Subtyping of triple-negative breast cancers: its prognostication and implications in diagnosis of breast origin.

BACKGROUND: Triple-negative breast cancer (TNBC) subtyping by gene profiling has provided valuable clinical information. Here, we aimed to evaluate the relevance of TNBC subtyping using immunohistochemistry (IHC), which could be a more clinically practical approach, for prognostication and applications in patient management. METHODS: A total of 123 TNBC cases were classified using androgen receptor (AR), CD8, Forkhead box C1 protein (FOXC1), and doublecortin-like kinase 1 (DCLK1) into luminal androgen receptor (LAR), basal-like immunosuppressive (BLIS), mesenchymal-like (MES), and immunomodulatory (IM) subtypes. The IM cases were further divided into the IM-excluded and IM-inflamed categories by CD8 spatial distribution. Their clinicopathological and biomarker profiles and prognoses were evaluated. RESULTS: LAR (28.6%) and MES (11.2%) were the most and least frequent subtypes. The IHC-TNBC subtypes demonstrated distinct clinicopathological features and biomarker profiles, corresponding to the reported features in gene profiling studies. IM-inflamed subtype had the best outcome, while BLIS had a significantly poorer survival. Differential breast-specific marker expressions were found. Trichorhinophalangeal syndrome type 1 (TRPS1) was more sensitive for IM-inflamed and BLIS, GATA-binding protein 3 (GATA3) for IM-excluded and MES, and gross cystic disease fluid protein 15 (GCDFP15) for LAR subtypes. CONCLUSIONS: Our findings demonstrated the feasibility of IHC surrogates to stratify TNBC subtypes with distinct features and prognoses. The IM subtype can be refined by its CD8 spatial pattern. Breast-specific marker expression varied among the subtypes. Marker selection should be tailored accordingly.

Imaging manifestations of IgG4-related disease.

IgG4-related disease is a multisystem immune-mediated disorder associated with lesions manifesting an IgG4-rich plasma cell infiltrate and often raised serum IgG4 concentrations. The disease can mimic neoplastic, infective, and inflammatory processes due to features such as development of masses or organ enlargement. Prompt consideration of this diagnosis is essential to avoid unnecessary investigations and offer appropriate treatments, which can include steroids and other immunosuppressive agents. Although histology is typically diagnostic, imaging is critical to assess disease burden, determine biopsy targets, and evaluate response to treatment. Characteristic imaging features can also point towards the diagnosis in the absence of biopsy. This review highlights these features, as well as more atypical findings, grouped by organ or system. Differential diagnoses are emphasised. The full spectrum of imaging methods is discussed. Whole-body imaging with integrated 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)/computed tomography (CT) has an evolving role in the detection of multi-organ involvement and subsequent follow-up.

An international patient-centred study of retroperitoneal fibrosis.

BACKGROUND: The impact that rare chronic disorders, such as retroperitoneal fibrosis (RPF), can have on the physical and psychological aspects of a patient's health is poorly understood. Patient-related outcome measures and experiences provide a unique opportunity to understand the impact rare chronic disorders have on a patient's life as well as allowing healthcare providers to compare and improve performance. AIM: To understand the physical and psychosocial impact that RPF has upon peoples' lives. DESIGN: An international online questionnaire was therefore created to gain insights into how patients with RPF, a rare fibro-inflammatory condition, viewed their health and experiences. METHODS: An international online questionnaire comprising 62 questions/free text options, was designed in collaboration with two patient advocates and the multi-disciplinary Renal Association Rare Disease Registry (RaDaR) RPF Group the questionnaire was anonymous and freely accessible on a GOOGLE Form online platform for 6 months. RESULTS: A total of 229 patients from 30 countries across 5 continents responded. Four key issues were identified; (i) pain; (ii) therapy-related side effects; (iii) lack of informed doctors/information about their condition and its management; and (iv) psychological burden. Variations in diagnosis and management are highlighted with 55% undergoing a biopsy to reach a diagnosis of RPF; 75% of patients underwent a further interventional procedure with 60% concurrently treated medically. CONCLUSION: This study will guide further development of clinical and academic multi-disciplinary activity and shows the importance of trying to understand the impact of rare chronic disorders on the physical and psychological aspects of a patient's health.

IgG4-related disease in a multi-ethnic community: clinical characteristics and association with malignancy.

