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Objectives: In addition to various immunosuppressive agents, belimumab and anifrolumab became available in Japan. We aimed to investigate glucocorticoid-free clinical remission in a single-centre retrospective cohort in October 2023., Methods: Our cohort included patients with SLE who needed to start or increase glucocorticoids for disease activity and were followed up for more than 1 year. We investigated the rate of achievement of clinical remission off corticosteroids (CR off C), defined as no clinical score on the SLEDAI-2K without glucocorticoids, baseline predictors of CR off C, medications used when CR off C was achieved, and flare rates following CR off C., Results: Out of the 60 patients followed for an average of 5.4 (±2.6) years, 17 (28.3%) achieved CR off C in 3.6 (±1.2) years after enrolment. Use of belimumab and anifrolumab accounted for eight (47.1%) of the achievers. Among the baseline data, male sex, recent enrolment, high glucocorticoid dose, and detection of immune complex (IC) significantly predicted CR off C, while lupus nephritis (LN) and a low C3 level tended to predict it. In the multivariate analysis, IC detection was the only predictor of CR off C. Clinical flares were observed in 5.9% of the achievers during a median 1.2 years after achievement of CR off C., Conclusion: In the era of biologics, CR off C was achieved in 28.3% of the patient cohort requiring the start or increase of glucocorticoids for disease activity, with a relatively low rate of flares, suggesting that glucocorticoid-free clinical remission is an achievable target in SLE. IC disease, represented by male sex or nephritis, is likely to benefit from currently available medications., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Hiroshi Oiwa has received speaking fees from GSK, Astra-Zeneca, Asahi-kasei, Astellas, Taisho, Eisai, Pfizer, Eli Lilly, Abbvie, Ayumi, Chugai, and Boehringer Ingelheim. Takeshi Suga, none to declare; Yohei Hosokawa, none to declare; Kei Araki, none to declare. All other authors declare no conflict of interest.

Abstract: We present 2 cases of striking stromal corneal infiltrates months after COVID-19 infection. While we cannot prove that these infiltrates are caused by or directly related to COVID-19, we did not find any other plausible cause that could explain these ophthalmic signs. In these cases, the ongoing process was detected in relatively early stages due to scheduled visits with patients and responded positively to prednisolone acetate 1% ophthalmic suspension. However, we do not know the response to treatment in more advanced cases., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The presence of fluid attenuated inversion recovery (FLAIR)-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated cerebral cortical encephalitis with seizures (FLAMCES) was recently reported. However, the clinical characteristics and outcome of this rare clinico-radiographic syndrome remain unclear., Methods: The present study reported two new cases. In addition, cases in the literature were systematically reviewed to investigate the clinical symptoms, magnetic resonance imaging (MRI) abnormalities, treatments and prognosis for this rare clinico-radiographic syndrome., Results: A total of 21 cases were identified during a literature review, with a mean patient age at onset of 26.8 years. The primary clinicopathological characteristics included seizures (100%), headache (71.4%), fever (52.3%) and other cortical symptoms associated with the encephalitis location (61.9%). The common seizure types were focal to bilateral tonic-clonic seizures (28.6%) and unknown-onset tonic-clonic seizures (38.1%). The cortical abnormalities on MRI FLAIR imaging were commonly located in the frontal (58.8%), parietal (70.6%) and temporal (64.7%) lobes. In addition, pleocytosis in the cerebrospinal fluid was reported in the majority of the patients (95.2%). All patients received a treatment regimen of corticosteroids and 9 patients received anti-epileptic drugs. Clinical improvement was achieved in all patients; however, one-third of the patients reported relapse following recovery from cortical encephalitis., Conclusions: FLAMCES is a rare phenotype of MOG-associated disease. Thus, the wider recognition of this rare syndrome may enable timely diagnosis and the development of suitable treatment regimens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Liu, Lin, Liang, Zhao and Wang.)

Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002-a humanized IgG1 monoclonal antibody against human CCL20-was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a dose-responsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An extensive ex vivo analysis of large molecular weight protein complexes in monkey serum from this study and in human serum samples demonstrated a time-dependent aggregation of GSK3050002, that was not predicted by in vitro assays. The aggregates also contained complement components. These findings support the hypothesis that immune complexes of drug aggregates, not necessarily including anti-drug antibodies, can fix complement, accumulate over time, and trigger immune complex disease. A situation which may have increased clinical relevance than typical anti-drug antibody-associated immune complex disease in monkeys administered human antibody proteins., Competing Interests: Funding for this study was provided by GlaxoSmithKline and Morphotek, Inc. (NCT01984047). JR is an employee of Charles River Laboratories and principal investigator of the immunohistochemistry analysis. TR is an employee of Covance CRS, LLC (formerly Envigo CRS) and study director of the 26-week monkey toxicity study. LP was an employee of Envigo CRS for the duration of the study. All other listed authors were employees of GlaxoSmithKline (GSK) during the conduct of the study, hold GSK stock or stock options, and meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Estrogens have been shown to regulate the immune system and modulate multiple autoimmune diseases. 17α-ethinyl estradiol (EE), a synthetic analog of 17β-estradiol, is prescribed commonly and found in oral contraceptives and hormone replacement therapies. Surprisingly, few studies have investigated the immunoregulatory effects of exposure to EE, especially in autoimmunity. In this study, we exposed autoimmune-prone female MRL/lpr mice to a human-relevant dose of EE through the oral route of exposure. Since lupus patients are prone to infections, groups of mice were injected with viral (Imiquimod, a TLR7 agonist) or bacterial (ODN 2395, a TLR9 agonist) surrogates. We then evaluated autoimmune disease parameters, kidney disease, and response to in vivo TLR7/9 pathogenic signals. EE-exposed mice had increased proteinuria as early as 7 weeks of age. Proteinuria, blood urea nitrogen, and glomerular immune complex deposition were also exacerbated when compared to controls. Production of cytokines by splenic leukocytes were altered in EE-exposed mice. Our study shows that oral exposure to EE, even at a very low dose, can exacerbate azotemia, increase clinical markers of renal disease, enhance glomerular immune complex deposition, and modulate TLR7/9 cytokine production in female MRL/lpr mice. This study may have implications for EE-exposure risk for genetically lupus-prone individuals.

