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Abstract: Aim: Cytomegalovirus (CMV) infections are associated with morbidity and mortality. We aimed to describe the epidemiology, risk factors and outcomes of CMV infection among patients with glomerulonephritis (GN) who received potent immunosuppressants (IS). Methods: Single‐centre retrospective study of adults with biopsy‐proven GN prescribed methylprednisolone (MP), cyclophosphamide (CYC) or rituximab (RTX). Primary endpoint was CMV infection defined by significant CMV antigenaemia (>10 positive cells in 106 cells) or viraemia (>2000 copies/mL). Death was related to CMV if CMV infection occurred within the same hospitalization as death. Results: Ninety‐four patients were studied. CYC was prescribed in 65% and MP in 71% of the cohort. Only two patients received RTX and 15 patients received plasma exchanges (PEX). Median follow up was 31.9 (IQR: 13.7, 53.6) months. CMV infection occurred in 13 patients (13.8%) at 1.3 (0.6, 3.0) months from biopsy. Patients with CMV infection had higher serum creatinine [404 (272, 619) vs. 159 (93, 317) μmol/L, P < 0.001] and greater proteinuria [UPCR 7.5, (4.8, 11.8) vs. 4.2 (2.3, 8.4) g/g, P = 0.02] than those who did not have CMV infection. Also, more patients received CYC (92% vs. 60%, P = 0.03), RTX (15% vs. 0, P = 0.02) and PEX (38% vs. 12%, P = 0.01) than those who did not have CMV infection. Two patients had CMV‐related deaths. Conclusion: Cytomegalovirus infection is common in GN patients receiving potent IS. Surveillance and possibly anti‐viral prophylaxis should be considered for high‐risk patients. [ABSTRACT FROM AUTHOR]

Aims: Renal involvement in anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis contributes to significant morbidity and mortality in patients. In chronic inflammation, B cells are recruited to the inflamed tissue and organised lymphoid structures have been described in several autoimmune diseases. The aim of this study was to correlate the lymphoid organisation in renal biopsies with renal outcome in ANCA‐associated glomerulonephritis (GN). Methods and results: We investigated 112 renal biopsies from patients with newly diagnosed ANCA‐associated necrotising GN. We identified four different levels of the intrarenal organisation of lymphocytes: T cells without B cells, scattered B and T cells, clustered lymphocytic infiltrates and nodular compartmentally arranged B and T cell aggregates. Almost half the patients showed clusters of B and T lymphocytes in their biopsies. In 15 of these biopsies, a higher degree of organisation with lymphocytic compartments was detected. Inflammatory cell organisation was associated with renal failure, but not with tubular atrophy and interstitial fibrosis. Patients with organised lymphocytic infiltrates in their biopsy had worse renal function during follow‐up and were more likely to develop end stage renal disease. Conclusions: In the present study, we show that the renal lymphocytic organisation is associated with renal outcome in ANCA‐associated GN. The organisation of the lymphocytic infiltrate may be a morphological correlate of a perpetual and exaggerated inflammation in renal ANCA disease. Classifying the lymphocytic infiltrate could help to predict renal outcome, and might therefore be used for individualised adjustments in the intensity and duration of immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Dermatologic toxicity represents a substantial portion of all immune‐related adverse events (irAEs) associated with PD‐1/PD‐L1 inhibitors. Bullous pemphigoid (BP) is a rare cutaneous side effect of these medications, which can initially be clinically indistinguishable from other, low‐grade cutaneous toxicity. Objective: To better characterize the clinical features of BP associated with PD‐1/PD‐L1 inhibitors, evaluate the efficacy of various treatment regimens, determine the frequency of prodromal pruritus, and assess whether immunological diagnostic studies for BP are warranted in patients treated with checkpoint inhibitors who develop intractable pruritus. Methods: A comprehensive review of the English‐language medical literature was performed using key terms. Papers published on any date and from all origins were considered. Fourteen publications, containing 21 patient cases, were selected independently by two reviewers and deemed relevant to the present publication. Results: Pruritus was a prominent feature of the majority (12/21) of cases and preceded or occurred concurrently with BP development. Bullae developed within 6–8 months of initiation of PD‐1/PD‐L1 inhibitors; however, a smaller subset of patients did not develop bullae for 1–1.5 years following initiation of therapy. Mean time to pruritus was similar for pembrolizumab and nivolumab at 19 and 21 weeks, respectively. Development of BP required discontinuation of immunotherapy in 76% (16/21) of cases. Conclusion: Prodromal or “non‐bullous” variants of BP must be considered in patients treated with checkpoint inhibitors who develop protracted or worsening pruritus. Early diagnostic immunological evaluation of the skin may lead to improved patient outcomes by facilitating timely initiation of treatment and prevent disruptions in cancer therapy. [ABSTRACT FROM AUTHOR]

Aim: Matrix metalloproteinase-12 (MMP-12; macrophage elastase) is an enzyme that can cleave various extracellular matrix proteins and is required for macrophage infiltration and pulmonary fibrosis in experimental emphysema. We have shown previously that MMP-12 is highly up-regulated in experimental anti-glomerular basement membrane (GBM) disease. The aim of this study was to determine whether MMP-12 is required for glomerular macrophage infiltration and crescent formation in anti-GBM glomerulonephritis. Methods: Accelerated anti-GBM disease was induced in groups of MMP-12 gene deficient mice (MMP-12−/−) and wild-type C57BL/6J controls, which were killed 12 days after injection of anti-GBM serum. Results: Wild-type and MMP-12−/− mice developed glomerular damage and glomerular tuft adhesions to Bowman's capsule. Both groups developed severe proteinuria. Wild-type mice also developed significant loss of renal function and crescents in 22% of glomeruli, which were associated with macrophage infiltration and Bowman's capsule rupture. In contrast, MMP-12−/− mice were partially protected from renal function decline, crescent formation and Bowman's capsule rupture. This was associated with reduced macrophage infiltration in both glomeruli and the interstitium, and with reduced expression of CCL2, TNF-α and iNOS mRNA in MMP-12−/− kidneys. In addition, KIM-1 mRNA levels were reduced in MMP-12−/− mice indicating less tubular damage. Conclusion: These data demonstrate that endogenous MMP-12 facilitates macrophage accumulation and activation in anti-GBM glomerulonephritis which is required for glomerular crescent formation, Bowman's capsule rupture, tubular damage and renal function decline. [ABSTRACT FROM AUTHOR]

The diagnosis of serum sickness-like reaction ( SSLR) is typically based on clinical findings. Histopathologic examination is often deferred, as these eruptions commonly present in young children, and often to primary care providers. A PubMed literature search revealed only five existing cases of SSLR which describe cutaneous histopathologic features. We report two cases of SSLR, one each to bupropion and cefazolin. Skin biopsy findings in both cases showed a neutrophil-predominant urticarial pattern resembling neutrophilic urticaria or neutrophilic urticarial dermatosis. We also provide a summary of the histopathologic findings that can help support a diagnosis of SSLR. [ABSTRACT FROM AUTHOR]

