Autoantibodies against complement C1q in systemic lupus erythemathosus

Complement and C1q, the first component of the classical pathway of activation of the
complement system, are considered to be involved in the pathogenesis of systemic lupus
erythematosus (SLE), a systemic autoimmune disease. In fact, C1q deficiency is the
strongest disease susceptibility gene for human SLE. However, most SLE patients do not
have primary C1q deficiency, but a substantial number of patients with SLE develop
secondary hypocomplementemia with depletion of C1q and its deposition in affected
tissues. Furthermore, autoantibodies against C1q (anti-C1q) are frequently found in SLE
patients and they are strongly associated with the consumption of C1q as well as the
occurrence of severe lupus nephritis.
Anti-nucleosome antibodies as a marker of active proliferative lupus nephritis
To date there is no gold standard to predict severe nephritis in patients with SLE. Like
anti-C1q antibodies, anti-dsDNA antibodies and anti-nucleosome antibodies are also
considered to be useful markers of severe lupus nephritis. Therefore we aimed to
establish the true prevalence of anti-nucleosome and anti-dsDNA antibodies at the time
of active proliferative lupus nephritis, and compared this to inactive SLE controls who
either had or had not experienced nephritis in the past. Results were compared to anti-
C1q that had previously been investigated in the same cohort of patients. In this study,
anti-C1q autoantibodies had been shown to be an excellent marker of active proliferative
lupus nephritis, which suggests a pathogenic role in SLE. In contrast, our data on antinucleosome
antibodies and anti-dsDNA antibodies suggest that these autoantibodies are
of limited use in distinguishing patients with active proliferative lupus nephritis from
SLE patients without active renal disease.
Autoantibodies against complement C1q specifically target C1q bound on early
apoptotic cells
To better understand the pathogenic mechanisms in SLE, we intended to analyze the
conditions that lead to an autoimmune response against C1q. Since anti-C1q are known to
recognize neoepitopes on bound C1q but not on fluid phase C1q, we aimed to clarify the
origin of anti-C1q by determining the mechanism that renders C1q antigenic. We
analyzed the binding characteristics of anti-C1q antibodies, such as their ability to
recognise C1q bound on different classes of immunoglobulins, on immune complexes
and on cells undergoing apoptosis. Interestingly, we did not observe the binding of anti-
C1q to C1q bound on immunoglobulins or immune complexes. However, anti-C1q were
found to specifically target C1q bound on early apoptotic cells. Our findings provide a
direct link between human SLE, apoptosis and C1q. Due to the exceptional presentation
of neoantigens by the C1q molecule, our data suggest that early apoptotic cells are a
major target of the autoimmune response in SLE.
Anti-C1q autoantibodies do not correlate with the occurrence of nephritis in lupusprone
MRL/MpJ+/+ mice
In SLE patients, a strong correlation between the occurrence of anti-C1q antibodies and
lupus nephritis has been demonstrated. However, it is difficult to demonstrate in SLE
patients whether anti-C1q titers are predictive for a renal flare. Therefore we conducted a
follow-up study of lupus-prone MRL/MpJ+/+ mice with the aim to analyze the
occurrence of anti-C1q autoantibodies and their correlation with the onset, type and
severity of nephritis. Despite the abundant and early presence of anti-C1q, they did not
correlate with survival and severity of glomerulonephritis, contradicting our initial
hypothesis. However, different pathogenic mechanisms in glomerulonephritis in lupusprone
MRL/MpJ+/+ mice and human proliferative lupus nephritis might account for the
unexpected observation.