Background: Filamentous M13 phages have recently been utilized as components for developing novel functional soft materials in various fields such as sensor, device, and biomedical applications. Recently, we have developed liquid crystalline hydrogels composed of M13 phages and gold nanoparticles (GNPs) based on specific interactions between the components., Objectives: The main objective of this study was to clarify the self-healing capability of the hydrogels composed of M13 phages and GNPs., Methods: M13 phages displaying tag peptides with a sequence of YPYDVPDYA (HA phages) were genetically constructed through general molecular biology. The mechanical strength of hydrogels composed of the HA phages and anti-HA peptide antibodies-immobilized GNPs (HA-GNPs) was measured by indentation tests. The rupture point of the hydrogels was visually observed. An aliquot of buffer solution was added into the rupture point of the hydrogels after the indentation test. After incubation for 2 days, self-healing of the rupture point was checked visually. The indentation test was also performed after self-healing. To clarify the assembled structures of the components in the hydrogels, transmission electron microscopy (TEM) observation was performed by transferring the hydrogel onto a TEM grid before and after healing., Results: The strength of the original hydrogel (before self-healing) required for rupture was approximately 55 mN. Self-healing of the rupture point was confirmed visually, and the hydrogels behaved as uniform hydrogels again during the vial inversion tests. As a result of the indentation test for the self-healed points of the hydrogels, the rupture force of approximately 45 mN was detected, indicating the self-healing capability of the hydrogels. TEM observation of the before and after self-healing exhibited the regularly assembled structures composed of the HA-GNPs, suggesting that the ruptured networks were recovered into regularly assembled network structures. Importantly, control of the concentration of the HA-GNPs resulted in suppression of decreasing the rupture forces during the repetitive self-healing processes., Conclusion: Our results demonstrated the self-healing capability of structurally regular hybrid hydrogels composed of genetically engineered filamentous viruses displaying antigen peptides and antibody-immobilized GNPs. The results indicated that supramolecular hydrogels containing filamentous viruses would expand the applicability of virus-based soft materials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Context: Salvia przewalskii Maxim. (Lamiaceae) is a Chinese herbal medicine that has long been used for the treatment of cardiovascular disease., Objective: The study investigated the therapeutic efficacy of S. przewalskii total phenolic acid extract (SPE) on immune complex glomerulonephritis (ICG) in rats., Materials and Methods: Sixty-two Wistar rats were randomized into six groups. ICG was induced in all groups except normal control group. SPE was administered intragastrically at 24 h intervals for 40 consecutive days. Urine protein (UP), total serum protein (TSP), serum albumin (SA), serum cholesterol (SC) and serum urea nitrogen (SUN) were measured one day before, on day 20 and 40 after SPE administration. On day 40 after SPE administration, the kidneys were removed and prepared into pathologic sections. In addition, kidney wet mass was measured for calculating the kidney wet mass coefficient (KWMC)., Results: UP excretion was reduced significantly on day 20 after SPE administration in all three SPE groups as compared with that in medium group, and this effect was observable continuously until 40 days after SPE administration. Compared with medium group, TSP and SA were increased in all three SPE groups after 40 days treatment, while SC and SUN were decreased. KWMC was decreased significantly in 100 mg/kg SPE group after 40 days treatment compared with that in medium group. Histopathologic analyses showed that renal inflammatory infiltration and kidney intumesce were alleviated in all three SPE groups., Conclusions: SPE may be a potential therapeutic drug for glomerulonephritis.

Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk. Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G). Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials., (Published by Elsevier Ltd.)

Inflammation mediated by cells of the immune system and necrosis are the most striking features observed at the histologic level in patients with vasculitides, clinical entities classified according to pathologic findings involving different organs, to etiology, or to size of vessels involved. Small vessel vasculitides (SVV) are a peculiar group of systemic disorders electively involving small intraparenchymal arteries, arterioles, capillaries, or venules and leading to different levels of vascular obstruction, tissue ischemia and risk of infarction; they can be divided into anti-neutrophil cytoplasmic antibody-associated vasculitides and immune complex vasculitides. Despite the significant advances in understanding the whole disease process and pathophysiology of SVV, strong efforts are still needed to draft, share and spread guidelines in the therapeutic management of these protean disorders. After an accurate evaluation of different open or double-blind trials and cohort studies in this review, we analyze the actual medical tools suggested for treating granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, Henoch-Schönlein purpura, cryoglobulinemic vasculitis, anti-glomerular basement membrane disease and hypocomplementemic urticarial vasculitis.

