ROLE OF NEUTROPHILS IN MURINE CRYOGLOBULINEMIA

Murine IgG3 anti-IgG2a rheumatoid factor (RF) monoclonal antibodies (m Ab) with cryoglobulin activity, are able to induce, in normal mice, sk in leukocytoclastic vasculitis and lupus-like glomerulonephritis resem bling 'wire-loop' lesions (subendothelial immune deposits). The develo pment of glomerular, but not skin, lesions in immunoglobulin-deficient mice (lacking the corresponding IgG2a autoantigen) receiving IgG3 RF cryoglobulins indicates that the RF activity of IgG3 monoclonal cryogl obulins and subsequent formation of IgG3-IgG2a immune complexes play a critical role in the development of skin vasculitis. In contrast, nep hritogenic activity is solely contributed by IgG3-associated cryoglobu lin activity. Polymorphonuclear leukocyte (PMN) infiltration is one of the major pathologic changes observed in both types of lesions. Treat ment with mAbs against the adhesion molecules leukocyte function-assoc iated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) (both known for their involvement in PMN-endothelial cell interaction ) inhibits the development of skin vascular lesions. However, it has n o effect on the generation of glomerulonephritis. Apparently, adhesion molecule requirements for PMN interaction with glomerular capillary e ndothelial cells are different from those for PMN infiltration of the skin. However, the PMN depletion experiment has clearly shown that PMN s pray an active role in the development of 'wire-loop' glomerular les ions. In the absence of the glomerular PMN infiltration, IgG3 RF cryog lobulins induce a different type of glomerular lesion, characterized b y voluminous intracapillary thrombi and mesangial deposits, yet lackin g subendothelial deposits. This is consistent with the fact that the l atter lesions can be induced by certain IgG3 mAbs, which are unable to provoke glomerular PMN infiltration. Finally, the activation of the c omplement system does not appear to play a major role in either skin o r glomerular lesions induced by IgG3 RF cryoglobulins.