The Complement Abnormalities of Lipodystrophy

Sissons, J. G. P.; West, R; J, Fallows; Williams, D G; Boucher, B. J.; Amos, N.; Peters, D. K.

doi:10.1056/nejm197602262940902

Cited by 248 publications

(117 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These sera all showed evidence of marked classical pathway activation (greatly reduced total hemolytic complement [CH50] levels), which is a common finding in this disease (58)(59)(60). 3 of the 29 SLE sera did react in the alternative pathway ELISA; this confirmed the indications of activation of this pathway in the serum (61)(62)(63) and tissues (64, 65) of a proportion of patients with SLE. The relative contributions of the classical and alternative pathways to the pathogenesis and symptomatology of this disease are not understood.…”

Section: Discussionsupporting

confidence: 65%

Development and application of an enzyme-linked immunosorbent assay for the quantitation of alternative complement pathway activation in human serum.

Mayes¹,

Schreiber²,

Cooper³

1984

J. Clin. Invest.

View full text Add to dashboard Cite

As bstract. We have developed a new, specific, and highly sensitive enzyme-linked immunosorbent assay (ELISA) which quantitates activation of the alternative pathway in human serum, plasma, or on the surface of activators. The ELISA detects the third component of complement (C3b), proteolytic fragment of complement Factor B (Bb), and properdin (P) complex or its derivative product, C3b,P. In the method, activator-plasma mixtures, plasma containing an activated alternative pathway, or other samples are added to the wells of microtitration plates precoated with antibody to P. C3b,Bb,P or C3b,P complexes which become bound are quantitated by subsequently added, enzyme-labeled, anti-C3. The resulting hydrolysis of the chromogenic substrate is expressed as nanograms of C3b by reference to a C3 standard curve. In addition to absolute specificity for activation of the pathway because of the nature of the complex detected by the assay, the ELISA is highly sensitive and able to reproducibly detect 10-20 ng/ml of C3b,P complexes in serum. This value corresponds to 0.0015% of the C3 in serum. In a series of studies to validate the parameters of the ELISA, reactivity was found to be dependent on the presence of alternative pathway proteins, the functional integrity of the pathway, and on the presence of magnesium. Sheep erythrocytes were converted to activators by treatment with neuraminidase. By using a variety of activators, the kinetics ofactivation and the numbers of bound C3b molecules quantitated by the ELISA This is publication no.

show abstract

Section: Discussionsupporting

confidence: 65%

Development and application of an enzyme-linked immunosorbent assay for the quantitation of alternative complement pathway activation in human serum.

Mayes¹,

Schreiber²,

Cooper³

1984

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…CONCLUSION These differences in metabolic parameters for C5 between patients with SLE and those with MCGN and NeF presumably reflect the different mechanisms of complement activation in these two groups. In SLE the increased catabolism and EV distribution of C3 and C5 suggest that both proteins are playing a role in inflammatory tissue injury, whereas the failure to activate C5 and normal C5 distribution, in the patient with PLD may possibly explain the lack of overt tissue inflammation in such cases (32).…”

Section: Resultsmentioning

confidence: 99%

Metabolism of the fifth component of complement, and its relation to metabolism of the third component, in patients with complement activation.

