Albert-Ludwigs University Medical School, Department of Rheumatology and Clinical Immunology, Freiburg and
1 Institute for Immunology, Heidelberg, Germany
SIR, Acquired partial lipodystrophy is characterized by a regional loss of subcutaneous adipose tissue which usually starts in the face, extends downward to the waist, but spares the legs. The disease is often associated with the presence of an IgG autoantibody called C3 nephritic factor (C3Nef) which binds to and stabilizes C3bBb, the C3 convertase of the alternative complement pathway (Fig. 1) [1]. We here present a patient with acquired partial lipodystrophy in whom nephritis was absent despite persistent complement activation due to C3Nef. We show that this condition may be cosmetically improved with rosiglitazone, an agonist of the peroxisome proliferator-activated receptor (PPAR)-gamma, which promotes adipocyte differentiation.
|
|
In vitro experiments demonstrated that adipocytes are lysed by complement in the presence of C3Nef [3]. Adipocytes synthesize C3, factor B and factor D (adipsin), which allows C3bBb to be formed locally, but which usually does not result in the activation of the terminal lytic part of the complement pathway (C59). C3NeF prevents C3bBb from inactivation resulting in adipocyte lysis [1, 3]. Adipocytes synthesize factor D, the limiting component of the alternative complement pathway, which cleaves C3-bound factor B to its active enzymatic form [3]. Factor D is thought to be expressed to a higher extent in the fat cells of the upper half of the body than in the lower half and it is possibly this regional difference which accounts for the restriction of the fat loss to the head, arms and trunk [4].
C3Nef is also associated with type II, dense-deposit membranoproliferative glomerulonephritis in which subendothelial deposits of immunoglobulin and of C3 are probably due to a deregulated alternative complement pathway [4]. In our patient, the clinical course was not complicated by glomerulonephritis, indicating that the presence of C3Nef and systemic complement activation alone is not sufficient to cause glomerulonephritis. This is also supported by the description of a baby born to a mother with membranoproliferative glomerulonephritis. The baby had acquired C3Nef transplacentally but did not develop glomerulonephritis [5]. Although C3 and factor B are expressed in the kidney, this organ may be locally spared because of a lack of factor D production [4]. Alternatively, higher degrees of systemic C3 activation may be necessary for the manifestation of renal disease.
Only a minority of individuals with detectable C3Nef, ongoing systemic complement activation and frank glomerulonephritis presents with lipodystrophy. It has been speculated that interindividual variation in factor D expression may account for the variability of disease manifestation [4, 6] or that infections with subsequent cytokine release and complement up-regulation are important triggers for this acute-onset lipoatrophy [4, 7].
PPAR-gamma ligands promote adipocyte differentiation and seem to be beneficial in causally heterogeneous forms of lipodystrophy [8]. The patients' clinical course suggests that some regenerative capacity is retained in the areas of fat loss despite years of disease activity with ongoing complement activation. There may therefore be a balance between adipocyte destruction and adipocyte regeneration and the PPAR-gamma agonist may shift the equilibrium towards regeneration.
In summary, this case illustrates that acquired partial lipodystrophy with detectable C3Nef and complement activation can occur without concomitant glomerulonephritis and metabolic derangements. Lipoatrophy can be treated cosmetically with PPAR-gamma agonists despite ongoing complement activation, demonstrating some regenerative capacity of adipose tissue in this condition.
Notes
Correspondence to: U. A. Walker, Albert-Ludwigs University Medical School, Department of Rheumatology and Clinical Immunology, Hugstetterstr. 55, D-79106 Freiburg, Germany. E-mail: walkerrul{at}uni-freiburg.de
References
|