Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 683-691
Loxosceles intermedia spider envenomation induces
activation of an endogenous metalloproteinase, resulting in cleavage of
glycophorins from the erythrocyte surface and facilitating
complement-mediated lysis
Denise V. Tambourgi,
B. Paul Morgan,
Rute M. G. de Andrade,
Fábio C. Magnoli, and
Carmen W. van den Berg
From the Laboratório de Imunoquímica, Instituto
Butantan, São Paulo, Brazil; and the Departments of Medical
Biochemistry and of Pharmacology, Toxicology and Therapeutics,
University of Wales, College of Medicine, Cardiff, United Kingdom.
Loxosceles is the most venomous spider in Brazil, and
envenomation causes dermonecrosis and complement (C)-dependent
intravascular hemolysis. The authors studied the mechanism of induction
of C-induced hemolysis. Purified Loxosceles toxins rendered
human erythrocytes susceptible to lysis by human C but did not have an
effect on the E-bound C-regulators DAF, CR1, or CD59. However,
incubation with venom toxins caused cleavage of glycophorin from the
erythrocyte (E) surface, facilitating C activation and hemolysis. The
results suggest that glycophorin is an important factor in the
protection of E against homologous C. Cleavage of glycophorin (GP) A,
GPB, and GPC occurred at sites close to the membrane but could not be
accomplished using purified GPA and purified toxins, demonstrating that
cleavage was not an effect of a direct proteolytic action of the
Loxosceles toxins on the glycophorins. Inhibition of the cleavage of glycophorins induced by Loxosceles venom was
achieved with 1,10-phenanthroline. The authors propose that the
sphingomyelinase activity of the toxins induces activation of an
endogenous metalloproteinase, which then cleaves glycophorins. They
observed the transfer of C-dependent hemolysis to other cells,
suggesting that the Loxosceles toxins can act on multiple
cells. This observation can explain the extent of hemolysis observed in
patients after envenomation. Identification of the mechanism of
induction of susceptibility to C-mediated lysis after
Loxosceles envenomation opens up the possibility of the
development of an effective therapeutic strategy.
