Nephritic Factor Research Articles

Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome

Introduction: Abnormal control of the complement alternative pathway (CAP) (factor H, factor I and membrane cofactor protein (MCP) deficiencies) is a well established risk factor for the occurrence of haemolytic...

Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II)

We report a novel pathomechanism for membranoproliferative glomerulonephritis type II (MPGN II) caused by a mutant Factor H protein expressed in the plasma. Genetic analyses of two patients revealed deletion of a single Lys residue (K224) located within the complement regulatory region in domain 4 of Factor H. This deletion resulted in defective complement control: mutant protein purified from the plasma of patients showed severely reduced cofactor and decay-accelerating activity, as well as reduced binding to the central complement component C3b. However, cell-binding activity of the mutant protein was normal and comparable to wild-type Factor H. The patients are daughters of consanguineous parents. As both patients but also their healthy mother were positive for C3 nephritic factor, the mutant Factor H protein is considered relevant for unrestricted activation of the disease-causing activation of the alternative complement pathway. Replacement of functional Factor H by fresh frozen plasma (10-15 ml/kg/14 days) was well tolerated, prevented so far disease progression in both patients, and is in the long run expected to preserve kidney function.

Short-term outcomes of severe lupus nephritis in a cohort of predominantly African–American children

Renal involvement is one of the major determinants of the outcome in patients with systemic lupus erythematosus. Although African-American ethnicity has been suggested to be a poor prognostic factor in severe lupus nephritis in adult patients, information on outcomes of African-American children with this disease is still very limited. We retrospectively studied the patients diagnosed with severe lupus nephritis by renal biopsy at Le Bonheur Children's Medical Center from January 1990 to December 2003. All patients were below the age of 18 years at the time of biopsy. Clinical features assessed included age, gender, race, estimated glomerular filtration rate (GFR), presence of hypertension, gross hematuria, degree of proteinuria, complement 3 and 4 levels, serum albumin, renal histology and dose of oral prednisone. Forty-four patients were studied: 82% were African-American and 89% were female. Mean age at biopsy was 14.2+/-3 years (median 15.0 years; range 4.7 years to 17.0 years). Renal biopsies were assessed according to the WHO classification. Twenty-seven percent, 43%, and 30% were in class III, IV and V, respectively. At presentation, 55% had hypertension and 23% had a history of macroscopic hematuria. The patients had varying degrees of proteinuria, including 18% with nephrotic syndrome. Eighteen percent had moderate renal insufficiency with estimated GFRs less than 50 ml/1.73 m2 body surface area per minute. All the patients were treated with corticosteroids. Sixty-eight percent also received cyclophosphamide and 20% received either mycophenolate mofetil (MMF) or azathioprine (AZA). Two patients developed end stage renal disease and required chronic dialysis within 12 months of biopsy. At the 12-month follow-up visit, 23% of patients had complete remission and 48% had partial remission. The mean estimated GFR had increased from 96.0 ml/1.73 m2 per minute to 124 ml/1.73 m2 per minute (P=0.03). Mean serum creatinine levels decreased from 1.62 mg/dl to 0.91 mg/dl (P=0.03). Complement 3 levels increased from 54.3 mg/dl to 90.3 mg/dl (P<0.01). Mean serum albumin levels also increased from 2.8 mg/dl to 3.6 mg/dl (P<0.01) and urine protein-to-creatinine ratio decreased from 5.8 to 1.0 (P<0.01). The average prednisone dose decreased from 0.96 mg/kg per day to 0.41 mg/kg per day (P=0.64). In our center, with predominantly African-American children, patients with lupus nephritis presented similarly to those in other studies with predominantly Caucasian patients, and short-term renal outcomes were not different.