BACKGROUND: Immunoglobulin-G4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory condition that can affect multiple organs. Despite growing interest in this condition, the natural history and management of IgG4-RD remain poorly understood. AIM: To describe the clinical characteristics, treatment and outcomes of IgG4-RD in a multi-ethnic UK cohort, and investigate its possible association with malignancy. DESIGN: Retrospective analysis of case-note and electronic data. METHODS: Cases were identified from sub-specialty cohorts and a systematic search of an NHS trust histopathology database using 'IgG4' or 'inflammatory pseudotumour' as search terms. Electronic records, imaging and histopathology reports were reviewed. RESULTS: In total, 66 identified cases of IgG4-RD showed a similar multi-ethnic spread to the local population of North West London. The median age was 59 years and 71% of patients were male. Presenting symptoms relating to mass effect of a lesion were present in 48% of cases and the mean number of organs involved was 2.4. Total of 10 patients had reported malignancies with 6 of these being haematological. 83% of those treated with steroids had good initial response; however, 50% had relapsing-remitting disease. Rituximab was administered in 11 cases and all achieved an initial serological response. Despite this, seven patients subsequently relapsed after a mean duration of 11 months and four progressed despite treatment. CONCLUSIONS: We report a large UK-based cohort of IgG4-RD that shows no clear ethnic predisposition and a wide range of affected organs. We discuss the use of serum IgG4 concentrations as a disease marker in IgG4-RD, the association with malignant disease and outcomes according to differing treatment regimens.

Interactions between head motion and coil sensitivity in accelerated fMRI.

BACKGROUND: Parallel imaging is widely adopted to accelerate functional MRI (fMRI) data acquisition, through various strategies that involve multi-channel receiver coils. However, the non-uniform spatial sensitivity of multi-channel receiver coils may introduce unwanted artifacts when head motion occurs during the few-minute long fMRI scans. Although prospective correction provides a promising solution for alleviating the head motion artifacts in fMRI, the relative position of the fixed multi-channel receiver coils moves in the moving reference frame, potentially resulting in artifactual signal. NEW METHOD: We used numerical simulations to investigate this effect on fMRI using two parallel imaging schemes: sensitivity encoding (SENSE) and generalized autocalibrating partially parallel acquisitions (GRAPPA) with acceleration factors 2 and 4, towards characterizing the regime over which parallel-imaging fMRI with prospective motion correction will benefit from updating coil sensitivities to reflect relative positional change between the head and the receiver coil. Moreover, six subjects were scanned with acceleration factors 2 and 4 while performing a simple finger-tapping task with and without overt head motion. RESULTS: Updating coil sensitivities showed significant positive impact on standard deviation and activation maps in presence of overt head motion compared to that obtained with no overt head motion. COMPARISON WITH EXISTING METHODS: The parallel imaging fMRI with updated coil sensitivity maps were compared to that with the coil sensitivity maps acquired at the reference position. CONCLUSIONS: Head motion in relation to a fixed multi-channel coil can adversely affect the quality of parallel imaging fMRI data; and updating coil sensitivity map can mitigate this effect.

Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child.

PURPOSE: To investigate whether intravitreal ranibizumab injections administered to a child alter systemic plasma levels of total and free VEGF 165. METHODS: A 9-year-old child sustained a choroidal rupture from blunt trauma. He subsequently developed a secondary choroidal neovascular membrane, which was treated with five ranibizumab injections over a period of 8 months. Peripheral venous blood samples were taken at each visit over a period of 12 months and plasma was extracted. Plasma VEGF 165 levels were determined using enzyme-linked immunosorbent assay and were assayed both pre- and post-immunodepletion to remove complexed VEGF. RESULTS: Plasma VEGF 165 levels proved labile following intravitreal injection of ranibizumab. Levels increased by 30% above baseline following the first intravitreal ranibizumab injection, but then returned to baseline despite two subsequent injections. There was then a rebound increase of 67% in total plasma VEGF levels following a further injection, which remained above baseline for 12 weeks despite two further intravitreal ranibizumab injections. Baseline levels were re-attained 26 weeks after the final injection. CONCLUSIONS: These results suggest intravitreal ranibizumab injections can cause significant, multiphasic changes in systemic VEGF levels. This may be of particular clinical significance in children as VEGF is known to be vital in the development of major organs, in addition to its role in the maintenance of normal organ function in adults.

Improved blood pressure, nitric oxide and asymmetric dimethylarginine are independent after bariatric surgery.