Background Hypocomplementemic urticarial vasculitis ( HUV) has been defined as a syndrome associated with urticarial lesions caused by leukocytoclastic vasculitis. It has been observed in patients with systemic lupus erythematosus and related conditions. Immunoglobulin G4 (IgG4)-related disease is a lymphoproliferative disorder characterized by sclerosing pancreatitis, retroperitoneal fibrosis, sclerotic cholangitis, acute interstitial nephritis, and Mikulicz's disease, and associated with elevated levels of IgG4 and hypocomplementemia. Various cutaneous lesions may occur in IgG4-related disease. Methods We report a 74-year-old woman with HUV, followed by systemic organ involvement suggestive of IgG4-related disease. Symptoms included submandibular gland swelling, lymphadenopathy, interstitial nephritis, and a thyroid nodule. Laboratory examinations revealed an elevated serum IgG4 level of 637 mg/dl in a total IgG level of 2176 mg/dl, and the production of autoantibodies such as rheumatoid factor and antiphospholipid antibodies. In the swollen lymph node, neither clonal proliferation of T or B cells nor Epstein-Barr virus infection was detected, although the structure had been destroyed by the infiltration of lymphocytes and plasma cells. Among total IgG-producing cells, approximately 40% were positive for IgG4. Results All symptoms and abnormal laboratory findings improved in response to oral prednisolone. Conclusions Hypocomplementemic urticarial vasculitis may represent a clinical symptom of IgG4-related disease. [ABSTRACT FROM AUTHOR]

Aims Due to the paucity of studies focusing on primary glomerulonephritis, the second commonest cause of end-stage-kidney-disease in most of the developed world, we sought to review outcomes of these renal pathologies. Methods We reviewed renal outcomes and mortality for primary glomerulonephritis patients enrolled in the New Zealand Glomerulonephritis Study between 1972 and 1983. Results There were 765 patients with median follow-up of 30 years (range 0.1-42 years). They were predominantly New Zealand European, male and hypertensive. Poor renal outcomes and increased mortality were associated with hypertension, heavy proteinuria, impaired renal function and older age at diagnosis. Ethnicity was not significantly associated with progression to end-stage-kidney-disease although NZ Maori patients were at significantly increased risk of death. Patients with rapidly progressive glomerulonephritis had the highest risk of reaching end-stage-kidney-disease while the cumulative incidence of end-stage-kidney-disease was 20% and 30% for those with immunoglobulin-A nephropathy and membranous nephropathy respectively. Mortality risk was high for patients with rapidly progressive glomerulonephritis and anti-glomerular basement membrane disease. The era of diagnosis did not have much effect on outcomes except for patients with focal segmental glomerulosclerosis or immunoglobulin A nephropathy but this could be type II error. Conclusion We report one of the longest follow-up studies on biopsy-proven glomerulonephritides. Age, hypertension, and severity of chronic kidney disease at diagnosis were strong predictors of the development of end-stage-kidney-disease and death. The specific renal pathology had a profound impact upon prognosis and therefore should continue to drive efforts to find targeted therapeutic options for these glomerulonephritides. [ABSTRACT FROM AUTHOR]

Aims We report nine Chinese patients with collagen type III glomerulopathy. Methods and results Two males and seven females were studied, ranging in age from 21 to 67 years. Proteinuria and hypertension were the most common symptoms, with incidences of 88.9 and 77.8%, respectively. Two patients had abnormal renal function. Their histological appearances varied. Massive eosinophilic and weakly periodic acid-Schiff ( PAS)-positive substances were deposited along the capillary loops and in the mesangial area in three cases, while others had thickened capillary walls with a chain-like structure or double-contour appearance of the PAS- and silver-stained sections. Immunofluorescence analysis showed the abundant deposition of collagen type III. Electron microscopy revealed massive scattered or bundle-shaped fibre-like materials in the subendothelial and mesangial areas. During follow-up, 44.4% of the patients suffered a doubling of serum creatinine. The level of serum creatinine at biopsy was an independent predictor of this doubled serum creatinine value. Conclusions Collagen type III deposits in the subendothelial and mesangial areas. Some patients show global nodular lesions, while others show subtle changes only via PAS/silver staining. Proteinuria and hypertension are the most common symptoms, and the serum creatinine level at biopsy is an independent predictor of the doubling of serum creatinine during follow-up. [ABSTRACT FROM AUTHOR]

The article presents a case of a 49-year-old Chinese man who was presented with persistent nodules on his hands and feet. The lesions posted gradual growth in 10 years in which the patient suffered occasional burning and itching. Based on biopsy specimens, he has dense neutrophil and histiocyte infiltration with leukocytoclastic vasculitis (LCV) and patterned fibrosis. He was eventually diagnosed with erythema elevatum diutinum (EED) with pustule formation.

Aim C3 glomerulonephritis ( C3GN) is a recently described disease that is related to membranoproliferative glomerulonephritis ( MPGN). We retrospectively compared the frequencies, clinical characteristics, treatment modalities, and outcomes of C3GN and MPGN in a cohort of Japanese children. Methods Children who were pathologically diagnosed with MPGN (type I or III) in our hospital were divided into two groups based on immunofluorescence imaging of renal biopsies: children with MPGN induced by classical complement pathway activation (classical MPGN) and children with C3GN. Results Of 14 children with MPGN (five boys), four had classical MPGN, eight had C3GN, and two had unclassifiable glomerulonephritis. Four children with classical MPGN and seven with C3GN received methylprednisolone pulse therapy followed by oral prednisolone for 2 years ( MPT+ PSL therapy). Subsequently, six of seven children with C3GN received combined therapy (prednisolone, azathioprine, and anticoagulants) for 2 years because they responded poorly to MPT+ PSL therapy. At the last follow-up visit, two children with classical MPGN and seven with C3GN had not achieved remission. One child with classical MPGN and five with C3GN had hypocomplementaemia at the last follow-up. None of the children had renal impairment. Conclusion More than half of the patients previously diagnosed with MPGN fulfilled the criteria for C3GN in children. C3GN may be more refractory than classical MPGN to immunosuppressant therapy. [ABSTRACT FROM AUTHOR]

Aim The risk of asymptomatic haematuria and/or proteinuria development into chronic progressive glomerulonephritis ( CPG) is unclear. The indications for renal biopsy and follow-up on these asymptomatic children remain controversial. Methods A multicenter, retrospective study was performed to investigate the renal histological features of school-age children with asymptomatic urine abnormalities. Results A total of 112 asymptomatic children's renal biopsy data were studied. Most of the children (71%) received a renal biopsy because of isolated microscopic haematuria ( IH), and these children were predominantly (60%) proven to have only mild lesions in the glomeruli. Approximately 30% of the children were biopsied because of asymptomatic proteinuria with or without microscopic haematuria ( HP or isolated asymptomatic proteinuria ( IP)), and these children were mostly (44-83%) indicated to have CPG, such as IgA nephropathy, focal segmental glomerulosclerosis, and Alport syndrome. The junior high school students had a greater percentage of HP than the primary school children. IgA nephropathy was the most common diagnosis in children who received renal biopsy because of HP. Conclusions Our findings indicate that IP and especially HP may have a high risk of development into CPG. IH, however, has a relatively low risk of severe histological lesions. Thus, IH per se might not be suggested as an indication for early renal biopsy. Long-term follow-up is necessary for these asymptomatic children. [ABSTRACT FROM AUTHOR]

