The role of complement-derived mediators in inflammatory skin diseases

Summary

The complement system represents an important nonspecific skin defense mechanism. Its activation leads to the generation of products that not only help to maintain normal host defenses but also mediate inflammation and tissue injury. Proinflammatory products of complement include large fragments of C3 with opsonic and cell-stimulatory activities (C3b and C3bi), low molecular weight anaphylatoxins (C3a, C4a, and C5a), and membrane attack complex. Among them C5a or its degradation product C5a des Arg seems to be the most important mediator because it exerts a potent chemotactic effect on inflammatory cells. Intradermal administration of C5a anaphylatoxin induces skin changes quite similar to those observed in cutaneous hypersensititivy vasculitis that occurs through immune complex-mediated complement activation. Complement activation is involved in the pathogenesis of the inflammatory changes in autoimmune bullous dermatoses. In pemphigus complement activation by pemphigus antibody in the epidermis seems to be responsible for the development of characteristic inflammatory changes termed eosinophilic spongiosis. In bullous pemphigoid (BP) interaction of basement membrane zone antigen and BP antibody leads to complement activation that seems to be related to leukocytes lining the dermoepidermal junction. Resultant anaphylatoxins not only activate the infiltrating leukocytes but also induce mast cell degranulation which facilitates dermoepidermal separation and eosinophil infiltration. Similar complement activation seems to play a more direct role in the dermoepidermal separation noted in epidermolysis bullosa acquisita and herpes gestationis. Anaphylatoxin generation via the alternative pathway activation under ligth irradiation is implicated in the development of the immediate erythematous phototoxic reactions induced by such well-known chemicals as porphyrin, chlorthiazide, demethylchlortetracycline, and chlorpromazine. It is known that a direct exposure of the stratum corneum to living skin tissues induces intense infammatory changes. In vitro study demonstrated that the stratum corneum activates complement via the antibody-independent alternative pathway to generate C5a anaphylatoxin. Thus, accumulated horny material from the follicular wall seems to play a crucial role in the induction of pustules in inflammatory acne lesions and abscesses in ruptured epidermal cysts via the activation of the alternative complement pathway. Meanwhile, in search for the chemotactic factors responsible for the transepidermal leukocyte chemotaxis noted in psoriasis and related sterile pustular dermatoses, we have detected the presence of unique chemotactic peptides in the scale extracts of lesional skin. Later studies identified the presence of C5a des Arg and IL-8 in this peptide fraction. The alternative complement pathway has been speculted for the complement activation at the subcorneal portion of the psoriatic epidermis by further immunological studies. Similar properties to activate the alternative complement pathway have been noted in various pathogenic fungi that induce inflammatory skin lesions. Generation of C5a anaphylatoxin beneath the fungus-laden stratum corneum seems to be responsible for the characteristic subcorneal pustule formation in superficial infections such as cutaneous candidiasis and dermatophytosis, whereas that around fungal spores in the dermis is presumed to play a role in the induction of mixed cell granuloma characterized by a dense neutrophil infiltration as noted in sporotrichosis and chromomycosis. AlthoughPityrosporum ovale constitutes ordinary skin microflora in seborrheic areas, its properties which activate complement via the alternative pathway are implicated in the pathogenesis of dandruff and seborrheic dermatitis, in which transepidermal neutrophil chemotaxis as noted in psoriasis is observed histopathologically.