Membranoproliferative Glomerulonephritis Type II (Dense Deposit Disease)

Membranoproliferative glomerulonephritis type II (MPGN II) is a rare disease characterized by the deposition of abnormal electron-dense material within the glomerular basement membrane of the kidney and often within Bruch's membrane in the eye. The diagnosis is made in most patients between the ages of 5 and 15 yr, and within 10 yr, approximately half progress to end-stage renal disease, occasionally with the late comorbidity of visual impairment. The pathophysiologic basis of MPGN II is associated with the uncontrolled systemic activation of the alternative pathway (AP) of the complement cascade. In most patients, loss of complement regulation is caused by C3 nephritic factor, an autoantibody directed against the C3 convertase of the AP, but in some patients, mutations in the factor H gene have been identified. For the latter patients, plasma replacement therapy prevents renal failure, but for the majority of patients, there is no proven effective treatment. The disease recurs in virtually all renal allografts, and a high percentage of these ultimately fail. The development of molecular diagnostic tools and new therapies directed at controlling the AP of the complement cascade either locally in the kidney or at the systemic level may lead to effective treatments for MPGN II.

IgG naturally occurring antibodies stabilize and promote the generation of the alternative complement pathway C3 convertase

Normal human IgG contains naturally occurring anti-C3 antibodies (anti-C3 NAbs) that have been proposed to regulate complement amplification. Here, we report a novel procedure for anti-C3 NAb purification. Pooled human IgG was fractionated on a DEAE column prior to affinity chromatography on IgG and then on C3. Anti-C3 NAbs co-purified with anti-F(ab′) 2 NAbs. In a refined protocol, IgG fractions were absorbed on Fc, F(ab′) 2, and C3, which allowed to isolate the directly accessible NAbs and to remove IgG hinge-region-specific NAbs. Since a substantial fraction of total anti-C3 NAbs in whole IgG pre-existed as complexes, IgG that did not bind to the three affinity columns was treated with urea and the affinity chromatography repeated to collect the dissociated NAbs. The urea-accessible anti-F(ab′) 2 NAbs were rather pure but anti-C3 NAbs yet contained substantial amounts of anti-F(ab′) 2 NAbs. Anti-C3 NAbs showed up to 400-fold and anti-F(ab′) 2 NAbs, up to 30-fold enrichment as compared to pooled normal human IgG. Anti-C3 NAb preparations exhibited nephritic factor activity that was up to 60 times stronger than that of total IgG from a patient with membranoproliferative glomerulonephritis type 2. In addition, anti-C3 NAbs promoted C3 convertase generation, when added to the convertase precursor or during convertase assembly, suggesting a non-nephritic-factor mechanism. Factors H and I reduced the overall level of activity but had no influence on the NAb dose–response curve meaning that NAbs did not interfere with factor H binding. Convertase promoting activity during assembly correlated with the content of anti-C3 NAbs in NAb complexes. In conclusion, anti-C3 NAbs associated with framework-specific anti-idiotypic NAbs stabilize C3 convertase and promote its generation but their activity is compensated for in whole IgG.

Facial Lipoatrophy following Systemic Lupus Erythematosus

Background: Acquired partial lipodystrophy is a rare disorder. An association with systemic lupus erythematosus has been reported. In these cases, an immunologic basis is suggested by the presence of C3 nephritic factor and hypocomplementemia. Objective: The following report presents the case of a woman who developed a rapid loss of facial subcutaneous fat a few months after complete spontaneous resolution of cutaneous lesions of lupus. Conclusion: Absence of C3NeF in this case suggests that other immunological factors may be involved in the pathogenesis.

Composition of nephritic factor[ndash ]generated glomerular deposits in membranoproliferative glomerulonephritis type 2

