Depletion of LAG-3+ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781.

Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4+ and CD8+ T cells. We describe the engineering and first-in-human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3+ cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3+ and CD3+ T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.

Effect of belimumab on proteinuria and anti-phospholipase A2 receptor autoantibody in primary membranous nephropathy.

BACKGROUND: Immunosuppressant drugs reduce proteinuria and anti-phospholipase A2 receptor autoantibodies (PLA2R-Ab) in primary membranous nephropathy (PMN) with varying success and associated toxicities. This study aimed to evaluate the effect of belimumab on proteinuria and PLA2R-Ab in participants with PMN. METHODS: In this prospective, open-label, experimental medicine study, 14 participants with PMN and persistent nephrotic-range proteinuria received up to 2 years belimumab monotherapy (10 mg/kg, every 4 weeks). Changes in proteinuria (urinary protein:creatinine ratio), PLA2R-Ab, albumin, cholesterol, B-cell subsets and pharmacokinetics were analysed during treatment and up to 6 months after treatment. RESULTS: Eleven participants completed to the primary endpoint (Week 28) and nine participants completed the study. In the intention-to-treat population population, baseline proteinuria of 724 mg/mmol [95% confidence interval (CI) 579-906] decreased to 498 mg/mmol (95% CI 383-649) and 130 mg/mmol (95% CI 54-312) at Weeks 28 and 104, respectively, with changes statistically significant from Week 36 (n = 11, P = 0.047). PLA2R-Ab decreased from 174 RU/mL (95% CI 79-384) at baseline to 46 RU/mL (95% CI 16-132) and 4 RU/mL (95% CI 2-6) at Weeks 28 and 104, respectively, becoming statistically significant by Week 12 (n = 13, P = 0.02). Nine participants achieved partial (n = 8) or complete (n = 1) remission. Participants with abnormal albumin and/or cholesterol at baseline gained normal/near normal levels by the last follow-up. Adverse events were consistent with those expected in this population. CONCLUSIONS: Belimumab treatment in participants with PMN can reduce PLA2R-Ab and subsequently proteinuria, important preludes to remission induction.

Positive antineutrophil cytoplasmic antibody serology in patients with lupus nephritis is associated with distinct histopathologic features on renal biopsy.

Class IV-S lupus nephritis is often associated with more necrosis and fewer subendothelial immune deposits compared to class IV-G lupus nephritis, suggestive of necrotising glomerular inflammation found in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. ANCAs are present in a significant proportion of patients with lupus nephritis. Here we determine whether ANCAs are associated with distinct clinical and histopathologic features of lupus nephritis. Thirty-two ANCA-positive biopsies were compared to 222 ANCA-negative biopsies from patients with lupus nephritis. The majority (82%) of ANCA-positive patients had antimyeloperoxidase antibodies. Class IV-S lupus nephritis and glomerular necrosis were significantly more common (36% vs. 16% and 35% vs. 15%, respectively) and isolated Class V lupus nephritis significantly less common (10% vs. 29%) in the ANCA-positive group. ANCA-positive patients had significantly higher dsDNA titers (335u/ml vs. 52u/ml), significantly lower serum C4 concentrations (0.125g/L vs. 0.15g/L) and significantly higher serum creatinine (130µmol/L vs. 84µmol/L) at the time of biopsy. Hence ANCAs appear to influence the histological pattern of lupus nephritis and are associated with worse baseline renal function and more active lupus serology. There was no significant difference in outcome between groups when matched for severity of disease and treatment using propensity scoring. Thus, further studies are needed to examine whether ANCAs in patients with lupus nephritis have a pathogenic role and whether they are associated with worse renal outcomes or are simply a marker of more severe disease.

Long-term Outcomes of Rituximab Therapy in Ocular Granulomatosis with Polyangiitis: Impact on Localized and Nonlocalized Disease.

