LONDON - The cause of systemic lupus erythematosus (SLE) has been a mystery since the autoimmune disease first was described in 1845. Now, new research - including the generation of a mouse model for SLE - has confirmed that a defect in the complement pathway may play a role in the development of this condition.
SLE affects more than 1 million women in the U.S. and is nine times more common in women than in men. It causes a characteristic “butterfly“ rash over the cheeks and bridge of the nose. The body's own antibodies attack connective tissue as though it were foreign, causing inflammation of various tissues. The effects of these autoantibodies, particularly in organs such as the kidneys, may be fatal, although improved treatment means that patients with SLE live much longer today than they once did.
A minute proportion of people with SLE have an inherited deficiency resulting in the lack of a protein called C1q, which is part of the complement cascade. Only about 40 individuals with this genetic defect have been identified worldwide, and almost all in this group develop SLE regardless of their gender. Researchers have therefore regarded this group as holding a powerful clue to at least one of the causes of this disease.
To investigate the role of this complement protein, researchers at Imperial College School of Medicine, in London, with collaborators at the Institute of Medical Microbiology and Hygiene, in Mainz, Germany, and at the Memorial Sloan Kettering Cancer Center, in New York, developed a knockout mouse which lacks the gene for C1q.
They report their study in the May issue of Nature Genetics, in a letter titled “Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.“
Mark Walport, professor of medicine at the Hammersmith campus of Imperial College School of Medicine, who is last author of the paper, told BioWorld International the gene-targeted mouse, deficient in expression of C1q, develops a disease similar to the SLE seen in C1q-deficient humans. “This means we now have a good animal model with which to explore the links between complement deficiency and the development of SLE,“ he said.
Walport and his team found the C1q-deficient mice had higher titres of autoantibodies than controls of the same strain. The researchers also observed the kidneys of the knockout mice had a buildup of cells dying from apoptosis (programmed cell death).
The latter finding, Walport said, raises the question of whether complement is involved in the clearance of apoptotic cells from the body, and provides clues potentially helpful in solving the mystery of why patients with SLE develop the autoantibodies they do.
No one has been able to explain this, given that the autoantibodies are directed against antigens that occur in every cell of the body, such as DNA, chromatin and ribonucleoprotein. A further puzzle has been how the immune system comes into contact with such antigens, since these normally are expressed intracellularly.
Cell-Scavenging Mechanism May Break Down
“There is some evidence to suggest that cells that die by apoptosis express the autoantigens that are found in lupus on the cell surface - so, if you like, any defect in the clearance of apoptotic cells could then provide the source of antigen that drives the autoimmune response in lupus,“ Walport said.
It has been shown that apoptotic cells produce surface structures called blebs, which contain components of the nucleus or cytoplasm, including the kinds of antigens to which autoantibodies are produced in SLE. Furthermore, one study has demonstrated that C1q can bind to such blebs on apoptotic keratinocytes.
“Although only a tiny minority of patients have hereditary deficiency of complement, many of them have acquired deficiency of complement,“ Walport said. “This could be part of a vicious cycle. The nature of the inflammation in lupus means that the complement system is activated and consumed, and this might then mean that there is a secondary defect in clearance of apoptotic cells.
“Our findings,“ he concluded, “contribute to the evidence that the source of autoantigens in lupus is from apoptotic cells, and that lupus may develop when the normal mechanisms of clearance of dead cells from the body are defective. It is possible that, when the scavenging mechanisms to clear cellular debris break down, autoantigens - instead of being cleared away in a harmless fashion - get presented to the immune system.“
Next, Walport and his colleagues plan to carry out experiments to test the hypothesis that C1q and other complement proteins do play a role in the clearance of apoptotic cells, both in the animal model and in humans with SLE. *