Different pathways leading to cutaneous leukocytoclastic vasculitis in mice

To investigate the pathomechanisms of leukocytoclastic vasculitis (LcV) we compared mouse models of LcV with non-vasculitic irritant contact dermatiti s (ICD). Criteria for LcV as met by the immune complex-mediated Arthus reac tion (Art-r) were also fulfilled by the localized Shwartzman reaction (Shw- r) and by cutaneous Loxoscelism (Lox) (injection of venom from Loxosceles r eclusa containing sphingomyelinase D). After depletion of PMN (by gamma -ir radiation) vessel damage could not be elicited in these models, distinguish ing them from models of direct endothelial insult (necrotizing ICD). Deplet ion of complement could only delay, but not inhibit the Art-r, and did not change ICD, Lox or the Shw-r. The Shw-r exclusively revealed a sustained lo cal expression of vascular adhesion molecules for 24 h in the preparatory p hase (LPS s.c.), not observed in the Art-r, in Lox or ICD. Subsequent chall enge with LPS i.p. was associated with upregulation of Mac-1 and ICAM-1 on PMN, but not of VLA-4 or LFA-1 (FACS analysis). Cytokines which were able t o replace LPS in priming for LcV in the Shw-r (TNF-alpha and IL-1 beta) als o induced sustained expression of adhesion molecules, whereas IL-12 and IFN -gamma did neither. Neutralizing IL-12 or IFN-gamma also inhibited neither LcV nor sustained expression of adhesion molecules, whereas anti-TNF-alpha inhibited both. Anti-TNF-alpha had no marked inhibitory effects in the Art- r, in Lox or ICD. Combined (but not separate) neutralization of both E-sele ctin and VCAM-1 by antibodies suppressed LcV independent from reducing infl ux of PMN, proving that their sustained expression is decisive for the Shw- r and interferes with normal diapedesis. Since Loxosceles venom is known to dysregulate diapedesis and degranulation of PMN in vitro, since adherent i mmune complexes activate PMN at the vessel wall, and since adhesion molecul es are dysregulated in the Shw-r, we suggest that LcV develops when activat ion of PMN coincides with vascular alterations which interfere with normal diapedesis.