Metabolic Studies of the Third Component of Complement and the Glycine-Rich Beta Glycoprotein in Patients with Hypocomplementemia

Charlesworth, J. A.; Williams, D G; Sherington, E.; Lachmann, P. J.; Peters, D. K.

doi:10.1172/jci107708

Cited by 143 publications

(73 citation statements)

References 21 publications

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“…Plasma C3 levels are clearly influenced by both C3 synthetic rate and the degree of C3 activation. Notably, depression of C3 synthesis during hypocomplementemia has been reported in humans and was most pronounced in patients with circulating C3dg (45). In contrast, C3 synthesis was not altered in a patient with hypocomplementemia due to factor I deficiency, which also prevented the generation of plasma C3dg (45).…”

Section: Figurementioning

confidence: 75%

“…Notably, depression of C3 synthesis during hypocomplementemia has been reported in humans and was most pronounced in patients with circulating C3dg (45). In contrast, C3 synthesis was not altered in a patient with hypocomplementemia due to factor I deficiency, which also prevented the generation of plasma C3dg (45). Hence, the difference in the magnitude of depression of plasma C3 between factor H and factor I deficiency may be a consequence of differential C3 synthetic rates.…”

Section: Figurementioning

confidence: 83%

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Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

Rose¹,

Paixão-Cavalcante²,

Fish³

et al. 2008

J. Clin. Invest.

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The inflammatory kidney disease membranoproliferative glomerulonephritis type II (MPGN2) is associated with dysregulation of the alternative pathway of complement activation. MPGN2 is characterized by the presence of complement C3 along the glomerular basement membrane (GBM). Spontaneous activation of C3 through the alternative pathway is regulated by 2 plasma proteins, factor H and factor I. Deficiency of either of these regulators results in uncontrolled C3 activation, although the breakdown of activated C3 is dependent on factor I. Deficiency of factor H, but not factor I, is associated with MPGN2 in humans, pigs, and mice. To explain this discordance, mice with single or combined deficiencies of these factors were studied. MPGN2 did not develop in mice with combined factor H and I deficiency or in mice deficient in factor I alone. However, administration of a source of factor I to mice with combined factor H and factor I deficiency triggered both activated C3 fragments in plasma and GBM C3 deposition. Mouse renal transplant studies demonstrated that C3 deposited along the GBM was derived from plasma. Together, these findings provide what we believe to be the first evidence that factor I-mediated generation of activated C3 fragments in the circulation is a critical determinant for the development of MPGN2 associated with factor H deficiency.

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Section: Figurementioning

confidence: 75%

Section: Figurementioning

confidence: 83%

Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

Rose¹,

Paixão-Cavalcante²,

Fish³

et al. 2008

J. Clin. Invest.

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“…We think that such a parallel C3 activation seems to be the most probable mechanism. However, an extravascular activation of complement, mainly in rheuma- 866 Nydegger, Zubler, Gabay, Joliat, Karagevrekis, Lambert, and Miescher tic nodules or in unrecognized lesions (6,24) (25). The contribution of various extravascular sites to the plasma pool of C3d is difficult to assess.…”

mentioning

confidence: 99%

Circulating complement breakdown products in patients with rheumatoid arthritis. Correlation between plasma C3d, circulating immune complexes, and clinical activity.

Nydegger¹,

Zubler²,

Gabay³

et al. 1977

J. Clin. Invest.

112

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“…The differences in CH50 levels between group A and group B were not statistically significant, in SLE patients (31-39), probably by recruitment from classical pathway activation (29,40). Poor synthesis and increased extravascular distribution of C3 also occur in SLE, and have been documented when turnover studies have been performed using radiolabeled complement components (7,8,29,30,40).…”

Section: Discussionmentioning

confidence: 98%

“…Evidence for this comes from studies of radiolabeled complement components (7,8) and from the frequent finding of classical pathway complement activation products in sera and plasma of SLE patients (13,20,30). Alternative pathway activation does occur * See Results for definition of groups.…”

Section: Discussionmentioning

confidence: 99%

Hypocomplementemia with low Cls‐Cl inhibitor complex in systemic lupus erythematosus

Lockshin

Qamar

Redecha

et al. 1986

Arthritis & Rheumatism

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Ninety-three serum and plasma samples from 45 patients with systemic lupus erythematosus were analyzed for the complex formed by Cls and its inhibitor, as well as for C3, C4, C4a desarginine, and staphylococcal protein A-bound immune complexes. There were statistically significant correlations between Cls-C1 inhibitor complex and CH50, between Cls-C1 inhibitor complex and C4, and between Cls-C1 inhibitor complex and C4a desarginine. Serial studies were performed on 24 patients over a period of 6 months. Seven of 21 patients with hypocomplementemia had persistently normal levels of Cls-C1 inhibitor complex, 7 had transiently abnormal levels of Cls-C1 inhibitor complex, and 7 had sustained abnormal levels of Cls-C 1 inhibitor complex. Two of 3 pregnant patients with normal levels of complement had abnormal levels of Cls-Cl inhibitor complex. Staphylococcal protein A-bound immune complexes demonstrated no correlation with any of the complement assays. Complement activation, as measured by Cls-C1 inhibitor complex, is often a transient phenomenon in systemic lupus erythematosus patients with persistent hypocomplementemia. (SLE) is the assumption that serum complement, measured as CH50, C3, or C4, reflects the rate of in vivo complement activation (1-6). Testing of this hypothesis is cumbersome, however (7,s); it requires the administration, to patients, of radiolabeled complement components.Several assays for products of complement activation are now available. These assays measure the complex formed by Cls and the C1 inhibitor (9-12), C3d (13-15), C4d (16), C5a (17,18), membrane attack complex (19), and other products (20,21). Studies relevant to SLE have, in general, concluded that these assays correlate well with the clinically used measures of complement, CH50, C3, and C4.In contrast, in a previous study of pregnant SLE patients, we noted that Cls-C1 inhibitor complex did not reflect clinically measured hypocomplementemia (22). The serum specimens analyzed in our prior report were obtained from single patients at single points in time. These observations now are extended by findings on a new group of 45 SLE patients (27 nonpregnant, 18 pregnant), 24 of whom we have followed serially. In these patients, we compared levels of CIS-C1 inhibitor complex with levels of CH50, C3, C4, C4a desarginine, and staphylococcal protein A-bound immune complexes. Our results indicate that the levels of Cls-C1 inhibitor complex are frequently either normal or are only transiently abnormal when levels of CH50, C3, and C4 are persistently abnormal, which suggests that activation of the classical complement pathway occurs sporadically in patients with sustained hypocomplementemia. In addition, measurements of C4a desarginine and staphylococcal protein A binding correlate poorly with other complement measures.

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Metabolic Studies of the Third Component of Complement and the Glycine-Rich Beta Glycoprotein in Patients with Hypocomplementemia

Cited by 143 publications

References 21 publications

Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

Factor I is required for the development of membranoproliferative glomerulonephritis in factor H–deficient mice

Circulating complement breakdown products in patients with rheumatoid arthritis. Correlation between plasma C3d, circulating immune complexes, and clinical activity.

Hypocomplementemia with low Cls‐Cl inhibitor complex in systemic lupus erythematosus

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