PURPOSE: To evaluate the long-term outcomes of rituximab (RTX) treatment in patients with ocular granulomatosis with polyangiitis (GPA) with localized or generalized disease. DESIGN: Retrospective cohort. PARTICIPANTS: Thirty-seven patients with ocular GPA receiving RTX in a multidisciplinary vasculitis clinic between 2004 and 2013. METHODS: A total of 100 patients who received a course of RTX were identified, and notes were reviewed. Baseline demographic details, clinical characteristics (including organ involvement), drugs used, and outcome measures were recorded. MAIN OUTCOME MEASURES: The percentage in remission (inactive disease with prednisolone ≤7.5 mg with or without maintenance treatment) at 6 months, time to remission, percentage relapsing, side effects, B-cell count, antineutrophil cytoplasm antibody titers, induction, and maintenance regimens. RESULTS: The median follow-up time after the first RTX course was 36.5 months. Twenty patients had scleritis, and 17 patients had orbital disease; 86% achieved remission at 6 months. The percentage in remission versus partial remission was not statistically significant between patients with scleritis and patients with orbital disease (85% vs. 15% with scleritis and 82% vs. 18% with orbital disease; P = 1.00). The percentage relapsing was not statistically significant (P = 0.33) between scleritis (60%) and orbital disease (41%). Localized disease (ocular ± ear-nose-throat/lung) was observed in 57%, and generalized disease (ocular plus other organs) was observed in 43%, the former having a median duration of disease of 40 months. There was no statistically significant difference (P = 0.37) in the percentage in remission between localized and generalized ocular disease. Relapses occurred in 51%, with localized disease being a significant risk factor for relapse. Fifty percent of patients with generalized disease versus none with localized disease received cyclophosphamide (CYP) as part of the induction regimen. Patients who received CYP during induction had significantly (P = 0.027) lower ratios of baseline 12-month proteinase 3 titers than patients who did not have CYP. Infections were observed in 16% of patients, with 8% requiring hospital admission. CONCLUSIONS: Our long-term data suggest that RTX is effective for inducing disease remission in localized and generalized ocular GPA. Localized disease is a significant risk factor for relapse, which may be related to less use of CYP in the induction regimen.

Necrotizing and crescentic glomerulonephritis presenting with preserved renal function in patients with underlying multisystem autoimmune disease: a retrospective case series.

OBJECTIVE: Necrotizing and crescentic GN usually presents with rapidly declining renal function, often in association with multisystem autoimmune disease, with a poor outcome if left untreated. We aimed to describe the features of patients who have presented with these histopathological findings but minimal disturbance of renal function. METHODS: We conducted a retrospective review (1995-2011) of all adult patients with native renal biopsy-proven necrotizing or crescentic GN and normal serum creatinine (<120 µmol/l) at our centre. RESULTS: Thirty-eight patients were identified. The median creatinine at presentation was 84 µmol/l and the median proportion of glomeruli affected by necrosis or crescents was 32%. Clinicopathological diagnoses were ANCA-associated GN (74%), LN (18%), anti-GBM disease (5%) and HScP (3%). Only 18% of cases had pre-existing diagnoses of underlying multisystem autoimmune disease, although the majority (89%) had extra-renal manifestations accompanying the renal diagnosis. All patients received immunosuppression and most had good long-term renal outcomes (median duration of follow-up 50 months), although two progressed to end-stage renal disease within 3 years. We estimate that renal biopsy had an important influence on treatment decisions in 82% of cases. CONCLUSION: Necrotizing and crescentic GN may present in patients with no or only minor disturbance of renal function. This often occurs in patients with underlying systemic autoimmune disease; early referral for biopsy may affect management and improve long-term outcomes in these cases.

Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors.

BACKGROUND: Anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis with renal involvement requires treatment with potentially toxic drugs to reduce morbidity and mortality, and there is a major challenge to determine clinical and histological features predictive of renal prognosis. The aim of our study was to evaluate the use of the 2010 international histological classification for ANCA-associated glomerulonephritis (AAGN) as a predictor of renal outcome when used in conjunction with other prognostic factors. METHODS: One hundred and four patients with AAGN treated at our centre were included: 23 were classified as focal, 26 as crescentic, 48 as mixed and 7 as sclerotic. Renal outcomes were based on estimated glomerular filtration rate (eGFR) at 1 and 5 years, and on renal survival. RESULTS: By univariate analysis, patients in the focal class had the best renal outcome, those in the sclerotic class the worst outcome, and those in the mixed and crescentic classes had intermediate renal survival. There was no significant difference in outcome between the mixed and crescentic classes. In multivariate models, histological class did not improve model fit or associate with renal outcome after adjusting for established prognostic factors. Lower percentage of normal glomeruli, greater degree of tubular atrophy (TA), MPO-ANCA positivity, increasing age and lower starting eGFR, all correlated with poorer renal outcomes. CONCLUSIONS: We conclude that, in our cohort of patients, the international histological classification is predictive of renal outcome in AAGN, but did not appear to be additionally informative over other established prognostic factors in multivariate analysis. However, it may be of value to combine the current histological classification with other established parameters, such as TA and percentage normal glomeruli.

