BioWorld International Correspondent

LONDON - Inappropriate activation of the complement system - part of the innate immune system that helps to protect animals from infection - can lead to a form of kidney damage frequently seen in patients with autoimmune diseases. The discovery may eventually make it possible to develop new therapies to treat a type of kidney disease called membranoproliferative glomerulonephritis (MPGN).

Working with mice that had been genetically manipulated to remove one of the proteins that plays a key role in the complement system, researchers at Imperial College in London showed that it resulted in the development of MPGN with deposition of complement proteins in the kidneys.

Marina Botto, reader in rheumatology at Imperial College, told BioWorld International: "We will be able to understand why our innate immune system becomes noxious to us in some situations and understand the pathogenetic mechanism by which kidney damage occurs in patients. This will also allow us to understand better what therapeutic approaches we might use to avoid these damaging effects."

Botto and her colleagues report their experiments in a paper in the July 1, 2002, issue of Nature Genetics titled "Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H."

Having already shown that mice lacking the complement protein C1q, which were unable to adequately activate the complement system, developed autoimmune inflammation of the kidney, Botto and her colleagues decided to investigate what the effect on the kidney would be if uncontrolled activation of complement occurred.

When the complement system is triggered, a protein called C3 is split into two parts, one of which is an enzyme called C3 convertase. That enzyme generates the protein C3b, which is crucial to the formation of the group of proteins called the membrane attack complex, which punches a lethal hole in the membranes of bacteria.

C3 convertase is regulated by factor H, which prevents its formation and promotes its breakdown. Studies of families with inherited deficiency of factor H, and of a similar condition in pigs, have shown that, without factor H, levels of C3 in the plasma fall dramatically, and MPGN occurs in the kidney.

Botto and her team therefore decided to generate mice in which the gene encoding factor H was disrupted. "All of these mice spontaneously developed a kidney disease similar to the MPGN that can occur in humans," Botto said. "As we would have predicted, they had large deposits of complement proteins in their kidneys."

The group then went one step further, knocking out the gene for another complement protein, called factor B, which normally prevents the breakdown of C3. "So we had a mouse which could not activate its complement system, nor was it able to regulate its complement system. These mice had normal levels of C3, and their kidneys were healthy," Botto said. "Thus, removing the factor that would normally activate the complement system rectified the defect that had caused the disease, and rescued the mice. Together, these experiments show clearly that MPGN is caused by the uncontrolled activation of the complement system."

Commenting on the paper in a "News & Views" article titled "Complement in glomerulonephritis" in the same issue of Nature Genetics, Thomas Welch of Upstate Medical University in Syracuse, N.Y., described the experiments as "convincing" evidence that that is indeed the case.

Although spontaneous MPGN is relatively rare, Botto said, occurring in only 2 percent or 3 percent of all patients with kidney failure, it is present in about 30 percent of all patients with kidney damage due to the autoimmune disease known as systemic lupus erythematosus. "We now want to investigate the control of the complement system in these patients," she said.

Further experiments reported in the Nature Genetics paper indicated, she pointed out, that the mice lacking factor H had deposits of complement proteins in their kidneys long before MPGN developed. When injected with a serum that is normally toxic to the kidneys, more of the genetically manipulated mice died than did wild-type controls. "This shows," Botto said, "that these mice were already highly susceptible to kidney damage. We want to investigate how this occurs and how infection or environmental factors can further contribute to inflammatory disease in the kidney. This chain of events is similar to what happens in some patients who present with MPGN following a systemic infection."