Sissons¹,

Liebowitch²,

Amos³

et al. 1977

J. Clin. Invest.

View full text Add to dashboard Cite

A B S T R A C T The metabolism ofthe fifth component of complement (C5), and its relationship to metabolism of the third component of complement (C3), has been studied in normal subjects and patients by simultaneous administration of radioiodine labeled C5 and C3. In seven normal subjects the fractional catabolic rate of C5 ranged from 1.5 to 2.1% of the plasma pool/h and extravascular/intravascular distribution ratio from 0.22 to 0.78, these values being similar to those obtained for C3, and synthesis rate from 71 to 134 ,g/kg per h. In patients with complement activation the increase in fractional catabolic rate of C5 was nearly always less than that of C3. The data also showed that there was increased extravascular distribution of C3 and C5 in most patients and considerable extravascular catabolism of both proteins in some. However, there were differences in metabolic parameters between patients with different types of complement activation. In patients with systemic lupus erythematosus, fractional catabolism and extravascular distribution of C3 and C5 were both increased, and there was marked extravascular catabolism of both proteins. There was increased fractional catabolism and extravasctular distribution of C3 in patients with mesangiocapillary nephritis and (or) partial lipodystrophy, and fractional catabolisim of C5 was also increased in three of six studies although distribution of C5 was always within the normal range; however, in two patients with nephritic factor in their serum fractional catabolism of C5 was normal despite markedly increased C3 turnover, suiggesting that in patients with alterna- INTRODUCTIONThe fifth component of complement (C5)1 is the major component of the final common pathway of complement activation-the membrane attack complex C5-9. The cleavage of C5-the final enzymatic step in the complement sequence-yields a larger fragment, C5b, which binds C6-9 to formn the membrane attack complex, and a smaller fragment, C5a, which has anaphylatoxic and chemotactic activity.The suibunit structure of C5 is very similar to that of the third component (C3) (1), and this is reflected by the similarity of the C3 and C5 cleaving enzymes (convertases) which are generated after activation of complement by the classical or alternative pathways. Thus the classical pathway C3 convertase, C4b2a, binds the major cleavage fragment of C3, C3b, to become a C5 convertase C423b.The mechanism of formation and composition of the alternative pathway C3 and C5 convertases has been the subject of mtuch recent investigation. Upon activation of the alternative pathway C3b is generated and interacts with factors B and D (D cleaving Factor B) in the C3b feedback or amplifica-

show abstract

“…With very few exceptions, however, lipodystrophy is associated with impaired insulin sensitivity and dyslipidaemia. One such exception is the form of acquired partial lipodystrophy commonly associated with the presence of an IgG autoantibody which stabilises C3 (complement component C3) convertase leading to low C3 complement levels (Sissons et al 1976). This so-called 'nephritic factor' is also associated with glomerular disease (typically mesangiocapillary glomerulonephritis type II (Williams 1997)).…”

Section: Visceral Versus Subcutaneous Fatmentioning

confidence: 99%

Lipodystrophy: metabolic insights from a rare disorder

Huang-Doran¹,

Sleigh²,

Rochford³

et al. 2010

Journal of Endocrinology

183

147

View full text Add to dashboard Cite

Obesity, insulin resistance and their attendant complications are among the leading causes of morbidity and premature mortality today, yet we are only in the early stages of understanding the molecular pathogenesis of these aberrant phenotypes. A powerful approach has been the study of rare patients with monogenic syndromes that manifest as extreme phenotypes. For example, there are striking similarities between the biochemical and clinical profiles of individuals with excess fat (obesity) and those with an abnormal paucity of fat (lipodystrophy), including severe insulin resistance, dyslipidaemia, hepatic steatosis and features of hyperandrogenism. Rare lipodystrophy patients therefore provide a tractable genetically defined model for the study of a prevalent human disease phenotype. Indeed, as we review herein, detailed study of these syndromes is beginning to yield valuable insights into the molecular genetics underlying different forms of lipodystrophy, the essential components of normal adipose tissue development and the mechanisms by which disturbances in adipose tissue function can lead to almost all the features of the metabolic syndrome.

show abstract

The Complement Abnormalities of Lipodystrophy

Cited by 248 publications

References 20 publications

Development and application of an enzyme-linked immunosorbent assay for the quantitation of alternative complement pathway activation in human serum.

Development and application of an enzyme-linked immunosorbent assay for the quantitation of alternative complement pathway activation in human serum.

Metabolism of the fifth component of complement, and its relation to metabolism of the third component, in patients with complement activation.

Lipodystrophy: metabolic insights from a rare disorder

Contact Info

Product

Resources

About