Two observations suggest that nephritic factors (NFs) may be nephritogenic. First, glomerulonephritis is present in unusual frequency in three conditions in which the function of factor H is blocked, a dysfunction also produced by NFs. Second, in membranoproliferative glomerulonephritis (MPGN) type 2, subepithelial deposits on the paramesangial portion of the glomerular basement membrane are found only in renal biopsy specimens obtained during hypocomplementemia when NF is presumably present. In the present study, the composition of these deposits with respect to C3 derivatives was assessed by immunohistological evaluation using anti-C3c and anti-C3d. The assessment used routinely obtained photomicrographs, as well as immunohistologic examination of freshly cut tissue using the double-antibody method. Deposits in patients with typical hypocomplementemic MPGN type 2 reacted only with anti-C3c, whereas those in two patients with rapidly progressive MPGN type 2, six patients with poststreptococcal acute glomerulonephritis, and five patients with juvenile acute nonproliferative glomerulitis reacted with anti-C3d, as well as anti-C3c. Because all products derived from the breakdown of C3 except C3c react with anti-C3d, the deposits in typical MPGN type 2 must be composed only of C3c. With complete breakdown of bound C3b, C3c is released into the fluid phase. Therefore, the C3c in the deposits cannot be a product of a glomerular complement reaction, but instead must be formed in the circulation by the reaction of NF with native C3. Supporting C3c as the only constituent of these deposits is the observation that they are devoid of properdin and C5 is present in only small amounts.

A C3 convertase assay for nephritic factor functional activity

C3 nephritic factor (C3NeF) is an autoantibody against the C3 convertase which stabilizes this otherwise inherently labile neoenzyme and induces a continuous activation of the alternative pathway with C3 depletion. NeF is found in patients with membranoproliferative glomerulonephritis and/or partial lipodystrpohy. NeF activity is usually detected in plasma by hemolytic tests. In order to obtain reproducible data for the functional activity of purified C3NeF IgG a solid phase assay was developed. C3 convertase was generated on immobilized C3b by incubation with factors B and D in the presence of Ni 2+. Convertase sites were left to decay in the presence of normal IgG or NeF IgG. Residual convertase activity was measured by adding 125I-C3 and capturing nascent 125I-C3b on the plate surface via covalently coupled NH 2-Glu-Tyr dipeptide. In the presence of factor H during C3 convertase decay, a dose dependent stabilizing activity was shown for NeF IgG including NeF IgG purified from urine. A second format of the assay was developed in which C3 convertase was assembled on C3b 2–IgG complexes in the presence of Mg 2+. Since these complexes are more efficient as convertase precursors the signal was five-fold higher than with C3b. Convertase decay, on the other hand, was not influenced by the nature of the precursor and in both systems the stabilizing activity of NeF IgG was similar.

Partial lipodystrophy and renal disease

Partial lipodystrophy is a rare disorder with both autosomal recessive and familial forms. The cutaneous findings, which are often subtle, consist of a gradual loss of subcutaneous fat from the face and upper body. Low levels of C3, occasionally low C5 and the presence of the nephritic factor help to identify these patients. Associated systemic abnormalities include the development of mesangiocapillary glomerulonephritis and an increased incidence of autoimmune diseases. Recognition of this unusual disorder is essential for diagnosis and treatment of underlying potentially life- threatening disease.

The alternative pathway C3 convertase and glomerular deposits.

Five conditions in which the alternative pathway C3 convertase, C3b,Bb, circulates in excess as a result of factor H dysfunction are frequently accompanied by nephritis. These convertase-related nephritides are seen in association with heterozygous absence of a binding site for factor H on C3b (Marder disease), homozygous factor H deficiency, circulating factor H inhibitor, and with the nephritic factors, one of the amplification loop and the other of the terminal pathway, found in membranoproliferative glomerulonephritis (MPGN) types II and III, respectively. Observations which relate convertase to glomerular deposits are: (1) in MPGN type II, subepithelial deposits on the paramesangial segments of the glomerular basement membrane are with high frequency present in patients hypocomplementemic at biopsy, but not in those normocomplementemic; (2) in MPGN type III paramesangial deposits are similarly found with hypocomplementemia but are present for up to 1 year after normocomplementemia is achieved; (3) in MPGN type III, subendothelial deposits are present only with hypocomplementemia. The principal deposits found in factor H deficiency and in Marder disease are also paramesangial. Differences in the incidence, severity, and morphology of the nephritides accompanying convertase in excess may relate to the characteristics of the circulating convertase and/or to the C3 conversion products formed by it.

