Complement-mediated adipocyte lysis by nephritic factor sera.

Recent data indicate a previously unsuspected link between the complement system and adipocyte biology. Murine adipocytes produce key components of the alternative pathway of complement and are able to activate this pathway. This suggested to us an explanation for adipose tissue loss in partial lipodystrophy, a rare human condition usually associated with the immunoglobulin G(IgG) autoantibody nephritic factor (NeF) which leads to enhanced alternative pathway activation in vivo. We hypothesized that in the presence of NeF, there is dysregulated complement activation at the membrane of the adipocyte, leading to adipocyte lysis. Here we show that adipocytes explanted from rat epididymal fat pads are lysed by NeF-containing sera but not by control sera. A similar pattern is seen with IgG fractions of these sera. Adipocyte lysis in the presence of NeF is associated with the generation of fluid-phase terminal complement complexes, the level of which correlates closely with the level of lactate dehydrogenase, a marker of cell lysis. Lysis is abolished by ethylenediaminetetraacetic acid, which chelates divalent cations and prevents complement activation, and reduced by an antibody to factor D, a key component of the alternative pathway. These data provide an explanation for the previously obscure link between NeF and fat cell damage.

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

The metabolism of the fifth component of complement (C5), and its relatonship 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 mug/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 extravascular distribution of C3 in patients with mesangiocapillary nephritis and (or) partial lipodystrophy, and fractional catabolism 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, suggesting that in patients with alternative pathway activation by nephritic factor little or no C5 convertase is generated.

Metabolic studies of the third component of complement and the glycine-rich beta glycoprotein in patients with hypocomplementemia.

Metabolic studies using radioiodine-labeled third component of complement (C3) and the glycine-rich beta glycoprotein (GBG), a major component of the C3b-feedback pathway, were undertaken in normal subjects, in 22 patients with evidence of complement activation, and in 11 patients with various renal diseases without evidence of complement activation. In seven normal subjects GBG was found to be a rapidly metabolized protein with catabolic rates ranging from 1.7% to 2.2% of the plasma pool/h, synthesis rates from 0.14 to 0.21 mg/kg per h. and extravascular/intravascular distribution ratios from 0.81 to 1.31. In patients with reduced plasma C3, both increased C3 fractional catabolic rates and reduced C3 synthesis rates were observed, and in some patients there was evidence of increased extravascular distribution of the protein. GBG catabolism was usually increased when there was evidence of C3 activation, presumably reflecting activation of the C3b-feedback; but GBG turnover was normal or only slightly accelerated in some patients with accelerated C3 catabolism and profound hypocomplementemia, suggesting that reduced C3 synthesis had limited activation of the C3b-feedback.

Anti-glomerular basement membrane autoantibodies in the Brown Norway rat: detection by a solid-phase radioimmunoassay.

A solid-phase radioimmunoassay (RIA) is described for the detection of IgG autoantibodies to glomerular basement membrane (GBM) induced in the Brown Norway rat by mercuric chloride. The assay involves the adsorption of a collagenase digest of GBM to plastic microtitre plates and detection of bound antibody with affinity purified radiolabelled rabbit anti-rat IgG. Comparison with existing immunofluorescence methods for detection of anti-GBM antibody showed that the solid-phase RIA is highly sensitive, allowing detection of antibody in solutions with as low as 0.5 ng protein/ml. The assay is suitable for detection of anti-GBM antibody both in serum and in eluates from nephritic kidneys. The assay proved to be specific in competitive studies of inhibition brought by GBM, keyhole limpet antigen and ovalbumin. This solid-phase RIA is reproducible, robust and easy to perform.

Plasma exchange and immunosuppressive drugs in the treatment of glomerulonephritis due to antibodies to the glomerular basement membrane.

Glomerulonephritis due to autoantibodies to the glomerular basement membrane (GBM) usually results in the rapid development of renal failure in untreated patients. We report our experience of the use of plasma exchange and immunosuppressive drugs in the management of this condition. Treatment consisted of daily 4 litre plasma exchanges for plasma protein fraction, together with prednisolone 60 mg daily (reducing to 20 mg daily by 4 weeks), cyclophosphamide 3 mg/kg daily and azathioprine 1 mg/kg daily. It was found that plasma exchange was generally required for 2 weeks, and cytotoxic drugs for 8 weeks. Forty four patients, aged 4 to 72 years, were treated. Anti-GBM antibody production was rapidly controlled, and in 21 of 34 patients antibody was undetectable within 8 weeks. Of 22 oliguric patients, none recovered renal function, 16 remained dialysis-dependent and 6 died; of 5 patients whose initial plasma creatinine was greater than 600 mumol/l, one improved and 4 proceeded to dialysis; and of 17 patients whose creatinine was less than 600 mumol/l, 15 recovered renal function, one became dialysis-dependent and one died. Long term follow-up of those who improved revealed that 2/16 subsequently deteriorated. Our results represent a great improvement in the prognosis of anti-GBM disease, and demonstrate that the majority of patients will recover renal function if treated before irreversible glomerular damage has occurred.

Childhood sexual abuse and current suicidality in college women and men.

In previous research, adults who reported childhood sexual abuse have been more suicidal than nonabused adults, but no research has examined their cognitive deterrents to suicide. Strict definitions of sexual abuse in these studies have excluded (a) unwanted sexual experiences with peers, and (b) exploitive experiences not involving genital contact (i.e., unwanted sexual invitations or suggestions, unwanted exposure to others' genitals via exhibitionism, unwanted kissing or hugging in a sexual way). The present study compared suicidal behavior and cognitive deterrents to suicide in 266 college students using both a strict and a liberal definition of sexual abuse. Both women and men abused by adults or peers were more suicidal as adult college students than were women and men with no such history. Women reported similar degrees of suicidality as men, but greater survival and coping beliefs and more fear of suicide. Those whose sexual abuse involved touching were more suicidal, and felt less able to cope, and less responsibility for their families, than nonabused adults. Implications are that adults who experienced childhood sexual abuse that involved touching are more suicidal and have less cognitive deterrents to suicide than adults who have not, regardless of whether they are men or women or whether they were abused by adults or by peers.

Factors distinguishing samples of lesbian and heterosexual women.

This study utilized non-clinical samples of women and examined historical, familial, sexual, and attitudinal variables to assess differences between groups endorsing heterosexual or homosexual orientations. Drawing from social learning theory, researchers expected the lesbian group to report more negative childhood sexual experiences with males, more positive childhood sexual experiences with females, more accepting parental attitudes toward sexuality and sexual experimentation, and more distant relationships with parents. Results indicate that, rather than childhood sexual experiences distinguishing groups, respondents' current attitudes are significant between-group discriminators. These findings are consistent with the recent body of literature that suggests that sexual orientation cannot be explained in terms of early sexual trauma or negative heterosexual experiences.