Preclinical Research Vanillic acid (VA) is a dihydroxybenzoic acid derivative widely used as a flavoring agent. It has chemopreventive effects on experimentally-induced carcinogenesis and in ulcerative colitis. The object of the present study was to investigate the effects of VA, alone and in combination with methylprednisolone (MP), on cationic bovine serum albumin (cBSA induced immune-complex glomerulonephritis in female BALB/c mice. Pre-immunization was carried out with cBSA in BALB/c mice and repeated (cBSA, 13 mg/kg, 3 times/week, i.v.) for 6 weeks to induce glomerulonephritis which was confirmed by the presence of severe proteinuria. The effect of VA (50, 100, and 200 mg/kg, p.o.) and its combination with MP (12.5 mg/kg, p.o.) was assessed in the nephrotic disease model. Treatment with VA decreased inflammatory nephrotic injury as evidenced by decreased proteinuria, serum creatinine, blood urea nitrogen, serum IgG1 and TNF-α levels. Co-administration of VA with MP showed an improvement in the immunohistochemistry of glomerular nephrin and podocin. The present results indicate that VA has a nephroprotective effect in the management of autoimmune nephritis. Drug Dev Res 77 : 171-179, 2016.   © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: An association has been suggested between asthma and orbital immunoglobulin G4-related disease (IgG4-RD)., Objective: To explore this association, including asthma characteristics and risk factors., Methods: A retrospective, computer-assisted search identified patients with orbital IgG4-RD seen at Mayo Clinic in Rochester, Minnesota from 1997 to 2014. Asthma prevalence and its related clinical and radiologic characteristics were studied., Results: Thirty-one patients (17 men) with biopsy-proven orbital IgG4-RD were identified. Mean age at diagnosis was 54.3 years (SD 11.0 years). Median duration from onset of orbital symptoms to IgG4-RD diagnosis was 1.96 years (range 0.1-31.8 years). Twenty-two patients (71%) were not smokers, 6 (19%) were former smokers, and 3 (10%) were current smokers. Sixteen patients (52%) had asthma. Three patients had childhood asthma onset, and median age at asthma onset in the 7 patients with data available was 56 years (range 15-62 years). In this cohort, the most common findings at chest computed tomography were mediastinal and hilar lymphadenopathy (44%), linear scarring (20%), and nodules and bronchial wall thickening (16%). Bronchial wall thickening correlated with presence of asthma. Chronic sinusitis (94%) was most commonly associated with asthma. Serum IgG4 was markedly increased in patients with asthma (median 195.0 mg/dL, range 31.8-1,790.0 mg/dL) vs patients without asthma (median 78.9 mg/dL, range 7.7-166.0 mg/dL; P = .02). Treatment was commonly prednisone and then rituximab; rituximab helped control asthma in most cases. Two deaths were reported (median follow-up 4.2 years)., Conclusion: Asthma is commonly associated with orbital IgG4-RD and generally manifests as adult-onset bronchial wall thickening seen at computed tomography, increased serum IgG4 levels, and good rituximab response., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

IL-33 is a new member of the IL-1 family that plays a role in inflammation. In this study, we evaluated the potential of IL-33 inhibition as a treatment for systemic lupus erythematosus (SLE) using the lupus-prone model MRL/lpr mice and the underlying mechanisms of action. We treated mice with anti-mouse IL-33 antibody (anti-IL-33Ab) via intraperitoneal injection every other day from week 14 until week 20 for 6 weeks. A control group received the same amount of IgG control. Renal damage and mouse survival were compared. Cytokines, antibodies, immune complex, Tregs, myeloid-derived suppressor cells (MDSCs), and Th17 cells were also analyzed. Correlations between serum IL-33 and SLE disease activity index in human SLE were also investigated. MRL/lpr mice treated with anti-IL-33Ab showed reduced proteinuria and reduced serum anti-dsDNA levels. Nephritis, immune complex deposits, and the circulating antibodies and immune complex besides the mortality were significantly reduced by anti-IL-33Ab. Anti-IL-33Ab remarkably increased Tregs and MDSCs and reduced the Th17 cells and IL-1β, IL-6, and IL-17 levels in MRL/lpr mice. These results suggest that IL-33 inhibition may inhibit SLE via expansion of Tregs and MDSCs and inhibition of Th17 cells and proinflammatory responses, indicating that blockade of IL-33 has a protective effect on SLE.

Classical Goodpasture's (GP) syndrome is a monophasic illness characterized by pulmonary hemorrhage and rapidly progressive glomerulonephritis with linear IgG deposition along the glomerular and distal tubular basement membrane and estructive necrotizing diffuse extracapillary crescentic glomerulonephritis. The majority of patients have circulating anti-glomerular basement membrane (GBM) antibodies, detectable with standard anti-GBM ELISA. Concurrence of GP syndrome with proliferative glomerulonephritis has only rarely been described. In this report, for the first time we describe in a 21-year-old woman GP syndrome with 50% crescentic sclerosing glomerulonephritis with linear immunofluorescence characteristic of anti-GBM pathogenesis, combined with mixed membranous and membranoproliferative glomerulonephritis with granular immunofluorescence and subepithelial, mesangial and subendothelial deposits characterizing immune complex pathogenesis. The clinical picture was also unusual for GP syndrome, manifesting a recurrent but non-progressive course, nephrotic syndrome, normal renal function and low values of anti-GBM antibodies, identified only by novel more sensitive techniques.

Objectives: Type 2 lepra reaction is a Th2-mediated type III hypersensitivity reaction in leprosy, with a characteristic cutaneous manifestation in the form of erythema nodosum leprosum (ENL). We describe unusual presentations of Type 2 lepra reaction in five patients., Methods: Patient data and dermatological findings were analyzed in three men and two women diagnosed with Hansen's disease., Results: Findings included multiple tender, polycyclic, necrotic lesions distributed over the face in one patient, and painful, fluid-filled lesions on both arms and lower limbs in another. The third patient showed erythematous, tender nodules, bullae, and necrotic ulcers over the back and upper and lower limbs. The fourth showed erythematous tender nodules over the face, neck, back, and extremities, predominantly in sun-exposed areas. The fifth revealed multiple erythematous, severely tender nodules and urticarial plaques mimicking those of Sweet's syndrome. Diagnosis of borderline or lepromatous leprosy with atypical Type 2 reaction were made in all cases., Conclusions: Type 2 lepra reactions are antigen antibody-mediated immune complex reactions that present with constitutional symptoms and ENL characterized by tender, erythematous, evanescent nodules mainly on the face, arms, and legs. Over 50% of lepromatous leprosy patients and 25% of borderline lepromatous leprosy patients experienced type 2 lepra reactions prior to the advent of multi-drug therapy. Thalidomide is the drug of choice for severe atypical lepra reactions because of its anti-tumor necrosis factor-α action. Awareness of these atypical variants and prompt diagnosis and treatment are essential to prevent mortality and morbidity in potentially treatable patients., (© 2013 The International Society of Dermatology.)