Is complement a target for therapy in renal disease?

Complement deposition in the injured kidney is common, especially in glomerulonephritis. The precise role of the complement system in the mediation of tissue injury in the kidney has been defined in recent years, and this has assumed extra importance with the recent development of specific forms of therapy directed at the complement pathway. As well as the induction of cell lysis, complement has many subtle effects on cell biology, particularly on endothelial cells. Complement components are produced locally in the kidney. Detailed studies of certain rare forms of nephritis have provided evidence that complement activation can directly cause tissue injury. Appreciation of the importance of complement in hyperacute rejection of xenotransplants has given new impetus to the development of complement inhibitors. A narrative review is provided, with a brief overview of the complement pathway and its regulatory mechanisms, mechanisms of complement-induced tissue injury, local complement production, and the renal consequences of complement dysregulation. Currently available forms of therapy aimed at the complement system are reviewed, and possible future therapeutic strategies are suggested. The complement system plays a direct causal role in tissue injury in certain forms of renal disease. Specific forms of therapy are becoming available that can selectively interrupt complement activation or promote its regulation. Much of the drive for the development of these therapies comes from the field of xenotransplantation, but these forms of therapy should also be tested in various primary renal diseases.

Partial lipodystrophy, mesangiocapillary glomerulonephritis, and complement dysregulation. An autoimmune phenomenon.

Partial lypodistrophy (PLD) is a rare disease in which, there is loss of fat usually from the upper part of the body. The disease is frequently associated with mesangiocapillary (membranoproliferative) glomerulonephritis Type II (MCGN II). In the early 1970s, it was noticed that MCGN II and/or PLD was sometimes associated with dysfunction of the complement system as reported in several case descriptions and studies. Subsequently, an IgG autoantibody was detected-C3 nephritic factor (C3NeF). The target of this autoantibody is the alternative pathway C3 convertase-C3bBb. There are sporadic case reports that linked PLD, MCGNII, and C3NeF with autoimmune diseases. This association may be more than a coincidence. The complement deficiency may lead to perturbation of the immune system, which may trigger some of the autoimmune diseases. This article will be focused on the association among PLD, MCGN II and C3NeF.

Membranoproliferative glomerulonephritis type III: Association of glomerular deposits with circulating nephritic factor-stabilized convertase

Deposits in the glomerular ultrastructure of 44 renal biopsy specimens from 21 patients with membranoproliferative glomerulonephritis (MPGN) type III have been compared with those in the ultrastructure of 34 biopsy specimens from 19 patients with MPGN type I. Previous studies have concluded that subepithelial deposits on the paramesangial portion of the glomerular basement membrane in MPGN types II and III are closely associated with circulating nephritic factor-stabilized convertase. In the present study, subendothelial deposits in MPGN type III were also found to be closely associated with nephritic factor; they were present in 14 of 26 (54%) biopsy specimens obtained during hypocomplementemia but in none of the 18 biopsy specimens obtained during normocomplementemia (P < 0.001). Subepithelial loop deposits in type III were also more frequent in biopsy specimens obtained during hypocomplementemia and are probably in some way also associated with circulating stabilized convertase. Taken together, the results of this and previous studies are compatible with the hypothesis that an excess of the C3b-dependent convertase in the circulation is basic to the pathogenesis of MPGN types II and III as well as of several other nephritides associated with factor H dysfunction. The half-life, structural complexity, and size of the convertases circulating in these nephritides increase in the following order: native convertase, convertase stabilized by the nephritic factor of the amplification loop (NFa), and convertase stabilized by nephritic factor of the terminal pathway (NFt). In the same order, the nephritides associated with these convertases more frequently manifest and have increasing amounts of glomerular deposit. This relationship of glomerular deposits with circulating convertase, however, is only circumstantial. There is no evidence that the convertase or a part thereof is a constituent of the deposits. The lesion that is the hallmark of MPGN type III is one in which interruptions of lamina densa are associated with subendothelial and subepithelial deposits, often confluent, and interspersed with multiple layers of new lamina densa-like material. This “type III lesion,” which by implication is also associated with circulating nephritic factor, is the most persistent of the glomerular deposits. For reasons that are not yet clear, the type III lesion was absent in three patients who were severely hypocomplementemic, and the diagnosis of type III was made only after this lesion appeared in biopsy specimens obtained later. In MPGN type I, differing from type III, subendothelial deposits were present in 100% of biopsy specimens obtained during hypocomplementemia and in 47% of those obtained during normocomplementemia. Their persistence in type I may reflect rearrangement and condensation of the deposited material, shown by other investigators to be dependent on the presence of immunoglobulin G, which is largely absent from the deposits in type III. The comparison of deposits in types I and III indicates that relating the presence of subendothelial and paramesangial deposits to the C3 level at the time of biopsy can be helpful in distinguishing types I and III when the type III lesion is not present. (Am J Kidney Dis 1998 Jul;32(1):56-63)