Commensal bacteria regulate the homeostasis of host effector immune cell subsets. The mechanisms involved in this commensal-host crosstalk are not well understood. Intestinal epithelial cells (IECs) not only create a physical barrier between the commensals and immune cells in host tissues, but also facilitate interactions between them. Perturbations of epithelial homeostasis or function lead to the development of intestinal disorders such as inflammatory bowel diseases (IBD) and intestinal cancer. IECs receive signals from commensals and produce effector immune molecules. IECs also affect the function of immune cells in the lamina propria. Here we discuss some of these properties of IECs that define them as innate immune cells. We focus on how IECs may integrate and transmit signals from individual commensal bacteria to mucosal innate and adaptive immune cells for the establishment of the unique mucosal immunological equilibrium. [ABSTRACT FROM AUTHOR]

ABSTRACT: Aims: Goodpasture's syndrome, glomerulonephritis and pulmonary haemorrhage, may be due to a variety of causes. Rarely, patients with Goodpasture's syndrome present with both anti-glomerular basement membrane (GBM) and antineutrophil cytoplasmic antibody (ANCA). The aim of this report was to determine the incidence, clinical features, management and outcomes of patients presenting with concurrent ANCA and anti-GBM disease in Auckland. Methods: Potential patients were identified by an electronic search of serology for ANCA and anti-GBM antibody, diagnostic renal biopsy, or in-hospital admissions using ICD9 and ICD10 codes between 1998 and 2008. A retrospective case-note review of all potential cases was performed. Results: Six cases were identified: two women and four men. The incidence was estimated at 0.47 cases per million people per year. The mean age of presentation was 59 years (range 25-85 years). One patient was a smoker and two patients were ex-smokers. All subjects were anaemic, had haemoptysis and an abnormal chest X-ray at presentation. The mean creatinine at presentation was 225 µmol/L (range 126-406 µmol/L); all patients had haematuria and proteinuria. All patients received corticosteroids and cyclophosphamide. Two patients were not plasma exchanged and died. Four patients received plasma exchange and are alive. One patient had a clinical relapse 6 years after their initial presentation and is on renal replacement therapy. Conclusion: Concurrent ANCA and anti-GBM disease is rare. The mortality rate is high. Aggressive immunosuppression with steroids, cyclophosphamide and plasma exchange can induce remission and preserve renal function. Long-term monitoring for relapses should occur. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is the classical immune-complex disease. Involvement of vital organs, particularly the kidneys and brain, accounts for significant morbidity and mortality. A number of imaging tools are currently available for evaluation of inflammatory conditions. By targeting the increased glucose uptake of infiltrating granulocytes and tissuemacrophages, positron emission tomographywith fluorine-18 fluorodeoxyglucose ([18F]FDGPET/CT) hasbeen showntodelineateinflammationwith highsensitivity. Because activatedlymphocytes have increased glucose metabolism, [18F]FDG PET has been successfully used to visualize large concentrations of these cells in lymphoid organswhere antigen presentation and lymphocyte activation occur.Widespread increased FDG uptake in lymph nodes of patients with active SLE, as well as increased thymic uptake, has been described. The most prevalent and dramatic PET/CT finding in neuropsychiatric SLE (NP-SLE) patients is parieto-occipital hypometabolism. In conclusion, PET/CT has become an excellent ancillary tool to assess disease activity and prognosis in SLE patients. [ABSTRACT FROM AUTHOR]

1. Hepatocyte growth factor (HGF) has the therapeutic potential to improve renal fibrosis and proteinuria in rodents with chronic kidney disease. In contrast, long-term administration of human HGF to normal rats reportedly elicits proteinuria. Thus, the role of HGF during proteinuria remains contentious. The aim of the present study was to demonstrate that human HGF is antigenic to rodents and that immune complex formation causes proteinuria. 2. We administered either human or rat HGF to normal rats for 28 days. Albuminuria was evaluated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The renal phenotypes of the two HGF treatments were examined using histological techniques. 3. Administration of human HGF (1 mg/kg per day, i.v.) to rats led to severe albuminuria and glomerular hypertrophy in association with increased blood levels of anti-human HGF IgG and IgG deposition in mesangial areas. Furthermore, an immune complex between human HGF and anti-human HGF IgG stimulated the production of proteinuric cytokines (including transforming growth factor-β) in rat cultured mesangial cells. In contrast, treatment of healthy rats with rat HGF for 4 weeks caused neither mesangial IgG deposition nor elevated anti-HGF IgG in the blood. Overall, rat HGF did not provoke albuminuria. 4. We conclude that human HGF produces pseudotoxic effects in normal rat kidneys via an immune complex-mediated pathway, whereas syngenic HGF is safe due to less deposition of glomerular IgG. Our results affirm the safety of the repeated use of syngenic HGF for the treatment of chronic organ diseases, such as renal fibrosis and liver cirrhosis. [ABSTRACT FROM AUTHOR]

Primary immunodeficiency diseases (PID) are a genetically heterogenous group of >150 disorders that affect distinct components of the innate and adaptive immune system and are often associated with autoimmune diseases. We describe PID affecting T-regulatory cells, complement and B cells or their products and discuss the possibility of a cause-effect relationship. The high concordance of T-regulatory cell defects to organ-specific autoimmune disease implies an obligatory role of these cells in maintaining tolerance to epithelial and endocrine tissues; the absence of central nervous system involvement may reflect immunological privilege. Congenital defects in C1q, C1r/s and C4 are strongly associated with systemic lupus erythematosus (SLE), and this pattern along with laboratory evidence suggests a major importance of classical pathway activity in safe elimination of immune complexes and prevention of immune complex disease (ICD). It is debatable whether this ICD is to be regarded as an autoimmune disease (resulting from a breakdown of immunological ignorance to antigens that are normally hidden), as autoantibodies may be absent, and tissue damage because of deposition of immune complexes could account for all of the pathology observed. Evidence for a causative link between primary antibody deficiencies and autoimmune disease is much less compelling and may in fact involve a common genetic background. However, arguments have also been made in favour of the notion that an intense antigen load as a result of recurrent or persistent infections may affect either tolerance or ignorance, e.g. by molecular mimicry or the presence of superantigens. Similar immunological mechanisms might account for the vast majority of autoimmune diseases. [ABSTRACT FROM AUTHOR]

An 81-year-old man was admitted to our hospital because of leg edema. Serological studies for anti-neutrophil cytoplasmic antibody (ANCA), anti-double stranded DNA antibodies, and antibodies to hepatitis C and B were negative. Severe hypocomplementemia was present and a cryoglobulin was detected with serum immunoelectrophoresis being positive for the immunoglobulin (Ig)M κ type. The cryoglobulin was characterized by immunoelectrophoresis which showed that the protein was composed of polyclonal IgG and κ-type monoclonal IgM. A diagnosis of essential type II cryoglobulinemia was made and the patient underwent a renal biopsy. The renal biopsy revealed endocapillary and mesangial cell proliferation with increased matrix. The resultant lobular appearance of the glomerulus and double contours of the basement membrane were indicative of membranoproliferative glomerulonephritis (MPGN). Immunofluorescence studies demonstrated granular staining in the capillary wall for IgG, IgA, IgM and C4 with little C3 deposition but no C1q. He was finally diagnosed with MPGN due to mixed cryoglobulinemia type II. MPGN with essential cryoglobulinemia type II without evidence of hepatitis C virus infection, like that found in the present case, is very rare. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is characterized by Th2-polarized immune response. Soluble HLA (sHLA) molecules play an immunomodulatory activity. So far, however, no study investigated them in AR. Objective: The aim of this study was to evaluate sHLA-G and sHLA-A,-B,-C serum levels in AR patients with pollen allergy and in a group of healthy controls. Methods: Forty-nine AR patients were enrolled. A group of healthy nonallergic subjects was considered as control. sHLA-G and sHLA-A,-B,-C serum levels were determined by immunoenzymatic method. The study was conducted during the winter, such as outside the pollen season. Results: Allergic patients had significantly higher levels of both sHLA-G ( P < 0.0001) and sHLA-A,-B,-C ( P = 0.011) molecules than normal controls. Moreover, there was a significant relationship between these two soluble molecules ( r = 0.69) in allergic patients. Conclusion: The present study provides the first evidence that both sHLA-G and sHLA-A,-B,-C serum levels are significantly increased in AR patients with pollen allergy. [ABSTRACT FROM AUTHOR]