BACKGROUND: Obesity is associated with hypertension, but the exact mechanism is not fully understood. Bariatric surgery significantly decreases weight and blood pressure (BP). Low plasma nitric oxide (NO) and raised asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO, concentrations are associated with both obesity and hypertension. Correlations between the changes in these parameters were studied after bariatric surgery. METHODS: Weight, BP, plasma ADMA and NO were measured in 29 obese patients (24 female, 5 male) before and six weeks after bariatric surgery. RESULTS: Patients were 39.2 ± 1.2 (mean ± SEM) years old and weighed 126 ± 3 kg. Six weeks after the surgery, patients had lost 10 ± 0.7 kg (P < 0.0001) and mean arterial pressure (MAP) decreased by 11 ± 1.0 mmHg (P < 0.0001). The plasma ADMA concentration decreased by 24 ± 2% from 5 ± 0.4 to 4.0 ± 0.3 µmol/L (P < 0.0001). The plasma total nitrite concentration increased by 15 ± 1% from 51.4 ± 2.6 to 60 ± 3 µmol/L (P < 0.0001). The correlation between the decrease of ADMA and increase of NO subsequent to weight loss was significant (P < 0.0001). However, MAP was not correlated to the changes in ADMA or NO. CONCLUSIONS: After bariatric surgery, beneficial changes in BP, NO and ADMA occur, but our findings suggest that these BP changes are independent of changes in the NO-ADMA axis. Other causes for the changes in BP should therefore be considered.

The prevalence of depression and its associated factors among elderly patients attending health centres in Trinidad

BACKGROUND: Depression is the most common mood disorder in the elderly. Internationally, most studies have found the prevalence of depression in the elderly population to range from appoximately 13% to 18%. In 2010 it is estimated that persons over 60 years of age made up 10% of the population of Trinidad and Tobago. The ageing population faces many complex issues such as chronic illness, disability, loneliness, isolation and adverse socio-economic circumstances that may contribute to depression. Locally, no studies have been done that investigate the depression specifically in the elderly. This study aims to establish preliminary data on this topic for the elderly population of Trinidad. METHODS This was a cross sectional descriptive study of patients over age 60, attending four health centres in Trinidad (Arima, St. Joseph, Freeport and Couva). Convenience sampling was used and participants completed a demographic questionaire and the Zung self rating depression scale. Data was analyzed using SPSS for Windows version 10.0 and the Chi-square test was used to determine statistically significant associations. RESULTS: There were 348 participants consisting of 200 females (57.4%) and 148 males (42.6%). Those 60-79 years made up 90.8%, while the remaining 9.1% were 80 years or older. Indo-Trinidadians made up 60.1%, Afro-Trinidadians 31.2% and mixed or others made up 8.7%. The prevalence of depression in this elderly population was found to be 17.2%. Depression was found to be associated with level of education (p=0.016). No association was found between gender (p=0.470), marital status (p=0.066), ethnicity (p=0.742)....... CONCLUSION: The prevalence of depression found in this population (17.2%), its association with level of education is comparable to that found in other elderly population internationally. Depression is intertwined with social and economic well being and self-perceived health and is an important consideration when caring for the elderly in Trinidad.

Primary infective spondylodiscitis caused by Lactococcus garvieae and a review of human L. garvieae infections.

We report the first case of primary infective spondylodiscitis due to Lactococcus garvieae, confirmed by 16S rRNA gene sequencing, in the absence of concomitant endocarditis in a patient with long-standing gastritis on famotidine. He responded to a 6-week course of ampicillin. The gastrointestinal tract is probably the source of infection.

Renal cytokines improve early after bariatric surgery.

BACKGROUND: Bariatric surgery has been suggested to improve arterial hypertension and renal function. This prospective controlled observational study aimed to investigate changes in renal inflammation, renal function and arterial blood pressure before and after bariatric surgery. METHODS: Blood pressure was measured, and urine and blood samples were collected from 34 morbidly obese patients before and 4 weeks after bariatric surgery. Serum levels of cystatin C, creatinine, albumin, cholesterol and C-reactive protein (CRP) were measured, along with urinary cytokine/creatinine ratios for macrophage migration inhibitory factor (MIF), monocyte chemotactic protein (MCP) 1, chemokine ligand (CCL) 18 and CCL-15. RESULTS: Mean(s.e.m.) bodyweight dropped from 124·1(2·6) to 114·8(2·4) kg (P < 0·001) and mean arterial blood pressure decreased from 105·7(1·8) to 95·5(1·2) mmHg (P < 0·001) in 4 weeks. Systemic and urinary inflammatory markers improved, with a reduction in serum CRP level (P < 0·001), and decreased urinary MIF/creatinine (P < 0·001), MCP-1/creatinine (P < 0·001) and CCL-18/creatinine (P = 0·003) ratios. In contrast, urinary CCL-15/creatinine ratios did not change and the glomerular filtration rate, measured by serum cystatin C, was unchanged (P = 0·615). CONCLUSION: Surgically induced weight loss contributed to a decrease in blood pressure and markers of renal inflammation. The reduced levels of CRP and urinary cytokines suggest that bariatric surgery attenuates systemic and renal inflammatory status.