Glomerular paramesangial deposits: Association with hypocomplementemia in membranoproliferative glomerulonephritis types I and III

Of 22 subjects previously reported with some form of factor H dysfunction, 12 had a glomerulonephritis that appeared to not be of immune complex origin. Factor H dysfunction results in elevated circulating levels of the C3b-dependent C3 convertase, C3b,Bb. Of the 12 cases with glomerulonephritis, the glomerular deposits in the six whose biopsy specimens were studied were predominately subepithelial on the paramesangial portion of the glomerular basement membrane. In a subsequent study, similar deposits were found in patients with membranoproliferative glomerulonephritis (MPGN) type II, also a nephritis that is probably not of immune complex origin. Paramesangial deposits were found in these patients only in biopsy specimens obtained when the C3 level was low, at which time convertase stabilized by nephritic factor would be present in the circulation. This association of paramesangial deposits with circulating convertase was further tested by correlating these deposits with the level of C3 at the time of biopsy in MPGN types I and III. The results in type III MPGN were similar to those in type II; paramesangial deposits were frequently present when the C3 level was low as a result of circulating nephritic factor of the terminal pathway, NFt, and were usually absent when the C3 level was in the upper two thirds of the normal range. Deposits persisted in those patients with C3 levels that had been low but that had increased during the year before biopsy to within the lower one third of the normal range. The persistence of paramesangial deposits in MPGN type III, as compared with MPGN type II, may be related to the differences in composition and function of the two NF stabilized convertases (C3bn,Bb,P,NFt and C3b,Bb,NFa, respectively) that circulate in these two disorders. In contrast to MPGN type III, the hypocomplementemia in MPGN type I is thought to be, for the most part, the result of classical pathway activation, which is not associated with elevated circulating convertase levels. In agreement with this, paramesangial deposits were found in only two of 34 biopsy specimens. At the time of those two biopsies, both patients had a complement profile indicating that the NFt was circulating, as in MPGN type III. In three other cases with profiles compatible with circulating NFt, paramesangial deposits were not found. In all patients with type I MPGN, electron microscopy and immunofluorescence of the glomeruli gave results typical of an immune complex nephritis. Thus, even though the complement profile in MPGN type I may at times indicate the presence of a nephritic factor, circulating immune complexes appear to be basic to pathogenesis. The observations support the hypothesis that elevated levels of the C3b-dependent convertase, as found in the “experiments of nature” with factor H dysfunction and in MPGN types II and III, are associated with paramesangial deposits. The nature of this association and the role of these deposits in producing the nephritis is not clear. (Am J Kidney Dis 1998 Mar;31(3):427-34)

Hypocomplementaemia caused by C3 nephritic factors (C3 NeF): clinical findings and the coincidence of C3 NeF type II with anti‐C1q autoantibodies