Current and future prospects in the management of granulomatosis with polyangiitis (Wegener's granulomatosis).

Granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) is a multisystem autoimmune condition associated with anti-neutrophil cytoplasm antibodies. Management of GPA can be complex, owing to the sometimes fulminant and multisystem nature of the presentation, the age demographics of the affected population, and a significant incidence of disease relapse. In this paper, we discuss how some of the challenges in the management of GPA have been and continue to be addressed including: reducing the toxicity of induction therapy; developing biomarkers to determine who can safely stop maintenance immunosuppression; improving the efficacy of maintenance therapy for relapsing patients; managing localized disease; and management of disease and treatment-associated comorbidity. Consideration is also given to emerging therapeutics in the treatment of GPA.

Issues in trial design for ANCA-associated and large-vessel vasculitis.

Randomized clinical trials (RCTs) have informed the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, although challenges still exist. The evidence base for treating large-vessel vasculitis (LVV) is weaker, but initiatives to standardize diagnostic criteria and outcome measures, and to validate biomarkers in LVV, together with newly initiated RCTs should start to address this need. In this Perspectives, we discuss the prerequisites for RCTs in vasculitis, existing trial evidence, continuing unmet needs, potential therapeutic avenues to explore and considerations in the design of future trials.

FcγRIIb on myeloid cells and intrinsic renal cells rather than B cells protects from nephrotoxic nephritis.

FcγRIIb is the sole inhibitory FcR for IgG in humans and mice, where it is involved in the negative regulation of Ab production and cellular activation. FcγRIIb-deficient mice show exacerbated disease following the induction of nephrotoxic nephritis (NTN). In this study, we determined the cellular origin of the FcγRIIb-knockout phenotype by inducing NTN in mice with a deficiency of FcγRIIb on either B cells alone (FcγRIIB(fl/fl)/CD19Cre(+)) or myeloid cells (FcγRIIB(fl/fl)/CEBPαCre(+)). Deletion of FcγRIIb from B cells did not increase susceptibility to NTN, compared with wild-type (WT) mice, despite higher Ab titers in the FcγRIIB(fl/fl)/CD19Cre(+) mice compared with the WT littermate controls. In contrast, mice lacking FcγRIIb on myeloid cells had exacerbated disease as measured by increased glomerular thrombosis, glomerular crescents, albuminuria, serum urea, and glomerular neutrophil infiltration when compared with WT littermate controls. The role for FcγRIIb expression on radioresistant intrinsic renal cells in the protection from NTN was then investigated using bone marrow chimeric mice. FcγRIIb(-/-) mice transplanted with FcγRIIb(-/-) bone marrow were more susceptible to NTN than WT mice transplanted with FcγRIIb(-/-) bone marrow, indicating that the presence of WT intrinsic renal cells protects from NTN. These results demonstrate that FcγRIIb on myeloid cells plays a major role in protection from NTN, and therefore, augmentation of FcγRIIb on these cells could be a therapeutic target in human Ab-mediated glomerulonephritis. Where there was a lack of FcγRIIb on circulating myeloid cells, expression of FcγRIIb on intrinsic renal cells provided an additional level of protection from Ab-mediated glomerulonephritis.

Increased incidence of anti-GBM disease in Fcgamma receptor 2b deficient mice, but not mice with conditional deletion of Fcgr2b on either B cells or myeloid cells alone.

Fcgamma receptor 2b (Fcgr2b) is the only inhibitory Fcgamma receptor in both humans and mice, and is implicated in both antibody production and effector responses to antibody complexes. Reduced function of Fcgr2b has previously been associated with anti-glomerular basement membrane antibody (anti-GBM) disease in mice. However, the mice used had 129 genetic elements flanking the deleted Fcgr2b gene, which are known to increase susceptibility to autoimmunity. In order to confirm a role for Fcgr2b in protection from anti-GBM disease, wild type (WT) mice, mice lacking Fcgr2b on a pure C57BL/6 background, or mice lacking Fcgr2b on a C57BL/6 background with 129 flanking sequences, were immunized with the recombinant NC1 domain of alpha 3 Type IV collagen. Twenty two weeks after immunization, there was a higher incidence of crescentic glomerulonephritis, macrophage infiltration and renal dysfunction in both groups of Fcgr2b-/- mice, indicating an important role of Fcgr2b in regulating the development of anti-GBM disease, on both genetic backgrounds. In order to determine the cellular origin of the Fcgr2b-associated effect, disease was induced in mice with deficiency of Fcgr2b on either B cells alone (CD19Cre), or a subset of myeloid cells (LysozymeMCre). Neither B cell nor myeloid specific knockout mice developed crescentic glomeruonephritis with higher incidence than WT mice indicating that Fcgr2b deficiency on either B cells or a subset of myeloid cells alone is not sufficient to increase susceptibility to anti-GBM disease, but that a combination of cell types, or deficiency of Fcgr2b in a different cell type, is also required.