Endoglin is a proliferation-associated and hypoxia-inducible protein expressed in endothelial cells. The levels of soluble circulating endoglin and their prognostic significance in patients with acute myocardial infarction (AMI) are not known. In this observational prospective study serum endoglin levels were measured by ELISA in 183 AMI patients upon admission to hospital and 48 hrs later and in 72 healthy controls. Endoglin levels in AMI patients on admission were significantly lower than in healthy controls (4.25 ± 0.99 ng/ml versus 4.59 ± 0.87 ng/ml; P = 0.013), and decreased further in the first 48 hours (3.65 ± 0.76 ng/ml, P < 0.001). Upon follow- up (median 319 days), patients who died had a significantly greater decrease in serum endoglin level over the first 48 hrs than those who survived (1.03 ± 0.91 versus 0.54 ± 0.55 ng/ml; P = 0.025). Endoglin decrease was an independent predictor of short-term (30 days) (hazard ratio 2.33; 95% CI = 1.27-4.23; P = 0.006) cardiovascular mortality, and also predicts overall cardiovascular mortality during the follow-up (median 319 days) in AMI patients (hazard ratio 2.13; 95% CI = 1.20-3.78; P = 0.01). In conclusion, early changes in serum endoglin may predict mortality after AMI. [ABSTRACT FROM AUTHOR]

Mycophenolate mofetil (MMF) is an immunosuppressive agent initially used in the treatment of transplant recipients. MMF has been used in renal, heart, and liver transplantation, where it seems more effective than other immunosuppressive regimens in reducing the incidence of acute rejection episodes. MMF has a variety of immunosuppressive effects, including selective suppression of T and B lymphocyte proliferation, and has been more recently used in many autoimmune inflammatory conditions. Systemic lupus erythematosus (SLE) is an autoimmune disease that can potentially involve any organ or system of the human body. Glomerulonephritis (GLN) has been recognized as the most frequent severe manifestation of SLE, leading to poor long-term prognosis. In the treatment of lupus GLN, several therapeutic approaches, all including immunosuppressive drugs, such as cyclophosphamide, azathioprine, or cyclosporine A, have been used. The short- and long-term toxicity of these drugs limits their use in a substantial number of patients. Over the last few years, MMF has emerged as an alternative therapeutic regimen in lupus GLN, mainly for patients refractory to other therapies. These studies have shown that it is highly effective and generally well tolerated. [ABSTRACT FROM AUTHOR]

Lupus nephritis (LN) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). As the course of LN is often unpredictable, it is important to identify reliable, noninvasive methods to repeatedly assess the condition of the kidneys in these patients. Urinary biomarkers are easily obtained and probably are best at reflecting the current renal status, as they specifically represent local inflammatory activity. In this article, we review a number of potential urinary biomarkers, including Lipocalin-2, MCP-1, IP-10, IL-6, and IL-8. Additionally, we provide evidence for the possible utility of the novel cytokine TWEAK as a urinary biomarker for LN. [ABSTRACT FROM AUTHOR]

Aim: Post-streptococcal glomerulonephritis (PSGN) is a frequent cause of acute nephritis in children. Numerous studies have described PSGN in high-risk populations yet few data describing PSGN in a low-incidence population exist. This study aimed to describe the epidemiology, clinical manifestations, diagnosis, complications and outcomes of PSGN in an urban Australian population. Methods: A 16-year retrospective review of case notes and laboratory data was conducted at a tertiary Sydney paediatric hospital. Results: Thirty-seven children were treated for PSGN with a mean age of 8.1 years (range 2.6–14.1 years). Twenty-eight subjects (75.7%) had a history of a recent upper respiratory tract or skin infection. Hypertension and/or oedema was present in 29 subjects (78.4%). Streptococcal pharyngitis was identified as the likely source in 17 subjects (45.9%). Skin infections occurred less frequently. Antibodies against streptolysin O, streptokinase or deoxyribonuclease B were elevated when a single titre was measured in 35 subjects (94.6%). Thirty subjects (81.1%) developed renal impairment (median peak creatinine, 95 µmol/L, range 39–880 µmol/L). No correlation was demonstrated between peak creatinine, age, ethnicity, streptococcal titres and serum complement levels. The mean length of admission was 8.2 days. Seven subjects (18.9%) had a complicated course with three subjects requiring dialysis. Only one subject has ongoing renal dysfunction. Conclusion: Significant differences are seen in a low-incidence urban Australian population with PSGN when compared with endemic or epidemic disease in high-risk populations. The higher rates of complications that were seen compared with previously studied populations need further clarification. [ABSTRACT FROM AUTHOR]

Objective: Localized and sustained delivery of vascular endothelial growth factor (VEGF) is a promising approach to overcome the limited efficacy of bolus delivery. The authors examined the effects of host immune competence and local ischemia on the functionality of new vessel networks formed with this approach. Methods: Vessel structure and perfusion resulting from implantation of porous 85:15 poly(lactide-co-glycolide) scaffolds releasing VEGF165 were measured in both subcutaneous tissue and ischemic hindlimbs of immune competent C57BL/6 and immune deficient SCID mice. Results: Sustained VEGF delivery resulted in a similar ∼100% increase in vessel density within scaffolds in both implant sites, and both animal models. However, the resulting perfusion within scaffolds implanted in subcutaneous tissue increased modestly versus control (18–35%), while perfusion increased 52–110% above control when VEGF-releasing scaffolds were placed in ischemic hindlimbs of C57BL/6 or SCID mice. VEGF delivery improved perfusion in the entire ischemic limb (55 ± 18% of the normal value by week 6; 138% increase over control) in SCID mice. Although C57BL/6 mice demonstrated spontaneous recovery from ischemia, VEGF delivery accelerated recovery as compared to control. Conclusions: Localized and sustained VEGF delivery can create functional vasculature that amplifies recovery of tissue ischemia. However, increases in local and regional perfusion were highly dependent on the implantation site and the animal model. [ABSTRACT FROM AUTHOR]