Urinary proteomic profiles distinguish between active and inactive lupus nephritis.

OBJECTIVES: Key aims of the treatment of lupus nephritis (LN) are to induce and maintain remission with minimal side effects. However, assessing ongoing renal inflammatory activity is poorly served by current diagnostic tests apart from renal biopsy, but frequent biopsies cannot be justified. Our long-term aim is to identify novel biomarkers from urinary protein profiles to improve diagnosis and monitoring of activity and response to therapy in LN. METHODS: We used surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to identify biomarkers able to discriminate between urine samples from patients with inactive (n= 49) and active (n= 26) LN. Discriminant function analysis was used to define the minimum number of proteins whose levels best distinguished between the two patient groups. Serial urines of six biopsied patients were studied prospectively, and multiple regression (MR) scores calculated. RESULTS: Proteins with masses of 3340 and 3980 distinguished active from inactive LN with 92% sensitivity and specificity of 92% each. The prospective study of the biopsied patients demonstrated that MR scores could predict both relapse and remission earlier than traditional clinical markers. CONCLUSIONS: SELDI-TOF MS identified potential biomarker profiles strongly associated with activity in LN. Identification of these proteins will allow us to devise specific assays to routinely monitor disease progression, and alter immunosuppressive drug regimens accordingly. These proteins may also play a critical role in the pathogenesis of glomerulonephritis, and could therefore provide targets for therapeutic intervention.

Extremely low exposure of a community to severe acute respiratory syndrome coronavirus: false seropositivity due to use of bacterially derived antigens.

Estimates of seropositivity to a new infectious agent in a community are useful to public health. For severe acute respiratory syndrome (SARS), the figures are conflicting. Herein, we screened 12,000 people in a community stricken by SARS 10 months previously and found 53 individuals (0.44%) who had immunoglobulin G antibodies to the SARS coronavirus (SARS-CoV) nucleocapsid (N) produced in bacteria. However, only seven of these (group 1) had sera which also reacted with the native N antigen expressed in SARS-CoV-infected Vero cells, N-transfected 293T cells, and tissues of infected SARS patients. Of these, six individuals had had SARS previously. The remaining person, as well as the 46 other individuals (group 2), were healthy and had no history of SARS. Group 1 antibodies recognized epitopes located slightly differently in N from those of group 2 antibodies, and a mouse hybridoma antibody resembling the former type was generated. Unusually, group 2 antibodies appeared to recognize cross-reactive bacterial epitopes that presumably were posttranslationally modified in eukaryotes and hence were probably not induced by SARS-CoV or related coronaviruses but rather by bacteria. The N antigen is thus highly unique. The extremely low rate (0.008%) of asymptomatic SARS infection found attests to the high virulence of the SARS-CoV virus.

Magnetoencephalographic study of vibrotactile evoked transient and steady-state responses in human somatosensory cortex.

Somatosensory responses to vibrotactile stimulation applied to the index fingertip were recorded with whole-head MEG in eleven healthy young adult participants. Stimulus trains were produced by a pneumatically driven membrane oscillating at 22 Hz for a trial duration of 1 s, separated by interstimulus intervals (ISIs) of 0.5, 1.0, 3.0, and 7.0 s. Data analysis was performed in two frequency bands. Transient onset responses in the lower frequency band (<20 Hz) contained a clearly expressed P50 component. The higher frequency band (18-30 Hz) revealed a gamma-band response (GBR) within the first 200 ms followed by rhythmic activity at the stimulus frequency that continued throughout the stimulus duration, known as the steady-state response (SSR). Dipoles associated with the transient responses and SSRs were localized in two distinct regions within the primary somatosensory cortex (SI), with transient responses located on average 3 mm more medial and inferior than the SSRs. The transient and GBR peak amplitudes increased with ISI, whereas the SSR amplitude showed no ISI dependence. These results may reflect functionally and spatially distinct neural populations. Further investigations are required to assess the implications of these findings for probing the somatosensory system using other functional neuroimaging methods such as fMRI.