Mice with defective Fas ligand are protected from crescentic glomerulonephritis.

Fas ligand is a well-known inducer of apoptosis in cells expressing its receptor Fas; it also prevents autoimmunity by inducing apoptosis of activated T cells. However, Fas ligand also mediates non-apoptotic functions involving inflammatory cell migration and cytokine responses. We sought here to study the role of Fas ligand in nephrotoxic nephritis, a model of crescentic glomerulonephritis, using generalized lymphoproliferative disorder (GLD) mice on a C57BL/6 background, which have defective Fas ligand and display only mild autoimmunity. These mice were significantly protected from glomerular crescent formation, glomerular thrombosis, renal impairment, and albuminuria 15 days after the induction of glomerulonephritis in comparison with wild-type mice. There were a reduced number of apoptotic cells in the glomeruli of nephritic GLD mice but no defect in their antibody responses or splenocyte proliferation at 15 days following the induction of glomerulonephritis. Bone marrow transplantation from wild-type mice restored disease susceptibility to GLD mice; however, wild-type mice were not protected when transplanted with bone marrow from GLD mice. Mesangial cells express Fas ligand in vitro, and these cells isolated from GLD mice produced lower amounts of monocyte chemoattractive protein-1 following interleukin-1 stimulation compared with cells from wild-type mice. Thus, Fas ligand-defective mice are protected from nephrotoxic nephritis, a disease in which both circulating and intrinsic renal cells appear to have a role.

Crescentic glomerulonephritis: new aspects of pathogenesis.

This review provides a summary of recent advances in the understanding of crescentic glomerulonephritis, focusing on antineutrophil cytoplasm antibody (ANCA)-associated vasculitis and anti-glomerular basement membrane (anti-GBM) antibody disease. In ANCA-associated vasculitis (AAV), four main conceptual advances are discussed as follows: (1) evidence for the pathogenicity of ANCA, (2) molecular mimicry and the role of infection in AAV, (3) evidence for aberrant T-cell responses and T-cell regulation in AAV, and (4) advances in understanding of genetic predisposition to AAV. In relation to anti-GBM disease we discuss the following: (1) the nature of the Goodpasture autoantigens, (2) T-cell responses and regulation in anti-GBM disease, and (3) human leukocyte antigen and non-human leukocyte antigen genetic associations.

CCL18 in peritoneal dialysis patients and encapsulating peritoneal sclerosis.

BACKGROUND: Peritoneal fibrosis manifests clinically as membrane failure or encapsulating peritoneal sclerosis (EPS). There are no clinical or biochemical tests to determine the rate of progression of peritoneal fibrosis. CCL18/pulmonary and activation-regulated chemokine (PARC) is profibrotic and stimulates collagen production independent of the effect of transforming growth factor beta. This has not been studied in peritoneal dialysis (PD) patients. MATERIALS AND METHODS: We have prospectively studied 106 patients, free from infection/recent peritonitis. A high concentration of CCL18 was discovered by multiplex antibody arrays and quantified by ELISA. Serum and dialysate levels were examined for their prognostic values. RESULTS: By multiple regression analysis, dialysate CCL18 (6·76 ± 0·66 µg 4 h⁻¹) correlated with increasing membrane transport status (TS) (P < 0·0001) and total glucose exposure/24 h (P = 0·033). Serum CCL18 correlated with high TS (P = 0·0001) and duration of PD (P = 0·001). After 12 months of follow-up, 57 patients remained on PD while 12 patients were transferred to haemodialysis (HD) and seven developed EPS. Patients who subsequently developed EPS had higher baseline dialysate CCL18 (11·5 ± 3·6 µg 4 h⁻¹ vs. 5·6 ± 0·82 µg 4 h⁻¹, P = 0·03) and serum CCL18 (156·9 ± 12·8 ng mL⁻¹ vs. 124·8 ± 12·2 ng mL⁻¹, P = 0·02) compared with the stable PD group. CONCLUSION: This is the first report of high levels of CCL18 in the spent dialysate and serum from long-term PD patients. These levels correlated with dysfunction of peritoneal membrane transport status, therefore following CCL18 in a longitudinal study may be of interest.