Von Willebrand factor (VWF), a key player in hemostasis, is increasingly recognized as a proinflammatory protein. Here, we found a massive accumulation of VWF in skin biopsies of patients suffering from immune complex (IC)-mediated vasculitis (ICV). To clarify the impact of VWF on cutaneous inflammation, we induced experimental ICV either in mice treated with VWF-blocking antibodies or in VWF(-/-) mice. Interference with VWF led to a significant inhibition of the cutaneous inflammatory response. We confirmed the major findings in irritative contact dermatitis, a second model of cutaneous inflammation. In vivo imaging of cutaneous inflammation in the dorsal skinfold chamber revealed unaffected leukocyte rolling on anti-VWF treatment. However, we identified that reduced leukocyte recruitment is accompanied by reduced vascular permeability. Although VWF-mediated neutrophil recruitment to the peritoneum was described to require the VWF receptor on platelets (glycoprotein Ibα (GPIbα)), the VWF/GPIbα axis was dispensable for cutaneous inflammation. As assessed in tail bleeding assays, we could exclude interference of VWF blockade with hemostasis. Of particular importance, anti-VWF treatment was effective both in prophylactic and therapeutic administration. Thus, VWF represents a promising target for the treatment of cutaneous inflammation, e.g., leukocytoclastic vasculitis.

Background and Objectives: HIV-associated nephropathy (HIVAN) is well described, but the clinical features of a group of renal pathologies characterized by Ig or immune complex depositions referred to as HIV-associated immune complex kidney disease (HIVICK) have not been well established. The objective of this study is to assess risk factors for HIVICK compared with contemporaneous control participants., Design, Setting, Participants, & Measurements: A nested case-control study of 751 HIV-infected patients followed from January 1996 to June 2010 was conducted. Groups were compared using the chi-squared test or rank-sum analysis. Conditional logistic regression was used to estimate odds ratios (ORs) for HIVICK. Incidences of overall ESRD and with/without combined antiretroviral therapy (cART) exposure were calculated., Results: HIVICK patients were predominantly African American (92%). Compared with matched controls, patients with HIVICK were more likely to have HIV RNA >400 copies/ml (OR, 2.5; 95% confidence interval [95% CI], 1.2 to 5.2), diabetes (OR, 2.8; 95% CI, 1.1 to 6.8), and hypertension (OR, 2.3; 95% CI, 1.2 to 4.5). Compared with HIVAN, patients with HIVICK had more antiretroviral therapy exposure, lower HIV viral loads, and higher CD4 and estimated GFR. ESRD was less common in the HIVICK versus the HIVAN group (30% versus 82%; P<0.001), and the use of cART was not associated with ESRD in HIVICK patients (25% versus 26; P=0.39)., Conclusions: HIVICK was predominantly observed in African-American patients and associated with advanced HIV disease. ESRD incidence is lower in HIVICK patients compared with those with HIVAN. Unlike HIVAN, cART use was not associated with the incidence of ESRD in HIVICK.

Complement factor H (Cfh) is a key regulator of the complement cascade and protects C57BL/6 mice from immune complex-mediated complement-dependent glomerulonephritis. In chronic serum sickness (CSS) there are increased deposits of immune complexes in the glomeruli with inflammation and a scarring phenotype. As cucurmin is an effective anti-inflammatory agent and reduces complement activation, we hypothesized that it should alleviate renal disease in this setting. To determine the effectiveness of curcumin, an apoferritin-induced CSS model in Cfh-deficient (Cfh(-/-)) mice was used. Curcumin treatment (30 mg/kg) given every day in parallel with apoferritin reduced glomerulonephritis and enhanced kidney function (blood urea nitrogen, 45·4 ± 7·5 versus 35·6 ± 5·1; albuminuria, 50·1 ± 7·1 versus 15·7 ± 7·1; glomerulonephritis, 2·62 + 0·25 versus 2 + 0·3, P < 0·05). In line with reduced IgG deposits in mice with CSS given curcumin, C9 deposits were reduced indicating reduced complement activation. Mice treated with curcumin had a significant reduction in the number of splenic CD19(+) B cells and the ratio of CD19 : CD3 cells (P < 0·05) with no change in the T-cell population. Myeloperoxidase assay showed reduced macrophages in the kidney. However, a significant reduction in the M2 subset of splenic macrophages by apoferritin was prevented by curcumin, suggesting a protective function. Curcumin treatment reduced mRNA expression of inflammatory proteins monocyte chemoattractant protein-1 and transforming growth factor-β and matrix proteins, fibronectin, laminin and collagen. Our results clearly illustrate that curcumin reduces glomerulosclerosis, improves kidney function and could serve as a therapeutic agent during serum sickness., (© 2013 John Wiley & Sons Ltd.)

Fcγ receptors I and III are thought to be involved in the development of lupus nephritis. Expression of Fc receptor common gamma chain (FcRγ) is necessary for the stable expression of Fcγ receptors I and III. The aim of this study was to develop a novel agent for the treatment of immune complex related renal disease using a gene regulator, pyrrole(Py)-imidazole(Im) (PI) polyamide, targeting the mouse FcRγ gene promoter. Two PI polyamides targeting FcRγ promoters were designed and synthesized. The effect of the PI polyamides on FcRγ mRNA expression was evaluated in J774.A cells by real-time polymerase chain reaction (PCR), and CD16/32 protein expression was determined by immunocytochemical analysis and flow cytometry. The effects of these polyamides on FcRγ gene expression and CD16/32 protein expression were evaluated in mouse peripheral blood mononuclear cells (PBMCs). One milligram per kilogram body weight of PI polyamide was injected via the tail vein every 2 d for 1 week and PBMCs were collected and analyzed. PI polyamide showed a specific binding to the target DNA in a gel mobility shift assay. Treatment of J774.A cells with 1.0 µM PI polyamide 1 significantly reduced FcRγ mRNA expression and CD16/32 surface protein expression in J774.A cells. Similarly, PI polyamide significantly decreased expression of FcRγ mRNA and CD16/32 in the PBMCs of C57B6 mice. PI polyamide designed to bind the FcRγ promoter decreased FcRγ gene and CD16/32 protein expression. PI polyamide targeting the FcRγ gene may be a novel gene regulator for the prevention of lupus nephritis or other immune complex-related disease.