Interleukin-11 reduces renal injury and glomerular NF-kappa B activity in murine experimental glomerulonephritis.

BACKGROUND/AIMS: There is now considerable evidence implicating T cells and macrophages in glomerular injury in crescentic glomerulonephritis. Recently, it has been shown that interleukin-11 (IL-11) has an immune modulatory function through its effect on both macrophages and T cells. We, therefore, examined the therapeutic effect of IL-11 in a murine model of experimental glomerulonephritis. METHOD: Accelerated nephrotoxic nephritis was induced in C57BL/6 mice. IL-11 at a dose of 0.5 mg/kg/day (n = 10) in vehicle was given daily subcutaneously from the day of sensitization until day 14 after initiation of glomerulonephritis. Control mice (n = 10) received injection of vehicle alone with the same schedule. RESULTS: IL-11 treatment markedly decreased albuminuria (6.2 +/- 1.9 vs. 18.2 +/- 4.5 mg/day, p < 0.05), the number of glomerular macrophages (1.1 +/- 0.2 vs. 1.7 +/- 0.3 cells/glomerular cross-section, p < 0.05) and glomerular fibrin deposition (fibrin score 0.9 +/- 0.3 vs. 2 +/- 0.3, p < 0.05). There was no difference in the glomerular T cell numbers between the IL-11-treated and the vehicle group. Glomerular NF-kappaB activity was markedly suppressed by 75% in the treated group (p = 0.0015). CONCLUSION: In this study, we provide the first in vivo evidence that IL-11 treatment decreases glomerular NF-kappaB activity and reduces renal injury in experimental glomerulonephritis.

Assessing linear time-invariance in human primary somatosensory cortex with BOLD fMRI using vibrotactile stimuli.

The assumption of linear time-invariance (LTI) in the human primary somatosensory cortex (SI) is assessed for fMRI signals generated by variable-duration vibrotactile stimuli. Predictions based on time-shifted summation (TSS) of responses to 2 s stimuli overestimate observed BOLD signal amplitudes in response to longer-duration stimuli, in agreement with previous findings in other primary sensory cortices. To interpret these results, we undertook an alternative approach for LTI assessment by characterizing BOLD signals using two biophysical models. The first model assumes that the input stimulus envelope is proportional to neural activity. The second assumes that neural activity exhibits both transient and steady-state components, consistent with extensive electrophysiological data, and fits the experimental data better. Although nonlinearity remains evident for short stimulus durations, the latter model shows that the TSS procedure to assess LTI overestimates the BOLD signal because the temporal characteristics of neural activity have not been considered adequately. Further research to investigate the BOLD response to time-varying neural activity is required.

Glomerular protein sieving and implications for renal failure in Fanconi syndrome.

BACKGROUND: Glomerular sieving coefficients (GSCs) of proteins have been measured extensively in animals but not humans. We have studied the proteinuria of Fanconi syndrome, a "knock-out" of renal tubular protein reabsorption, to estimate GSCs and detect potential contributors to development of renal failure. METHODS: Immunoassay of proteins and polypeptides in serum and urine of patients with early Dent's disease (mean GFR = 83 mL/min, range 60 to 101, N = 5), Lowe's syndrome (N = 3), and ADIF (N = 2) were used. RESULTS: Twenty-one proteins, ranging in mass from insulin (5.1 kD) and parathyroid hormone (PTH; 9.4 kD) to transferrin (78 kD) and intact IgG (160 kD), were present in Fanconi urine at> 6 to 1000-fold normal. A simple model assuming complete "knock-out" of the reuptake of each protein filtered normally by the glomerulus was applied to protein excretion by Dent's patients. GSCs were estimated for 12 plasma proteins, including albumin (7.7 +/- 0.9 x 10-5) and IgG (4.2 +/- 0.28 x 10-5; mean +/- SEM). We calculated the albumin concentration in normal glomerular filtrate to be 3.5 +/- 0.41 mg/L (53 +/- 6.4 nmol/L), consistent with studies in rat and dog. CONCLUSIONS: To our knowledge, this study provides the first estimates of human in vivo GSCs. Our model explains why tubular proteinuria of Fanconi syndrome includes proteins of mass of albumin and above as well as low-molecular-weight proteins, and further characterizes the endocytic pathway(s) believed defective in these syndromes. High urinary concentrations of potentially bioactive hormones such as PTH, insulin, IGF-1 and the chemokine monocyte chemoattractant protein-1 (MCP-1), were found; their presence in tubular fluid may contribute to the hypercalciuria, interstitial fibrosis, and the progressive renal failure of Fanconi syndromes.