Assessing the validity of an abdominal CT scoring system in the diagnosis of encapsulating peritoneal sclerosis.

BACKGROUND AND OBJECTIVES: Encapsulating peritoneal sclerosis (EPS) is a severe peritoneal fibrotic reaction in patients on long-term peritoneal dialysis (PD). The early clinical features may be nonspecific. The purpose of the study is to assess the reliability and diagnostic utility of abdominal CT scanning in the diagnosis of EPS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Abdominopelvic CT scans of 27 patients diagnosed with EPS on clinical and radiologic grounds in our unit from 1997 to 2006 were retrospectively analyzed. In addition, 35 control CT scans were scored: 15 from hemodialysis patients (HD controls) and 20 from patients on PD (PD controls). Scans were anonymized and scored independently by three radiologists. RESULTS: Inter-rater agreement was moderate to very good (kappa = 0.40 to 0.75) for peritoneal calcification, bowel distribution, bowel wall thickening, and bowel dilation but poorer for loculation of ascites and peritoneal thickening. There was a strongly significant difference between the total CT scan scores at EPS diagnosis and controls (P < 0.00001). Each individual parameter also showed significant differences between EPS and controls (P < 0.006). Bowel tethering and peritoneal calcification were the most specific parameters, and. loculation was the least discriminatory parameter. Interestingly, prediagnostic scans a median of 1.5 yr before EPS diagnosis were normal or near-normal in 9 of 13 EPS patients. CONCLUSIONS: CT scanning is a valid and reliable adjunct to the diagnosis of EPS but may not be useful as a screening tool, as the prediagnostic scans did not show abnormalities in many patients who subsequently developed EPS.

Increased expression of the pro-apoptotic ATP-sensitive P2X7 receptor in experimental and human glomerulonephritis.

BACKGROUND: The involvement of IL-1beta and other pro-inflammatory cytokines in most forms of glomerulonephritis is now well established. The P2X(7) receptor, an ATP-sensitive P2X receptor, functions not only as a non-selective cation channel, but it is also involved in the rapid processing and release of IL-1beta, apoptosis and necrotic cell death. Therefore, we wanted to investigate if expression of this receptor is altered in the glomeruli of rodent models of glomerulonephritis. METHODS: P2X(7) receptor protein expression was investigated using immunohistochemistry, and apoptosis was assessed using the TUNEL assay and caspase-3 immunostaining. Real-time PCR with gene-specific primers was used to detect P2X(7), IL-1beta, p53, bax and bcl-2 mRNA expression. RESULTS: Although the levels of the P2X(7) receptor protein in mouse kidney are normally very low, or undetectable, we detected an increase in glomerular expression of this receptor and an increase in glomerular apoptotic cells in a mouse model of accelerated nephrotoxic nephritis. We also observed increased glomerular and tubular expression of the P2X(7) receptor protein in renal biopsy tissue of patients with autoimmune-related glomerulonephritis. Furthermore, P2X(7) receptor mRNA increased in the kidneys of a rat model of proliferative glomerulonephritis and this coincided with the onset of proteinuria. We also observed increased mRNA expression of Il-1beta and the pro-apoptotic markers p53 and bax, but not of anti-apoptotic bcl-2. CONCLUSION: Although there is an association between expression of the pro-inflammatory and pro-apoptotic P2X(7) receptor and glomerulonephritis in these rodent models, and in at least one form of human glomerulonephritis, the underlying relationship and its functional significance remain to be explored.

Fluorodeoxyglucose positron emission tomography detects the inflammatory phase of sclerosing peritonitis.

OBJECTIVE: We studied the effectiveness of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in detecting inflammation in known or suspected cases of sclerosing peritonitis in patients on peritoneal dialysis (PD). DESIGN: We undertook FDG-PET scanning in PD patients presenting with symptoms or signs suggestive of sclerosing peritonitis (SP), and in patients on long-term PD with no symptoms of SP. SETTING: The study was performed in a PD unit in a tertiary-care hospital. PATIENTS AND METHODS: Three patients with known or strongly suspected SP underwent FDG-PET scans, 1 within 3 months of presentation with symptoms and 2 who were scanned more than 9 months after presentation. One patient was scanned at an early and a late time point. Five patients who had been on PD for more than 5 years and who were asymptomatic also underwent FDG-PET scanning. Scans were interpreted by a specialist in nuclear medicine. RESULTS: The scan performed in the early stages of SP showed increased peritoneal uptake. However, three scans taken more than 9 months after presentation with suspected SP showed mild peritoneal abnormalities only. One of 5 asymptomatic long-term PD patients showed increased peritoneal uptake associated with loss of ultrafiltration and high transporter status. CONCLUSIONS: FDG-PET scanning may be a useful adjunct in the diagnosis of the acute phase of SP. More study is needed to define its role in the diagnosis of SP in asymptomatic PD patients.