Binding of Ag-Ab immune complexes to cellular FcgammaR promotes cell activation, release of inflammatory mediators, and tissue destruction characteristic of autoimmune disease. To evaluate whether a soluble FcgammaR could block the proinflammatory effects of immune complexes, recombinant human (rh) versions of FcgammaRIA, FcgammaRIIA, and FcgammaRIIIA were prepared. Binding of rh-FcgammaRIA to IgG was of high affinity (KD=1.7x10(-10) M), whereas rh-FcgammaRIIA and rh-FcgammaRIIIA bound with low affinity (KD=0.6-1.9x10(-6) M). All rh-FcgammaR reduced immune complex precipitation, blocked complement-mediated lysis of Ab-sensitized RBC, and inhibited immune complex-mediated production of IL-6, IL-13, MCP-1, and TNF-alpha by cultured mast cells. Local or systemic delivery only of rh-FcgammaRIA, however, reduced edema and neutrophil infiltration in the cutaneous Arthus reaction in mice. 125I-labeled rh-FcgammaRIA was cleared from mouse blood with a rapid distribution phase followed by a slow elimination phase with a t1/2gamma of approximately 130 h. The highest percentage of injected radioactivity accumulated in blood approximately liver approximately carcass>kidney. s.c. dosing of rh-FcgammaRIA resulted in lower serum levels of inflammatory cytokines and prevented paw swelling and joint damage in a murine model of collagen Ab-induced arthritis. These data demonstrate that rh-FcgammaRIA is an effective inhibitor of type III hypersensitivity.

Tissue damage in autoimmune diseases involves excessive production of reactive oxygen species (ROS) triggered by immune complexes (IC) and neutrophil (PMN) interactions via receptors for the Fc portion of IgG (FcgammaR) and complement receptors (CR). Modulation of both the effector potential of these receptors and ROS generation may be relevant to the maintenance of body homeostasis. In the present study, the modulatory effect of four flavonols (myricetin, quercetin, kaempferol, galangin) on rabbit PMN oxidative metabolism, specifically stimulated via FcgammaR, CR or both classes of receptors, was evaluated by luminol- and lucigenin-dependent chemiluminescence assays. Results showed that flavonol inhibitory effect was not dependent on the cell membrane receptor class stimulated but related to the lipophilicity of the compounds (their apparent partition coefficient values were obtained by high-performance liquid chromatography), and was also inversely related to the number of hydroxyl groups in the flavonol B ring and the ROS-scavenger activity (assessed by the luminol--H2O2--horseradish peroxidase reaction). Under the experimental conditions the flavonols tested were not toxic to PMNs (evaluated by lactate dehydrogenase release and trypan blue exclusion) and did not interfere with IC-induced phagocytosis (evaluated by transmission electron microscopy). Our results suggested that inhibition of IC-stimulated PMNs effector functions by the flavonols tested herein was the result of cooperation of different cellular mechanisms.

Introduction of heterologous anti-glomerular basement membrane antiserum (nephrotoxic serum, NTS) into presensitized mice triggers the production of IgG anti-NTS antibodies that are predominantly IgG2b and the glomerular deposition of pathogenic immune complexes, leading to accelerated renal disease. The pathology observed in this model is determined by the effector cell activation threshold that is established by the coexpression on infiltrating macrophages of the IgG2a/2b restricted activation receptor FcgammaRIV and its inhibitory receptor counterpart, FcgammaRIIB. Blocking FcgammaRIV with a specific monoclonal antibody thereby preventing IgG2b engagement or treatment with high dose intravenous gamma-globulin (IVIG) to down-regulate FcgammaRIV while up-regulating FcgammaRIIB, protects mice from fatal disease. In the absence of FcgammaRIIB, IVIG is not protective; this indicates that reduced FcgammaRIV expression alone is insufficient to protect animals from pathogenic IgG2b immune complexes. These results establish the significance of specific IgG subclasses and their cognate FcgammaRs in renal disease.

Although complement activation can make immune complex glomerulonephritis worse, the third complement component also can solubilize immune complexes and thus reduce the severity of disease. How C3 that is produced within the kidney contributes to this balance is unknown. This study therefore investigated the relative roles of systemic and local C3 production in a model of glomerular immune complex disease. Injection of sheep anti-glomerular basement membrane antibody into preimmunized mice resulted in accumulation of immune complexes and progressive loss of function over 14 d that was much more marked in C3-deficient (C3-/-) mice. In C3-sufficient mice that received a transplant of a C3-/- mouse kidney and in C3-/- mice with C3-sufficient mouse kidney transplants, the severity and the pattern of injury went with the complement status of the recipient. That is, mice with deficient circulating C3 developed severe glomerular immune complex disease, whereas those with a high level of circulating C3 had well-preserved glomerular structure and function. It is concluded that circulating C3 is a critical factor in reducing the glomerular accumulation of immune complexes. Local synthesis of C3 did not have a major influence on this aspect of glomerular disease.

We have studied the therapeutic efficacy of the sodium alginate in experimental immune complex glomerulonephritis. Bovine serum albumin (BSA) nephritis was induced in rats by a subcutaneous immunization and daily intravenous administration of BSA. Sodium alginate at two different doses (25 and 50 mg/kg) was administered intraperitoneally at regular 72-h intervals for 6 weeks. Onset of treatment was day 42. Urinary protein was measured weekly and serum anti-BSA antibody was assessed by ELISA method at different intervals. Animals were euthanized at the 12th experimental week and blood samples and kidney specimens were obtained. BUN, serum creatinine and serum cholesterol and triglyceride were measured at the time of sacrifice. Kidney specimens were processed for light and immunofluorescent microscopic examination. The tolerability and inhibitory effect of LVA on matrix metalloproteinase 2 (MMP-2) were tested using WEHI-164 cell line and zymography method. Results of this experiment showed that treatment with sodium alginate could significantly reduce the urinary protein excretion and serum creatinine in treated rats vs. nontreated controls. Anti-BSA antibody titers were lower in treated rats than in controls at the 12th week post-immunization. There was no significant difference in the level of BUN and serum lipids between two groups. Whereas, glomerular hypercellularity, PMN infiltration and glomerular deposition of BSA were less intense in treated rats vs. controls. Moreover, in vitro examinations revealed that treatment with LVA, as a very safe agent could diminish MMP-2 activity. These results suggest that treatment with sodium alginate as a new immunosuppressive agent can reduce proteinuria, inhibit MMP-2 activity and suppress the antibody production as well as the development of glomerular lesions in a rat model of immune complex glomerulonephritis.