VCAM-1 has a tissue-specific role in mediating interleukin-4-induced eosinophil accumulation in rat models: evidence for a dissociation between endothelial-cell VCAM-1 expression and a functional role in eosinophil migration.

Eosinophil accumulation has been associated with the pathogenesis of numerous allergic inflammatory disorders. Despite the great interest in this response, many aspects of eosinophil accumulation remain unknown. This is particularly true with respect to tissue-specific mechanisms that may regulate the accumulation of eosinophils in different organs. This study addressed this issue by investigating and comparing the roles of alpha(4)-integrins and vascular cell adhesion molecule 1 (VCAM-1) adhesion pathways in interleukin 4 (IL-4)-induced eosinophil accumulation in 2 different rat models of inflammation, namely pleural and cutaneous inflammation. Similar to our previous findings in studies in rat skin, locally administered IL-4 induced a time- and dose-dependent accumulation of eosinophils in rat pleural cavities, a response that was associated with generation of the chemokine eotaxin. The IL-4-induced eosinophil accumulation in skin and pleural cavities was totally inhibited by an antirat alpha(4)-integrins monoclonal antibody (mAb) (TA-2). In contrast, whereas an antirat VCAM-1 mAb (5F10) totally blocked the response in skin, IL-4-induced eosinophil accumulation in rat pleural cavities was not affected by VCAM-1 blockade. A radiolabeled mAb technique demonstrated that endothelial-cell VCAM-1 expression was induced in response to IL-4 in both skin and pleural membrane. The results indicate that although endothelial-cell VCAM-1 is present in skin and pleura, a functional role for it in IL-4-induced eosinophil accumulation was evident only in skin. These findings suggest the existence of tissue-specific adhesive mechanisms in regulating leukocyte migration in vivo and demonstrate a dissociation between VCAM-1 expression and eosinophil accumulation.

Isolation of leptin-binding peptides from a random peptide phage library.

Leptin plays a role in regulating the body weight in mice. Injection of recombinant mouse leptin expressed in Escherichia coli reduced the food intake and body weight in normal, ob/ob and diet-induced obesity mice. Hyperglycemia, hyperinsulinemia and hypothermia can also be corrected in ob/ob mice after leptin injection. Leptin is a 16-kDa secretory protein comprising 167 amino acids produced in adipose tissue and is secreted to blood stream. In this study, a recombinant mouse leptin was generated and purified from a baculovirus expression system. This protein was used to identify putative ligands using a phage library of random peptides. Three leptin-binding phage clones were found, which were characterized by DNA sequencing and ELISA methods. The amino acid sequences of the reactive peptides are: LAYCSDPVRCLVWWY, MFWISAVSFVDHALV and LVLVLSAFLCCGVG. All three clones bound to recombinant human and mouse leptins. These peptides may be useful tools to study leptin-receptor interaction, food intake and body weight regulation.

CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis.

Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by a single injection of rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. The role of T cells in the pathogenesis of EAG remains unclear. T-cell costimulation is provided by ligation of CD28 with either B7.1 (CD80) or B7.2 (CD86) on antigen-presenting cells, and can be inhibited by a soluble form of CTLA4 (CTLA4-Ig) that binds to both B7.1 and B7.2. We examined the effect of CD28-B7 blockade on the development of EAG using native CTLA4-Ig or mutant CTLA4-Ig (Y100F-Ig), which selectively blocks B7.1. Native CTLA4-Ig treatment ameliorated EAG by several measures, including the levels of circulating anti-GBM antibodies, albuminuria, the deposition of IgG and fibrin in the glomeruli, the severity of glomerular abnormalities, and the numbers of infiltrating T cells and macrophages. Y100F-Ig resulted in a similar reduction in the severity of nephritis, but produced no overall reduction in circulating anti-GBM antibodies, although there was a reduction in IgG2a antibodies. We concluded that CD28-B7 blockade reduced autoantibody production and cellular infiltration of glomeruli, and prevented target organ injury. Our results suggest a key role for B7. 1 in costimulation of Th1-like autoimmune responses in the rat, and show that glomerular injury in EAG is largely dependent on cell-mediated mechanisms.