This paper reports on the presentations from the second session of a 2-day workshop on genetic diversity and science communication, organized by the Institute of Genetics. The four talks in this session (by Sarah Cunningham-Burley, Gail Geller, Michael Hayden, and Theresa Marteau) focused on the topic of risk assessment in the context of genetic testing, screening and preventive medicine for complex disease. Each talk underscored the urgency and importance of evaluating when and for whom risk assessment may be useful. A recurrent theme was the need to attend closely to the diverse ways that risk is constructed, perceived and communicated in a variety of contexts and the significant implications of this for laypersons as well as experts. Although there was no consensus on when genetic risk assessment ceases (or might begin) to be useful, ensuing dialogue between presenters and participants reflected what is perhaps a new and critical engagement with how risk assessment itself is assessed. In response to this impetus, I use the word RISK as a heuristic to identify, extract and amplify four tendencies that appear to advance understandings of risk assessment towards a more explicitly reflexive, interpretive, and situated form of knowing. [ABSTRACT FROM AUTHOR]

Crescent formation in the renal glomerulus is a typical manifestation of progressive glomerulopathy associated with fatal renal failure; therefore, its prevention is of clinical importance. Little is known about the pathogenic mechanism for crescent formation. This study was undertaken in an attempt to identify the events that are critical for crescent formation in immune complex crescentic glomerulonephritis (CGN) by analyzing a novel mutant strain of mice.A spontaneous mutant strain of mice was isolated from the autoimmune‐prone strain EOD, which stably develops fatal CGN. The mutant phenotypes were assessed histopathologically, hematologically, and immunologically. The mutation was searched for with positional cloning using microsatellite markers.Compared with wild‐type EOD (WT‐EOD) mice, mutant EOD (mut‐EOD) mice showed marked improvement in CGN in conjunction with an improvement in spontaneous mortality. In WT‐EOD mice, an inverse correlation between blood urea nitrogen concentration and blood platelet count and massive accumulation of platelets in the glomerulus were evident, suggesting that an accumulation of platelets in the glomerulus contributes to the progression of CGN. The mutant platelets showed an abnormal aggregation in response to collagen and thrombin, associated with a bleeding tendency in mut‐EOD mice. Genetic analysis revealed a deleterious mutation in the cappuccino gene (cno), which encodes a protein that belongs to a complex called the biogenesis of lysosome‐related organelle complex 1 and is profoundly involved in platelet function. Morphologic examination revealed a partial defect in dense body formation in the δ‐granule of platelets.The present findings suggest that platelet functions have a critical role in crescent formation in autoimmune GN. [ABSTRACT FROM AUTHOR]

The different physicochemical and sterical properties of IgG subclasses may favour a selective enrichment of defined IgG subclasses in IgM–IgG immune complexes (IC) of human plasma under physiological conditions. Such enrichment of IgG subclasses in IgM–IgG IC of plasma may differ from the normal IgG subclass distribution in plasma itself, and contribute to the physiological functions of IgM–IgG IC. Systematic studies on the IgG subclass distribution in IgM–IgG IC in humans are lacking. Using specific analytical techniques to characterise IgM–IgG IC in human plasma (i.e. fast protein liquid chromatography, enzyme-linked immunosorbent assay, affinity biosensor technology), and taking warm autoimmune haemolytic anaemia (WAIHA) of humans as a disease model, we here demonstrate that: (i) IgG2 is the predominant IgG subclass in IgM–IgG IC under physiological conditions, (ii) the predominance of IgG2 within IgM–IgG IC may get lost in polyclonal IgG-mediated autoimmune disease and (iii) the IgG subclass distribution in IgM–IgG IC influences the interaction between IC and blood cells involved in antigen presentation. The data presented here therefore extend the physiological function of IgG2, which is the protective immune response towards carbohydrate antigens in bacterial infections, and suggest IgG2-dependent regulation of immune responses to self-immunoglobulin in humans. The disturbed IgG subclass distribution in IgM–IgG IC of patients with WAIHA might influence activity of self-reactive B cells involved in the pathophysiology of the disease. [ABSTRACT FROM AUTHOR]

Specific oral tolerance in food allergy can be induced by oral administration of the offending food, starting with very low dosages, gradually increasing the daily dosage up to an amount equivalent to a usually relevant dose for daily intake, followed up by a daily maintenance dose. Unfortunately, the body of scientific evidence concerning specific oral tolerance induction (SOTI) is still rather poor. Following a couple of case reports, only a few studies on a limited number of patients including different allergens are available. So far, no placebo-controlled, long-term study has been published. Concerning the underlying immunological mechanism, a limited number of studies have reported on changes in antibody production, and more recently on the role of different T-cell populations. The individual pattern of clinical reaction during SOTI seems to vary considerably between patients and from allergen to allergen. Arguments in favour of SOTI are the safety for an inadvertent intake of the offending food and the increased quality of life. Arguments against SOTI are the necessity for a regular intake and possible long-term compliance problems. Indications to consider SOTI in the future might be (i) importance of the incriminated food for the individual nutritional regimen, (ii) avoidance of the corresponding food cannot be assured and (iii) persistent severe food allergy. However, before SOTI can be recommended for the daily praxis, more studies are warranted to clarify whether certain patients may profit from SOTI and to understand the underlying mechanism. [ABSTRACT FROM AUTHOR]

The author reflects the systemic and specific treatment for a global disease. According to the author, allergy journals have been overwhelmed with original reports and reviews addressing different aspects of traditional and novel forms of allergen-specific immunotherapy and reflecting the revival of interest in the mode of treatment. The author has stated that clinical benefits from immunotherapy in allergic rhinitis or conjunctivitis patients have not been questioned.

Behçet's syndrome (BS; Adamantiades syndrome) is the association of the triple symptom complex of recurrent aphthous stomatitis (RAS) with genital ulceration, and eye disease (especially iridocyclitis) though a number of other systemic manifestations may also be seen. BS mainly affects young adult males, and there is an association with HLA-B5 and HLA-B51 (B5101). Features such as arthralgia and leucocytoclastic vasculitis suggest an immune-complex mediated basis, which is supported by finding circulating immune complexes and, although the antigen responsible is unidentified, heat shock proteins have been implicated. An inflammatory disorder, BS is now considered as a systemic vasculitis, characterised by a very wide spectrum of clinical features and by unpredictable exacerbations and remissions. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) and type I interferon (IFN) autocrine/paracrine loops are recognized as key mediators of signaling cascades that control a variety of cellular functions. Here, we describe a novel mechanism by which Toll-like receptor (TLR) agonists utilize these two autocrine/paracrine loops to differentially regulate the induction of PDGF-B, a growth factor implicated in a number of diseases ranging from tumor metastasis to glomerulonephritis. We demonstrate that CpG-specific induction of PDGF-B requires activation of Smads through TGFβ1 autocrine/paracrine signaling. In contrast, polyinosinic:polycytidylic acid strongly represses CpG's as well as its own intrinsic ability to induce PDGF-B mRNA through type I IFN-mediated induction of Smad7, a negative regulator of Smad3/4. Furthermore, we have shown that this crosstalk mechanism translates into similar regulation of mesangial cell proliferation. Thus, our results demonstrate the importance of crosstalk between TGF-β and type I IFNs in determining the specificity of TLR-mediated gene induction. [ABSTRACT FROM AUTHOR]

Presents abstracts of studies on the pathogenesis of systemic lupus erythematosus presented at the Experimental Biology/International Union of Physiological Sciences 2005 congress in San Diego, California. "Messenger RNA Editing in Gene Transcripts of Systemic Lupus Erythematosus (SLE) T Lymphocytes," by Dama Laxminarayana; "Non-Complement-Fixing IgG Antibody (AB) Protects Against Immune Complex (IC) Disease," by Richard Thomas Strait, Todd Woodrich, et al; "Toll-Like Receptor Agonists Stimulate "Tolerogenic" Anti-SnRNP B Cells for Activation," by Li Wang, Chuanlin Ding, et al.