Purpose: To report a case of nodular scleritis and panuveitis associated with erythema elevatum diutinum, a rare immunocomplex-mediated skin disease., Design: Observational case report., Methods: A 22-year-old woman who was diagnosed with erythema elevatum diutinum developed nodular scleritis and panuveitis of the right eye. She had experienced peripheral ulcerative keratitis with corneal perforation., Results: All other known causes of nodular scleritis and panuveitis were investigated and ruled out., Conclusions: Erythema elevatum diutinum should be considered as an underlying systemic disease associated with nodular scleritis and panuveitis as well as peripheral keratitis.

Connective tissue growth factor (CTGF) has been described as a novel fibrotic mediator. CTGF is overexpressed in several kidney diseases and is induced by different factors involved in renal injury. Angiotensin II (AngII) participates in the pathogenesis of kidney damage, contributing to fibrosis; however, whether AngII regulates CTGF in the kidney has not been explored. Systemic infusion of AngII into normal rats for 3 days increased renal CTGF mRNA and protein levels. At day 7, AngII-infused rats presented overexpression of CTGF in glomeruli, tubuli, and renal arteries, as well as tubular injury and elevated fibronectin deposition. Only treatment with an AT(1) receptor antagonist, but not an AT(2), diminished CTGF and fibronectin overexpression and ameliorated tubular damage. In rats with immune complex nephritis, renal overexpression of CTGF was diminished by the ACE inhibitor quinapril, correlated with a diminution in fibrosis. In cultured renal cells (mesangial and tubular epithelial cells) AngII, via AT(1), increased CTGF mRNA and protein production, and a CTGF antisense oligonucleotide decreased AngII-induced fibronectin synthesis. Our data show that AngII regulates CTGF in the kidney and cultured in mesangial and tubular cells. This novel finding suggests that CTGF could be a mediator of the profibrogenic effects of AngII in the kidney.

Background: Emerging evidence suggests that angiotensin II (Ang II) is not only a vasoactive peptide, but also a true cytokine that regulates cell growth, inflammation and fibrosis. Many studies have demonstrated that this peptide plays an active role in the progression of renal injury. Some of Ang II-induced effects are mediated by the production of a large array of growth factors. The aim of this study was to investigate whether Ang II could regulate the expression of cytokines and chemokines in the kidney and its correlation with the Ang II-induced renal damage., Methods: The model of Ang II-induced renal damage was done by systemic Ang II infusion into normal rats (50 ng/kg/min; subcutaneous osmotic minipumps). In addition, the implication of Ang II was investigated in a model of immune complex nephritis in rats treated with the angiotensin converting enzyme (ACE) inhibitor quinapril. The mRNA expression was analyzed by RT-PCR and/or Northern blot, and protein levels by Western blot and/or immunohistochemistry., Results: Rats infused with Ang II for 3 days caused elevated renal expression of tumor necrosis factor-alpha (TNF-alpha; gene and protein levels). TNF-alpha positive cells were observed in glomeruli (mainly in endothelial cells), tubules and vessels. In rats with immune complex nephritis, the renal overexpression of TNF-alpha was diminished by the ACE inhibitor quinapril. Systemic infusion of Ang II also increased renal synthesis of cytokines (interleukin-6, IL-6) and chemokines (monocyte chemoattractant protein-1; MCP-1) that were associated with elevated tissue levels of activated nuclear factor-kappaB (NF-kappaB) and the presence of inflammatory cell infiltration., Conclusions: Ang II in vivo increases TNF-alpha production in the kidney. Ang II also up-regulates other proinflammatory mediators, including IL-6, MCP-1 and NF-kappaB, coincidentally associated to the presence of glomerular and interstitial inflammatory cells in the kidney. All these data further strengthen the idea that Ang II plays an active role in the inflammatory response in renal diseases.

Undesired activation of the complement system is a major pathogenic factor contributing to various immune complex diseases and conditions such as hyperacute xenograft rejection. We aim for prevention of complement-mediated damage by specific inhibition of the classical complement pathway, thus not affecting the antimicrobial functions of the complement system via the alternative pathway and the lectin pathway. Therefore, 42 peptides previously selected from phage-displayed peptide libraries on basis of C1q binding were synthesized and examined for their ability to inhibit the function of C1q. From seven peptides that showed inhibition of C1q hemolytic activity but no inhibition of the alternative complement pathway, one peptide (2J) was selected and further studied. Peptide 2J inhibited the hemolytic activity of C1q from human, chimpanzee, rhesus monkey, rat, and mouse origin, all with a similar dose-response relationship (IC(50) 2-6 microM). Binding of C1q to peptide 2J involved the globular head domain of C1q. In line with this interaction, peptide 2J dose-dependently inhibited the binding of C1q to IgG and blocked activation of C4 and C3 and formation of C5b-9 induced via classical pathway activation, as assessed by ELISA. Furthermore, the peptide strongly inhibited the deposition of C4 and C3 on pig cells following their exposure to human xenoreactive Abs and complement. We conclude that peptide 2J is a promising reagent for the development of a therapeutic inhibitor of the earliest step of the classical complement pathway, i.e., the binding of C1q to its target.