The main purposes were to document manifestations associated with prolonged or clinically unexplained C3 deficiency and to approximate how often hypocomplementaemia of this kind is caused by C3 nephritic factors (C3 NeF), i.e. autoantibodies to alternative pathway C3 convertases. We also wished to distinguish between C3 NeF types I and II and to assess coincident autoantibody responses to the collagen-like region of C1q (C1qCLR). The investigation was based on serum samples referred to a specialized laboratory for complement analysis in the course of several years. Twenty-five persons with C3 concentrations lower than 0.43 g L-1, a third of the normal, were included in the study. Analysis using three methods provided evidence of C3 NeF in 20 persons with equal frequencies of C3 NeF types I and II. We also gave evidence of antibody specificity differences for the two types of C3 NeF. Six patients with C3 NeF type II showed antibodies to C1qCLR. Membranoproliferative glomerulonephritis was the predominant diagnosis and two patients had partial lipodystrophy reflecting the well-known association between these diseases and C3 NeF. Anaphylactoid purpura, systemic lupus erythematosus, and severe infection, mainly meningococcal disease, were also observed. The study group was probably fairly representative of C3 deficiency syndromes as encountered in clinical practice. The findings emphasize the heterogeneity of C3 NeF, and that acquired C3 deficiency syndromes caused by C3 NeF should perhaps be considered more often in diagnostic work.

Recurrent Disseminated Gonococcal Infection in a Patient with Hypocomplementemia and Membranoproliferative Glomerulonephritis

We describe a patient with three documented episodes of disseminated gonococcal infection in an 18-month period. Gonococcal dissemination is relatively uncommon and recurrence is rare in the absence of a complement deficiency because most Neisseria gonorrhoeae strains are susceptible to complement-mediated killing by serum. Our patient was hypocomplementemic and had previously been diagnosed with type I membranoproliferative glomerulonephritis (MPGN), a presently untreatable form of renal disease that is associated with excessive complement consumption due either to activation of the classical pathway by immune complexes or to the action of "nephritic factors" that block the regulators of C3 convertase activity. We believe it is likely that MPGN-associated hypocomplementemia reduced this patient's serum bactericidal activity, permitting gonococcal dissemination on multiple occasions after local reinfection. In view of the potential for more serious Neisserial infection, antibiotic prophylaxis was considered, but the patient was lost to follow-up before it could be instituted.

C3 nephritic factor and mesangiocapillary glomerulonephritis.

The association of a C3 splitting activity, known as C3 nephritic factor (C3NeF), with mesangiocapillary glomerulonephritis (MCGN), especially MCGN type II, has long been known. Several forms of C3NeF are now recognised, the main one being an IgG which acts as an autoantibody binding to factor H, a normally occurring component of the complement system. Complement is in a continuous state of activation with inbuilt checks and controls, and factor H plays a very important part in the controlling mechanisms by preventing the overwhelming activation of complement at the stage of C3 conversion. C3NeF binds to factor H, thus preventing its inhibitory action, and allowing complement activation to proceed with, in vivo, the well-known consequences in MCGN of very low serum levels of C3. The question naturally arose whether C3NeF causes MCGN. Complex relationships between MCGN, C3NeF and partial lipodystrophy, also characterised by C3NeF and hypocomplementaemia, but preceding the development of MCGN, suggest that hypocomplementaemia predisposes to MCGN. Another possibility is that C3NeF acts directly within glomeruli to cause local complement activation and ensuing damage. Neither possibility could be resolved, but some recent observations have restimulated interest in a possible causative role for C3NeF in MCGN. First, factor H deficiency, by mechanisms other than blocking by C3NeF, in animals and man is associated with MCGN. Second, adipocytes, now known themselves to produce complement system proteins, are lysed in vitro by C3NeF, thus suggesting a mechanism for partial lipodystrophy. By analogy, the C3NeF may produce glomerular damage, as glomerular cells produce complement components.

Expression of platelet-derived growth factor in lupus nephritis in MRL/MpJ-1pr/1pr mice.