Carnitine and its congeners may regulate the immune networks, and their influence on functions of immune cells predominantly or exclusively relies on carnitine-dependent energy production from fatty acids. A reduced pool of carnitines has been demonstrated in either serum or tissues, or both, from patients with a wide spectrum of disorders characterized by unregulated or impaired immune responses ranging from sepsis syndrome to systemic sclerosis, infection with human immunodeficiency virus, and chronic fatigue syndrome. Furthermore, experimental studies have consistently reported that the deranged immune responses and the less efficient inflammation towards infectious organisms associated with aging may be enhanced or modulated by treatment with carnitines. There is also evidence that carnitine deprivation could adversely affect the course of the sepsis syndrome, at least in experimental models, and preliminary studies suggest that carnitine deficiency is ultimately implicated in the pathophysiology of endotoxin-mediated multiple organ failure. Several data indicate that carnitine deficiency is a contributing factor to the progression of infection with human immunodeficiency virus, and carnitine therapy in those patients could counteract the unregulated process of lymphocyte apoptosis and improve CD4 counts. Some case reports have suggested the use of carnitine for the treatment of the severe lactic acidosis that complicates in some patients the use of reverse transcriptase inhibitors. [ABSTRACT FROM AUTHOR]

This retrospective study defined the clinical features and outcome of antineutrophil cytoplasmic antibody-associated glomerulonephritis in 18 seropositive Taiwanese patients (11 male, seven female; median age 64 years; range 21–82 years) with biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis.Fourteen patients had a diagnosis of systemic vasculitis including 10 with microscopic polyangiitis and four with Wegener's granulomatosis; the remaining four had only glomerulonephritis. At onset, 100% of the systemic vasculitis patients had pulmonary lesions with or without haemoptysis, and 29% presented with seizure in the absence of a defined brain lesion. Median serum creatinine concentration was 362.4 µmol/L (range 61.9–857.5 µmol/L) and dialysis therapy was needed in six patients. During follow up (median 16.5 months; range 2–72 months), treatment included cyclophosphamide and corticosteroids (n = 8) or corticosteroids alone (n = 7). In some patients, treatment improved (n = 4) or stabilized (n = 4) renal function. But chronic dialysis was needed in the other 10 patients. Follow-up death occurred because of sepsis (n = 3) and haemorrhage (n = 2). Patient survival rates were 78% (1 year) and 72% (5 years). Renal survival rates were 56 and 39% at 1 and 5 years, respectively. Of the candidate clinical and pathological parameters, chronic glomerular lesions in renal biopsy were the only determinant of poor renal outcome (P = 0.006).Antineutrophil cytoplasmic antibody-associated glomerulonephritis should be considered in nephritic patients with extrarenal manifestations, especially pulmonary infiltrate, unexplained seizure, and fever of an unknown origin in Taiwanese patients. Renal biopsy should be performed before initiating immunosuppressive therapy because the most common cause of mortality was sepsis. [ABSTRACT FROM AUTHOR]

To study the incidence, predictors, and outcome of renal flares after successful cyclophosphamide (CYC) treatment for diffuse proliferative glomerulonephritis (DPGN) in patients with systemic lupus erythematosus (SLE). Between 1988 and 2001, patients with biopsy‐proven SLE DPGN who were treated initially with prednisone and CYC were studied. Those who responded to CYC were followed up for the occurrence of renal flares. The cumulative risk, predictors, and outcome of renal flares were evaluated. We studied 189 patients (167 women; and 22 men) with SLE DPGN. All were initially treated with prednisone and CYC (49% orally; 51% by intravenous pulse). At the last dose of CYC, 103 patients (55%) and 52 patients (28%) had achieved complete and partial renal responses, respectively. Azathioprine (AZA) was given as maintenance therapy in 117 patients (75%). After a mean followup of 96.5 months, 59 patients (38%) experienced renal flares (42% nephritic; 58% proteinuric). The median time to relapse was 32 months. The cumulative risk of renal flare was 28% at 36 months and 44% at 60 months. Independent predictors of nephritic flares were persistently low C3 levels after CYC treatment and absence of AZA maintenance therapy. At the last clinic visit, 16 patients (10.3%) had developed doubling of the serum creatinine level (cumulative risk of creatinine doubling 7.4% at 5 years after renal biopsy and 14.3% at 10 years). Ten patients (6.5%) developed end‐stage renal disease (ESRD). Renal survival rates at 5 and 10 years were 94.9% and 87.5%, respectively. Increasing histologic chronicity scores, failure to achieve complete response, persistent hypertension after CYC treatment, and nephritic renal flares were unfavorable factors for doubling of the serum creatinine level and for ESRD by univariate analysis. The occurrence of nephritic flares was the only predictor of creatinine doubling by Cox regression analysis. In patients with SLE DPGN, renal flares are common despite initial responses to CYC. Nephritic renal flares are associated with a decline in renal function. Maintenance therapy with AZA reduces, but does not completely prevent, renal flares. More effective maintenance treatment for SLE DPGN after an initial response to CYC should be evaluated. [ABSTRACT FROM AUTHOR]

Histopathology of the kidney and clinical presentation are critical factors in the diagnosis of immune-mediated glomerulonephritis (GN). The histological manifestations of glomerular injury are shared by multiple underlying mechanisms. Work from our laboratory and from other investigators shows that antinuclear, antihistone or anti-dsDNA antibodies are neither required nor sufficient for development of lupus GN. In addition, antibody to dsDNA can be generated by mechanisms other than loss of tolerance to chromatin. Genetic analyses demonstrate that although there is some interaction between autoantibody production and renal disease, the phenotypes are regulated by distinct genetic intervals. Furthermore, renal failure is not an essential outcome of the immune-complex deposition and proliferative lupus GN. These data are also supported by published studies from systemic lupus erythematosus (SLE) patients. The immune regulation of lupus GN is distinct from other organ-specific diseases and not influenced by CD25+ or NK1.1+ regulatory T cells. Thus, fatal GN may depend upon a kidney-reactive T-cell response that, in turn, may be regulated by gender and intrinsic end-organ factors. The data discussed in this review call for a re-evaluation of the current paradigms for pathogenesis of SLE. An interactive model separating autoimmunity from end-organ susceptibility for the pathogenesis of SLE is proposed. [ABSTRACT FROM AUTHOR]