Treatment with cyclosporin A (CsA) improves proteinuria and reduces renal cellular infiltration in chronic serum sickness (CSS). We examined if these effects were associated with a reduced renal expression of CD54 and its ligands, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and MHC class II molecules. We studied two groups of rats in which CSS was induced by daily injections of ovalbumin (OVA): a group treated with CsA (OVA.CsA group, n = 11) and a group that received no treatment (OVA.CSS group, n = 11). An additional group of five rats (control group) received only phosphate buffer. Immunostaining techniques were used to follow CSS and to study the expression of CD54, CD18, CD11b/c, IFN-gamma, TNF-alpha and MHC class molecules. Proteinuria (mg/24 h) was reduced from 248.2 +/- 73.1 (OVA.CCS group) to 14.5 +/- 13.1 with CsA treatment (P < 0.0001). The renal expression of CD54 and its ligands (CD18 and CD11b/c) was reduced by 50% to 75%. Correspondingly, there was a 60% to 85% reduction in the number of infiltrating leucocytes. The number of cells expressing TNF-alpha, IFN-gamma and MHC II molecules was also reduced. CsA reduces expression of CD54 and its ligands. This effect is associated with a reduction of cellular infiltration, IFN-gamma, TNF-alpha-producing cells and with MHC II expression in the kidney. These findings suggest that expression of adhesion molecules plays a critical role in CSS and underline the importance of cellular immunity in this experimental model.

Macrophage Fcgamma receptors have an important role in host defense and the pathophysiology of immune mediated disorders. Alteration of splenic macrophage Fcgamma receptors expression predisposes to severe infection. Inhibition or blockade of splenic macrophage Fcgamma receptors is one of the mechanisms by which immune cytopenias improve. Dopaminergic drugs have clinically significant regulatory functions on the immune response. Using an experimental model in the guinea pig we assessed the effect of commonly used dopaminergic drugs on the expression of macrophage Fcgamma receptors. Three dopa-antagonists, bromocryptine, leuprolide, and pergolide, and seven dopa-antagonists, chlorpromazine, SCH 23390, metochlopramide, sulpiride, veralipride, alizapride, and cisapride, were studied. Following guinea pig treatment with dopaminergic drugs, the clearance of IgG-sensitized RBCs in vivo, the in vitro binding of IgG-sensitized RBCs by isolated splenic macrophages and flow cytometry with monoclonal antibodies were performed. Treatment with dopa-agonists enhanced the clearance of IgG-sensitized RBCs, the in vitro binding of IgG-sensitized RBCs by isolated splenic macrophages, and the cell surface expression of both macrophage Fcgamma receptors, and vice versa, dopa-antagonists impaired macrophage Fcgamma receptors expression. Macrophage FcgammaR1,2 was more sensitive than FcgammaR2 to such dopaminergic effect. These alterations of macrophage Fcgamma receptors expression are mediated by both D1 and D2 dopamine receptors, with a major participation of D2 receptors. Dopaminergic drugs alter the clearance of IgG-coated cells by an effect at the expression of splenic macrophage Fcgamma receptors., (Copyright 1999 Academic Press.)

Neutrophils play an important part in the development of acute inflammatory injury. Human neutrophils contain high levels of the serine protease elastase, which is stored in azurophilic granules and is secreted in response to inflammatory stimuli. Elastase is capable of degrading many components of extracellular matrix [1-4] and has cytotoxic effects on endothelial cells [5-7] and airway epithelial cells. Three types of endogenous protease inhibitors control the activity of neutrophil elastase, including alpha-1 protease inhibitor (alpha-1PI), alpha-2 macroglobulin and secreted leukoproteinase inhibitor (SLPI) [8-10]. A disturbed balance between neutrophil elastase and these inhibitors has been found in various acute clinical conditions (such as adult respiratory syndrome and ischemia-reperfusion injury) and in chronic diseases. We investigated the effect of NX21909, a selected oligonucleotide (aptamer) inhibitor of elastase, in an animal model of acute lung inflammatory disease [11-14]. This inhibitor was previously selected from a hybrid library of randomized DNA and a small-molecule irreversible inhibitor of elastase (a valine diphenyl ester phosphonate, Fig. 1), by the blended SELEX process [15]. We show that NX21909 inhibits lung injury and neutrophil influx in a dose-dependent manner, the first demonstration of efficacy by an aptamer in an animal disease model.

The present study is a prospective, controlled, blinded trial of enalapril therapy in experimental immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate (cynomolgus monkey [CYN]). Two groups of CYNs were studied: those with established GN (study A) and those in which GN was being induced (study B). In study A, 12 CYNs had GN established by 8 or 10 weeks of daily intravenous infusion of bovine gamma-globulin (BGG). These CYNs were then assigned to either 4 weeks of daily oral enalapril therapy (n = 6) or daily oral placebo therapy (n = 6). The daily BGG infusions were continued during the 4 weeks of enalapril or placebo therapy. At the start of the enalapril/placebo protocol, the two groups were similar with respect to proteinuria and level of precipitating antibody to BGG, which determined the daily BGG dose. Renal biopsy was performed in each CYN at the start and end of the 4-week period of enalapril/placebo protocol. In study B, 15 normal CYNs were immunized to BGG over a period of 4 weeks. The CYNs were then assigned to daily oral enalapril therapy (n = 8) or placebo therapy (n = 7) based on level of precipitating antibody to BGG. At this point, daily intravenous BGG was begun along with daily enalapril or placebo for 8 weeks. Renal biopsy was performed in each CYN before and at the end of this 8-week period. In study A, enalapril therapy was associated with a significant decrease in mesangial matrix volume (mean change, -27.7%; P = 0.031) and a trend toward decreased mesangial matrix deposits (mean change, -34.1%; P = 0.188). By contrast, in CYNs receiving placebo therapy, mesangial matrix volume increased compared with the enalapril group (P = 0.002) and mesangial deposits were unchanged. In study B, both the enalapril and placebo groups showed significant increases in mesangial matrix volume, mesangial deposits, mesangial cell volume, and capillary wall deposits during the 8 weeks of daily BGG infusion. However, none of the differences between the groups achieved statistical significance. Changes in mesangial cell volume and capillary wall deposits were also evaluated in study A and study B, but were not found to be different between the enalapril and placebo groups. In both study A and study B, blood pressure was lower in the enalapril groups. In conclusion, in the initial phase of IC-GN induction (0 to 8 weeks), enalapril therapy does not significantly influence the glomerular accumulation of mesangial matrix or immune deposits. However, in established IC-GN (after 8 weeks of GN induction), enalapril therapy significantly decreases the further accumulation of mesangial matrix and may decrease the further accumulation of mesangial deposits. Whether this benefit of enalapril therapy was related to lower blood pressure or to other effects of angiotensin-converting enzyme (ACE) inhibition was not determined in this study.

