The major discoveries that led to the modern era of work on systemic lupus erythematosus (SLE) were those of Hargraves et al.
in 1947 of the lupus erythematosus (or 'LE') cell phenomenon [1
], followed by the discovery of autoreactivity to nuclei [2
] and to nucleoprotein [4
]. Contemporaneous with these findings came the discovery that complement levels were abnormal in patients with SLE [5
] and the discovery a few years later that complement was deposited in inflammatory lesions in tissues [7
]. These findings led to a model for the pathogenesis of SLE in which autoantibodies formed immune complexes with their autoantigens, the resulting immune complexes activated complement, and the products of complement activation caused tissue injury and disease.
Subsequent findings have shown that the associations of complement with SLE are much more complex and it is now clear that complement may be friend as well as foe. The first finding was of a rare subgroup of patients with SLE with inherited homozygous deficiencies of certain complement proteins, particularly proteins of the early part of the classical pathway of complement activation. Subsequently it was discovered that up to a third of patients with SLE had high levels of autoantibodies to some complement proteins, especially to C1q, the very first protein in the classical pathway of complement.
These data allowed three deductions to be made about the association of complement with SLE. The first is that SLE is associated with complement activation, which may cause tissue injury. The second is that hereditary complement deficiency may cause SLE. The third is that the disease processes in SLE cause the development of autoantibodies to certain complement proteins. At first sight these statements appear to be mutually contradictory and difficult to reconcile one with the other.
In this chapter I will illustrate the evidence in support of these three deductions and develop some hypotheses that may explain these complex abnormalities of the complement system found in association with SLE.
The first section of this review will first describe the clinical associations of complement abnormalities with SLE, followed by the mechanisms of these associations. Finally a hypothesis will be proposed to explain the associations and consider the therapeutic implications.