McDonald KJ, McMillan MA, Rodger RSC, Junor BJR, Geddes CC, Briggs JD, Jardine AG. Persistent dipstick haematuria following renal transplantation. Clin Transplant 2004: 18: 321–326. © Blackwell Munksgaard, 2004 Despite widespread testing for dipstick haematuria following renal transplantation, there are no published series describing the prevalence and possible causes of this complication in an adult population. A cross-sectional study of 640 renal transplant recipients under review at our follow-up clinic was performed. Persistent haematuria was defined as a minimum of 1+ of blood on urinalysis stick testing detected at not fewer than 75% of clinic visits since its onset, or since the start of routine testing, present over a period of at least 4 weeks. The prevalence of persistent dipstick haematuria was 13.3%. Median serum creatinine was higher in patients with persistent haematuria but age, gender and length of time since transplantation were not significantly different. Potential explanations for persistent haematuria in 21 of 85 affected patients were chronic infection, ureteric stent without chronic infection, regular or intermittent self-catheterization, persistent menstrual bleeding, anticoagulant therapy, graft calculus, and allograft renal cell carcinoma. Recurrent or de novo glomerular disease was confirmed by graft biopsy in 10 of 85 patients. Among the 41 recipients whose original cause of renal failure was IgA nephropathy (IgAN), the prevalence of persistent haematuria was 31.7% compared with 12% in the remaining patients (relative risk 2.6, 95% CI: 1.6–4.3). Persistent haematuria in IgAN patients was not associated with gender, age or time since transplantation. After 29 months of follow-up, 20% of patients with haematuria had progressed to graft failure or death compared with 11.6% of the unaffected group (p = 0.029). However, despite the association with earlier graft failure, haematuria did not predict this endpoint independently of renal function. [ABSTRACT FROM AUTHOR]

Human serum amyloid P component (SAP) binds avidly to DNA, chromatin and apoptotic cells in vitro and in vivo. 129\Sv × C57BL\6 mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoantibodies and immune complex glomerulonephritis. SAP-deficient animals, created by backcrossing the 129\Sv SAP gene deletion into pure line C57BL\6 mice and studied here for the first time, also spontaneously developed broad spectrum antinuclear autoimmunity and proliferative immune complex glomerulonephritis but without proteinuria, renal failure, or increased morbidity or mortality. Mice hemizygous for the SAP gene deletion had an intermediate autoimmune phenotype. Injected apoptotic cells and isolated chromatin were more immunogenic in SAP-\- mice than in wild-type mice. In contrast, SAP-deficient pure line 129\Sv mice did not produce significant autoantibodies either spontaneously or when immunized with extrinsic chromatin or apoptotic cells, indicating that loss of tolerance is markedly strain dependent. However, SAP deficiency in C57BL\6 mice only marginally affected plasma clearance of exogenous chromatin and had no effect on distribution of exogenous nucleosomes between the liver and kidneys, which were the only tissue sites of catabolism. Furthermore, transgenic expression of human SAP in the C57BL\6 SAP knockout mice did not abrogate the autoimmune phenotype. This may reflect the different binding affinities of mouse and human SAP for nuclear autoantigens and\or the heterologous nature of transgenic human SAP in the mouse. Alternatively, the autoimmunity may be independent of SAP deficiency and caused by expression of 129\Sv chromosome 1 genes in the C57BL\6 background. [ABSTRACT FROM AUTHOR]

In acute inflammatory responses, such as wound healing and glomerulonephritis, arginine is the precursor for production of the cytostatic molecule nitric oxide (NO) and the pro-proliferative polyamines. NO is an early phase response whereas increased generation of polyamines is requisite for the later, repair phase response. The temporal switch of arginine as a substrate for the inducible nitric oxide synthase (iNOS)/NO axis to arginase/ornithine decarboxylase (ODC)/polyamine axis is subject to regulation by inflammatory cytokines as well as interregulation by the arginine metabolites themselves. Herein we describe the capacity of another arginine pathway, the metabolism of arginine to agmatine by arginine decarboxylase (ADC), to aid in this interregulation. Agmatine is an antiproliferative molecule due to its suppressive effects on intracellular polyamine levels, whereas the aldehyde metabolite of agmatine is a potent inhibitor of iNOS. We propose that the catabolism of agmatine to its aldehyde metabolite may act as a gating mechanism at the transition from the iNOS/NO axis to the arginase/ODC/polyamine axis. Thus, agmatine has the potential to serve in the coordination of the early and repair phase pathways of arginine in inflammation. [ABSTRACT FROM AUTHOR]

Presents a clinical analysis of renoprotective responding patients administered with oral adsorbent in chronic renal failure secondary to chronic glomerulonephritis. Progression of renal dysfunction; Decline in serum creatinine; Reversibility of severe chronic renal failure.

Unlabelled: Intravenous immunoglobulin (IVIG) has been used as an immunomodulatory treatment for several immune-mediated diseases. Early effects of high-dose IVIG treatment on biochemical profiles including lipids and proteins were evaluated in patients with Kawasaki disease (KD). Twelve children with KD (9 boys) were treated with IVIG at 2 g/kg over a period of 12 h. Serial sera samples were collected from the patients four times: before IVIG treatment and 2 h, 24 h and 7 d after IVIG treatment. The samples were frozen at -20 degrees C before biochemical analysis. A significant decrease in albumin concentration was found 2 h and 24 h after IVIG treatment, but this recovered to the pretreatment level after 7 d. Total cholesterol and triglyceride increased slightly after 7 d. A significant decrease in HDL-cholesterol and C-reactive protein was seen 2 h and 24 h after IVIG treatment.Conclusion: High-dose IVIG affects immediate changes in protein profiles and HDL-cholesterol in KD. Changes in HDL-cholesterol induced by IVIG may be the result of changes in systemic protein metabolism. [ABSTRACT FROM AUTHOR]

Mice, previously selected for the production of low affinity antibody after four injections of protein antigens in saline, fell into two groups on the basis of their antibody response after injection of adjuvantized antigen. One group produced antibody of sequentially rising affinity but the other produced only low affinity antibody. Mice from the latter group were interbred to produce low affinity non-maturing mice (low N/M mice). Daily injections in these mice produced a more rapid and severe glomerulonephritis than that observed in mice of the original low affinity line. Male low N/M mice were more severely affected than female low N/M mice. Susceptibility to the disease was associated not only with an inability to produce the maturational transition from low affinity to high affinity antibody with time but also with the production of low levels of antibody. It is suggested that these quantitative and qualitative defects in the antibody response may lead to increased susceptibility to immune complex disease. [ABSTRACT FROM AUTHOR]

The intravenous injection into mice of small amounts of heat-aggregated bovine serum albumin (BSA) results in deposition of BSA within the glomerulus. Injection of rabbit anti-BSA antibody at a time when all circulating BSA has been cleared results in in situ formation of BSA anti-BSA immune complexes with fixation of mouse C3. Subsequent injection of passively-prepared immune complexes gives much enhanced deposition of immune material when com- pared with mice given immune complexes alone. This paper shows that this is an antigen-specific phenomenon and not a result of non-specific trapping by damaged glomeruli. The implications of these observations on the pathogenesis of immune complex glomerulonephritis are discussed. [ABSTRACT FROM AUTHOR]

In rats given a single injection (500 μg) in the hind footpads of heterologous (water-soluble) renal glycoprotein and Freund's incomplete adjuvant, proliferative glomerulonephritis with immunofluorescent `mesangial pattern' was induced. Immunopathological and morphological changes of this group were very similar to those of rats which received a single injection of homologous and water-soluble renal glycoprotein. The nephritogenic renal glycoprotein does not show species specificity. [ABSTRACT FROM AUTHOR]