Platelet-derived growth factor (PDGF) plays an important role in the pathogenesis of mesangial proliferative glomerulonephritis. We examined PDGF expression and glomerular changes in lupus nephritis-prone MRL/MpJ-1pr/1pr (MRL/1) mice. The total number of nuclei per glomerular section and blood urea nitrogen (BUN) level were significantly increased in MRL/1 mice aged 20 weeks compared to those aged 8 weeks. A positive correlation existed between numbers of PDGF beta-chain-positive cells and glomerular cells in MRL/1 mice (r = 0.77, p < 0.01). The BUN level did not differ among MRL/MP-+2 (MRL/n) mice of different ages, but the glomerular cell number increased modestly with age. At the age of 20 weeks, the incidence of crescent formation per kidney tissue ranged from 9 to 32% (mean 19%) in MRL/1 mice but was 0 in MRL/n mice. PDGF beta-chain protein was expressed in the mesangium and crescents in 20-week-old MRL/1 mice but was expressed rarely in the glomeruli of MRL/n mice. These results suggest that the PDGF beta-chain plays an important role in glomerular cell proliferation and crescent formation in murine lupus nephritis.

Discordant renal histopathologic findings and complement profiles in membranoproliferative glomerulonephritis type III

Patients with membranoproliferative glomerulonephritis (MPGN) type III and a low serum C3 concentration tend to have evidence for a nephritic factor of the terminal complement pathway (Nft). Complement profiles were studied in three patients with MPGN type III and low serum C3 concentrations. Serum C3 concentrations were 52, 21, and 14 mg/dL (normal range, 83 to 177 mg/dL). Serum C1q, C2, C4, properdin, and C5 concentrations were normal in all patients, whereas two had a slight decrease of C7 or C8. This pattern of complement activation resembles that seen with MPGN type II in which a nephritic factor activates the amplification loop (NFa). We conclude that in patients with MPGN type III the previously reported profile/presence of Nft is not always found, at least in the chronic stage of the disease, despite a low C3 value.

Complement, adipocytes and the kiney

Summary: The complement system has traditionally been thought of as a group of circulating proteins predominantly produced in the liver, with functions in both afferent and efferent arms of the immune response, primarily concerned with host defence. In recent years, it has become apparent that many tissues synthesize and secrete complement components and that the complement cascade may have previously unsuspected local actions in these tissues in health and disease. Perhaps one of the most surprising organs in this respect is adipose tissue. the adipocyte is capable of producing all the key components of the alternative pathway, and produces particularly abundant quantities of factor D, previously thought to be mainly produced by cells of the monocyte/macrophage lineage. Adipose tissue is probably the main source of factor D in vivo: factor D expression is decreased in various experimental models of obesity, and is increased in fasting or catabolic states, suggesting that factor D (and hence the alternative pathway) may play a role in physiological regulation of adipose tissue. Another link between adipocytes and the complement pathway is illustrated by the recent demonstration that the complement cleavage product C3a has potent activity as an acylation stimulating protein, promoting the esterification of fatty acids into triglyceride. the production of factor D by adipocytes probably underlies the association between complement activation by the autoantibody nephritic factor (NeF) and adipose tissue loss in partial lipodystrophy (PLD): in vitro data indicate that serum containing NeF causes complement‐mediated lysis of adipocytes. There is preliminary evidence of a regional variation in factor D gene expression with higher levels of expression in the regions affected by adipocyte loss in PLD. This illustrates a novel toncept in immunopathology: by expression of factor D the adipocyte contributes to its own destruction when the normal regulation of the alternative pathway is subverted by the presence of NeF. In relation to the nephritis associated with NeF, we postulate that a similar mechanism may operate. Intrinsic renal cells are known to produce complement components, and NeF may lead to injury to these cells, aggravated perhaps by cytokines which are known to up‐regulate complement protein expression in renal cells. Other situations by which dysregulation of the alternative pathway occurs may lead to nephritis by a similar mechanism. For example, in rare human cases with factor H deficiency, and in a recently described variety of Yorkshire pig with factor H deficiency, nephritis is common and is histologically similar to the nephritis associated with NeF. Thus, recent advances in adipocyte biology have led to novel ideas about actions of complement, and similar principles may apply to physiology and pathology in the kidney.