility complex (MHC) class I and class II expression on epithelial cells [8–10] that leads to a loss of hair follicle immune privilege . Like other autoimmune diseases, AA is treated typically with corticosteroids [12,13], but at present, treatment with a contact sensitizer is regarded to be the most effective for extensive scalp hair loss [14–18]. In particular, squaric acid dibutylester (SADBE) has been shown to induce hair regrowth very efficiently in an animal model of spontaneously developing AA [10,19]. The underlying mechanism has not yet been explored. We expected that induction of an eczema may possibly restore immune homeostasis by expansion of CD4+ CD25+ regulatory T cells (T-reg) or by restoration of activation-induced cell death (AICD), defects in T-reg [20–22] and in AICD [23–25] being associated frequently with autoimmune disorders, including AA .
As well as the possible involvement of regulatory T cells and AICD, there has been another aspect that appeared of particular interest. We had noted that CD44v10 is important for the development of granulomas and for dinitrofluorobenzene-induced delayed-type hypersensitivity (DTH) reactions . In addition, induction of AA can be prevented by anti-CD44v10 , although anti-CD44v10 did not exert a therapeutic effect on overt AA. CD44v10 is expressed in the basal cell layer of the skin and of squamous epithelia [27,29]. On haematopoietic cells its expression is restricted mainly to monocytes [29,30]. Notably, it is the extravasation of monocytes into the sensitized skin in particular that could be prevented by anti-CD44v10 with high efficacy, i.e. CD44v10 is required mainly for the egress of monocytes . It has been decribed that CD44, particularly CD44 variant isoforms including CD44v10 (CD44v), bind osteopontin ([31–33] and M. Zöller, unpublished). Osteopontin exerts chemotactic and haptotactic activity [34–36] and binding of osteopontin to CD44 supports inflammatory TH1 reactions [32,33].
Another CD44 variant isoform, CD44v3, is also known to bind chemokines, such as basic fibroblast growth factor, that facilitate leucocyte recruitment and extravasation [37–39]. CD44v3 is expressed by T cells, although at a low level, and by activated endothelial cells . CD44v3 is the only CD44 variant isoform that is expressed by skin infiltrating lymphocytes (SkIL) and expression on SkIL is up-regulated significantly in most autoimmune diseases affecting the skin. Anti-CD44v3, similar to anti-CD44v10, inhibits the development of DTH reactions. Thus, CD44v10 and CD44v3 function apparently as homing receptors for SkIL, where CD44v10 probably affects predominantly monocyte egress and CD44v3 T cell infiltration [27,31,34,40,42,43].
The fact that both induction of a DTH reaction as well as induction of a skin-appendage autoimmune disease are associated with up-regulation of the same homing receptors, CD44v10 and CD44v3, and that antibody blockade prevents or mitigates both pathological reactions, suggests similar modes of action in each disease mechanism. However, the fact that one of these pathological reactions (AA) can be treated by induction of the other (eczema) [10,14,44] seems to contradict the apparently shared mechanism of leucocyte recruitment. Our study shows that the therapeutic effect of SADBE is unlikely due to restoration of immune homeostasis by expansion of CD4+ CD25+ T-reg or AICD. Instead, the chronic inflammatory reaction was accompanied by a a retention of CD44v10+ and CD44v3+ leucocytes in draining lymph nodes and an apparent impairment of activated leucocyte migration.
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