Many chronic degenerative diseases are suspected of resulting from autoimmune (Al) or immune complex (IC) mechanisms of unknown infectious etiology. Mycoplasmas have been associated with autoantibodies and tissue mimicry and with infertility and neonatal disorders, as well as with IC disorders. Their persistent colonization, which is clinically silent and common among healthy females, makes their etiopathogenic mechanisms difficult to assess. Finding the great apes to be colonized with and serologically expressing the human strains of mycoplasmas, as well as the anti-IgG rheumatoid factor (RF), provided us the ideal model of immunologically-related human disorders, in view of the etiopathologic role of IC in experimental vasculitis, especially collagen vascular diseases such as systemic lupus erythromatosus (SLE) with specific deposition on receptor sites of the vascular basement membranes, an investigation of IC's role in fetal and placental vascular disorders was initiated. The IgG-IC fractions isolated from solubilized human synovial and placental tissue extracts on affinity protein-A columns were further purified by pepsinization to minimize nonspecific Fc binding. Mycoplasmal antigens were identified in the F( ab)2-IC fractions by reacting the electroblots from SDS-PAGE with rabbit antisera to 6 IgG test serovars. Finding mycoplasmal and ureaplasmal antigens associated with the lgG-IC in synovial and placental tissues suggests their pathogenic rote in collagen vascular and reproductive disorders of both humans and the great apes. Mycoplasma cells cultured in rabbit-serum-enriched broth bound rabbit IgG as indicated by their specific reaction with goat anti-rabbit IgG. Polyclonal rabbit antisera raised against the mycoplasma cells binding the gnotobiotic rabbit IgG expressed idiotypic antibodies reactive with heterologous mycoplasmas cultured with whole sera but not with gamma-free or fetal bovine sera. [ABSTRACT FROM AUTHOR]

The novel lymphoproliferative and autoimmune lprcg gene, originally discovered in the CBA/KlJms (CBA) strain of mice, was transferred onto the MRL/MpJ (MRL) strain background, and the resultant partially congenic MRL-lprcg/lprcg carrying 93% or more MRL genomes on average were examined for immune-complex glomerulonephritis and serological aberrations. Ordinary histological studies revealed that MRL-lprcg/lprcg mice developed glomerulonephritis histologically indistinguishable from that in MRL-lpr/lpr but at a lower frequency than in MRL-lpr/lpr mice. Glomerular immune complex deposition was almost the same in MRL-lprcg/lprcg and MRL-lpr/lpr mice. The levels of serum Ig. circulating immune complexes and autoantibodies in MRL-lprcg/lprcg were comparable to or even higher than those in MRL-lpr/lpr mice. Comparison of the serological abnormalities between MRL-lprcg/lprcg with glomerulonephritis and CSA-lprcg/lprcg without it evidenced the enhanced class switch from IgM to IgG responses in both class-specific autoantibody responses and serum Ig levels in MRL lprcg/lprcg as in MRL-lpr/lpr mice. These results taken together indicate that that lprcg gene functions in much the same manner as lpr in induction of glomerulonephritis and serological abnormalities on the MRL background as expected from the allelism between the two mutant genes. [ABSTRACT FROM AUTHOR]

To study the role of local production of complement proteins during the evolution of a naturally occurring immune complex disease, C3, C4, C2 and Factor B mRNA expression was assessed in several tissues of the inbred mouse strains NZB and (NZB × W) F1 hybrid. In the NZB/W F1 hybrid strain, coincident with the development of glomerulonephritis a marked increase in kidney C3 and C4 mRNA was observed; Factor B mRNA, which is expressed as a doublet in kidney and intestine, showed an increase in expression of the smaller transcript. This alteration of kidney C3, (24 and Factor B mRNA is identical to that noted in association with lupus nephritis in the MRL lpr/lpr strain and following in vivo administration of endotoxin to the BALB/c strain. The development of systemic lupus erythematosis (SLE) in the NZB/W F1 was not associated with a marked change in hepatic complement gene expression. These findings support the hypothesis that local production of complement may play a role in the pathogenesis of glomerulonephritis and other tissue injury in SLE. [ABSTRACT FROM AUTHOR]

The article presents abstracts related to allergy, including "Anaphylaxis from mosquito bite," by P. A. Galindo and colleagues; "Idiopathic anaphylaxis: case report," by A. Peric-Popadic and colleagues; and "Anaphylactic reactions to snakebites," by A. R. Reimers and U. R. Muller.

The role of the β2 integrin cell adhesion molecules (CAM) in directing neutrophil accumulation and injury in acute anti-glomerular basement membrane antibody induced glomerulonephritis (anti-GBM GN) was assessed in rabbits by in vivo inhibition of CD 18 dependent neutrophil/endothelial cell interactions using a monoclonal anti-CD 18 antibody. Rabbits given horse anti-rabbit GBM antibody developed significant glomerular neutrophil influx (2.9 ± 0.1 neutrophils per glomerular crosssection [c/gcs], normal 0.1 ± 0.1 c/gcs, P = 0.002) and proteinuria (1389 ± 257 mg/16 h, normal 15 ± 4mg/16h, P = 0.0015) after 16 h. Rabbits rendered neutropenic (< 500 neutrophils/mL) by mustine hydrochloride, or complement depleted by cobra venom factor, did not develop glomerular neutrophil accumulation and had markedly reduced proteinuria after anti-GBM antibody, demonstrating complement-induced neutrophil recruitment is a major mechanism of glomerular injury in this model. Anti-CD 18 antibody treatment of rabbits developing anti-GBM GN abrogated dermal neutrophil influx in response to intradermal injection of fMLP and zymosan activated serum. Treated rabbits achieved levels of anti-CD 18 antibody in their serum which saturated the binding sites on rabbit neutrophils in vitro, and their circulating neutrophils had saturated anti-CD 18 antibody binding in vivo. However, glomerular neutrophil influx (3.5 ± 0.4 c/gcs) and proteinuria (1210 ± 428 mg/16 h) were both unaffected. Thus, in this model of antibody-initiated complement and neutrophil-dependent glomerular injury, in which neutrophil transmigration across the endothelium is not required, effective functional inhibition of β2 integrin CAM in vivo did not reduce glomerular injury or glomerular neutrophil influx. These studies demonstrate that β2 integrin CAM are not a requirement for neutrophil accumulation and glomerular injury in anti-GBM GN in rabbits. [ABSTRACT FROM AUTHOR]

Adherent cells emigrating from glomeruli of rabbits developing anti-glomerular basement membrane antibody induced glomerulonephritis were isolated and characterized as macrophages. Glomeruli were isolated using a sterile graded sieving technique and cultured in plastic tissue culture flasks. After varying culture times, emigrating adherent cells were harvested by 'cold shock' or trypsin-versene. These cells had the morphological and functional characteristics of macrophages. They were largely mononuclear, esterase-positive, phagocytic cells, which exhibited surface Fc receptors. A mean of 4. 8 ± 2.1 × 10⁴ macrophages could be isolated from 2 × 10⁴ glomeruli after 1 h in tissue culture. Greater numbers of macrophages could be isolated with further time in culture. After 72 h however, intrinsic glomerular cell contamination occurred. The majority of the cells were viable by fluorescein diacetate hydrolysis, and Trypan Blue exclusion. Further functional studies of these cells may provide some new insights into the cellular basis of macrophage-induced glomerular injury in experimental glomerulonephritis. [ABSTRACT FROM AUTHOR]