Lupus: complement cascade, Fc receptors...or both?

Abstract

The classic view of autoimmune diseases such as systemic lupus erythematosus is that the complement cascade is the predominant pathway to inflammation and tissue destruction. New evidence, though, indicates that Fc receptors, found predominantly on immune cells, might be playing an equal or greater role in the disease process. These findings could lead to new therapeutic targets for a chronic debilitating disease that primarily afflicts women in their 20s to 40s.To establish the primacy of Fc receptors, Jeffrey Ravetch at Rockefeller University (New York, NY, USA) knocked out the gene encoding the γ-chain of the receptor in one strain of mice. He then backcrossed the Fc-knockout mice with New Zealand Black/New Zealand White mice, which spontaneously develop lupus, in particular an aggressive pattern of kidney damage that kills them within one year.His group's recently published study [Clynes, R. et al. (1998) Science 279, 1052–1054] reported that 82 percent of the Fc knockout mice were alive after nine months, compared with less than 20 percent in the mice with intact Fc receptors. This protective effect was seen even in the presence of copious deposits of immune complexes in the kidney.`These results show that, despite the presence of immune complexes and C3 in the kidney, the inflammatory response is uncoupled, indicating that Fcγ-receptors are required for the initiation of the inflammatory cascade, and complement activation is not sufficient,' says Ravetch. `We've proven the concept, identified a new pathway, and now a novel therapeutic can be tested based on this pathway.'Kathleen Sullivan (Children's Hospital of Philadelphia, PA, USA), whose own work is on complement deficiencies in human lupus patients, is excited about Ravetch's work, saying that it `elegantly demonstrates that the presence of Fc receptors is essential for causing inflammation in this model of lupus.' However, his findings do not refute the complement theory of lupus; Sullivan rather believes that there is plenty of room for both causative factors. `People have devoted tons of time and energy to inhibiting complement as a way of treating lupus. This Fc work opens up a whole new avenue,' she says.Louis Matis, vice president of research-immunology at Alexion Pharmaceuticals (New Haven, CT, USA), which is testing complement inhibitors in humans, cautions against overinterpreting the Fc findings. `Dr Ravetch's study is important...He's extended the paradigm, but I don't think that it's been reversed.' In particular, Matis says scientists should be wary of generalizing from one species to another. For instance, there is evidence that immune complex inflammation is more Fc dependent in the mouse than in other species, such as rabbit and guinea pig, he explains.While Ravetch concedes that murine immunology has some differences from humans, he argues that this particular mouse model for lupus is quite a good mimic of the human disease state. The mice show the same 9:1 bias towards affected females, and the immune-complex deposition and lesions are almost identical in appearance to those seen in human lupus patients.But getting Fc receptor-based therapy into the clinic could take a while. At present, the few companies exploring lupus therapies seem to be focusing on complement blockade. And Ravetch says that, so far, there has been little industrial interest in his Fc technology.Meanwhile, Alexion has just launched a single center Phase I trial of its proprietary C5 complement inhibitor, which it will test in about 30 patients this year. This trial follows publication in 1996 [Wang, Y. et al. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 8563–8568] of a study showing that treatment of lupus mice with C5 inhibitor dramatically prolonged survival of the mice. At the end of a six month course of treatment, greater than 80 percent of treated animals were alive compared to just 5 percent of controls.Sullivan says that one way of exploiting Ravetch's findings in the near future could be to infuse patients with intravenous immunoglobulin. This therapy, which has been tried in the past, could act by overwhelming Fc receptors, thus inducing a blockade. Ravetch himself is working on monoclonal antibodies that target the Fc receptors, and could eventually have therapeutic benefits.Whatever therapies are developed, though, there is always a strong potential for side effects, says Sullivan. `When you muck around with the immune system you have substantial side effects', she says. She expects to see a considerable increase in knowledge about the precise roles that Fc receptors have in the human body, which will guide future development of Fc-based therapies.