Leptin-deficient mice are protected from accelerated nephrotoxic nephritis.

Leptin is an adipose tissue-derived hormone that signals nutritional status to the hypothalamus. Recent evidence indicates that leptin modifies proinflammatory immune responses and may provide a key link between nutritional deficiency and immune dysfunction. To study the influence of leptin deficiency on immune-mediated renal disease, susceptibility to accelerated nephrotoxic nephritis was examined in leptin-deficient C57BL/6-ob/ob mice and C57BL/6 wild-type controls. The model was induced with sheep anti-mouse glomerular basement membrane antibody injected to mice preimmunized against sheep IgG, and mice were sacrificed 8 days after induction of disease. The leptin-deficient ob/ob mice were strongly protected from glomerular crescent formation, macrophage infiltration, glomerular thrombosis, and albuminuria in this model. Our findings suggest that leptin is required for the induction and maintenance of immune-mediated glomerulonephritis, and that blockade of the leptin axis might provide an attractive therapeutic possibility in human autoimmune disease.

Role of Fcgamma receptors in glomerulonephritis.

Many forms of glomerulonephritis involve immune complex localization in the kidney. Fcgamma receptors (FcgammaR) expressed on the surface of leukocytes bind the Fc (constant) portion of IgG. They link immune complex deposition to innate immune responses, including phagocytosis, cytokine release, formation of reactive oxygen species, and antibody-dependent cytotoxicity. Activator and inhibitor FcgammaR co-exist on the surface of cells and set thresholds for immune responses. Inhibitor FcgammaR also have a specific role in the maintenance of B cell tolerance. Studies of gene-targeted mice lacking specific FcgammaR have demonstrated that animals lacking activator FcgammaR on circulating leukocytes were protected from immune complex induced glomerular injury, both in models of systemic lupus erythematosus (SLE) and anti-glomerular basement membrane antibody disease. In contrast, mice lacking inhibitor FcgammaR developed SLE-like auto-immunity on certain genetic backgrounds and were more susceptible to anti-glomerular basement membrane disease, with evidence of enhanced immune responses and dysregulated effector cells. There is also evidence for FcgammaR dysfunction in human SLE and for an association of 'low-binding' polymorphisms of FcgammaR with SLE. In the future, therapeutic possibilities may exist for the manipulation of the FcgammaR pathway in the treatment of glomerulonephritis.

Both Fcgamma receptor I and Fcgamma receptor III mediate disease in accelerated nephrotoxic nephritis.

Recognition of immune complexes in glomeruli by activator Fcgamma receptors (FcgammaRI and FcgammaRIII) is an important step in the development of glomerulonephritis. The low-affinity receptor (FcgammaRIII) has previously been shown to be important in passive heterologous immune complex glomerulonephritis. However, most forms of human glomerulonephritis involve an active immune response, and the relative importance of FcgammaRI (high-affinity receptor) and FcgammaRIII in an active model of glomerulonephritis is not known. We have now studied accelerated nephrotoxic nephritis in FcgammaRIII-/- mice and FcgammaRI/III double-deficient mice, and compared them with matched wild-type controls and FcRgamma chain-deficient (FcRgamma-/-) mice. Mice were immunized against sheep IgG and injected with sheep anti-mouse glomerular basement membrane antibody 5 days later. Both FcgammaRI/III double-deficient mice and FcRgamma-/- mice were strongly protected from renal injury. In contrast, FcgammaRIII-/- mice developed substantial nephritis, although there was a dose-dependent partial protection from glomerular crescents and thrombosis. Despite this histological protection from injury, the macrophage infiltrate was not reduced, implying a dissociation of macrophage accumulation from activation in the absence of activatory FcgammaRIII. Therefore, both FcgammaRI and FcgammaRIII play a role in this active model of glomerulonephritis, because both had to be deficient to protect markedly from disease.