The effect of a newly developed free radical scavenger (OPC-15161) on the progression of nephrotoxic serum (NTS) nephritis was evaluated. NTS nephritis rats were sacrificed immediately before and 1, 2, 3, 6, and 24 h and 13 and 19 days after intravenous injection of NTS. The tissue content of phosphatidylcholine hydroperoxide, the activity of superoxide, the activity of superoxide dismutase in the renal cortex, and the serum malondialdehyde levels were measured. The phosphatidylcholine hydroperoxide content in the renal cortex of OPC-15161-treated NTS nephritis rats was lower than that in the control rats 24 h after NTS injection. The activity of superoxide dismutase in OPC-15161-treated rats was sustained in contrast to the decrease in this activity in the control rats 6 h after injection of NTS. The effects of OPC-15161, dipyridamole, and prednisolone on NTS nephritis rats were investigated. OPC-15161 (20 mg/kg p.o.) showed a potent inhibitory effect on the urinary protein excretion, whereas dipyridamole (30 and 100 mg/kg p.o.) and prednisolone (2 mg/kg p.o.) had less suppressive effects. In view of these results, we conclude that OPC-15161 notably ameliorated the urinary protein excretion by way of the suppression of lipid peroxidation in the renal tissue of NTS nephritis rats.

The treatment of autoimmune and immune complex diseases of the vascular bed consists--similarly as of immunopathologic processes of other systems--in the use of risky immunosuppressive agents and antiinflammatory as well as symptomatic therapy. In the article the author informs about the possibility to use in these indications (and in addition also in other angiologic diseases) the systemic enzyme therapy, residing in the oral application of high-dosed combinations of several animal and plant proteolytic enzymes. About four tens years of positive medical empirical experience have been supported by a concentrated sophisticated research and approximately 150 clinical studies according to GCP. These revealed in most autoimmune and immune complex diseases a surprisingly high effectiveness and complete harmlessness of the enzyme therapy. After the short introduction mentioning the important indications for enzyme therapy in the field of clinical immunology, the major attention is paid to the results of enzymotherapy in angiology. Strong evidence indicates that enzymotherapy ameliorates the disturbed composition and properties of blood and vessel walls, acts preventively as well as therapeutically in thromboses, thromboflebitides and consequences of venous insufficiency; it seems be prospective in afflictions of arterial bed, including vasculitides and glomerulonephritides, also. The key feature of enzymotherapy is the immunomodulatory activity. There exists a strong evidence for the favourable modulation of pathogenic autoantibodies, inhibition of the neogenesis of immune complexes and cleavage of their deposits, normalization of the T cell system, network of cytokines, adhesion molecules and inflammatory cascades. Besides the direct peptidolytic and proteolytic effects of hydrolases, the indirect effects realized in the course of interaction between the resorbed enzymes and their natural "partners"--antiproteases (mainly alfa-2-macroglobulin)--have become a topic of intensive research. The author feels, that systemic enzyme therapy should become a regular component of the treatment of immunopathologic processes in general and of angiologic diseases specially. (Ref. 42.).

Background & Aims: Proinflammatory cytokines such as interleukin (IL) 1, IL-8, and tumor necrosis factor (TNF) have been implicated as primary mediators of intestinal inflammation. The aim of the present study was to determine the effects of a novel cytokine antagonist (CGP 47969A) in a rabbit model of acute colitis., Methods: Colitis was induced using the formalin-immune complex technique. Animals were pretreated intrarectally with CGP 47969A (30, 10, or 3 mg/kg), hydrocortisone (0.8 mg/kg), or vehicle (4 mL saline) 2 hours before the induction of colitis and twice daily thereafter until death 48 hours after the induction of colitis. The severity of inflammation of colonic tissue was assessed using histological analysis and myeloperoxidase activity assay, and IL-1 alpha, IL-8, TNF-alpha, and IL-1 receptor antagonist levels were determined., Results: Compared with vehicle, CGP 47969A (10 mg/kg) significantly reduced the acute inflammatory index by 58%, edema by 67%, necrosis by 99%, and myeloperoxidase activity by 49% (all P < 0.02) with efficacy similar to that of steroids. These effects were associated with a significant inhibition of colonic IL-1 alpha and IL-8 by 56% and 90%, respectively (p < 0.01)., Conclusions: Administration of CGP 47969A reduces inflammation and tissue damage in rabbit immune complex colitis through mechanisms involving the inhibition of mucosal proinflammatory cytokines.

Cicatricial pemphigoid is an autoimmune subepidermal blistering disease of the skin and mucous membranes. We report on eight patients in whom the clinical diagnosis was confirmed by direct immunofluorescence. The patients' age averaged 69 years; seven were female and one male. Initial symptoms were erosions of the oral mucous membranes in four patients, skin blisters in three patients, and in one patient an ocular involvement was the first manifestation of the disease. Indirect immunofluorescence on NaCl-split human skin revealed circulating IgG antibodies binding to the roof of the artificial blister in three patients. Immunoblotting of epidermal and dermal extracts disclosed binding of IgG antibodies of one of these patients to an epidermal 230-kD protein, whereas IgA-antibodies showed no specific binding. In four of five patients with a strong ocular involvement IgA deposits were found by direct immunofluorescence. These studies were done on biopsies of perilesional skin or oral mucous membranes, and they were positive in one patient even before the first ocular lesions appeared. Therefore, finding of IgA deposits by direct immunofluorescence may be taken as a prognostic criterion allowing selection of the proper treatment. We treated six patients with a dexamethasone-cyclophosphamide pulse therapy, while two patients received dapsone orally. The involvement of skin and oral mucous membrane responded well to both regimens, whereas the ocular lesions were progressive, except in one patient. On the basis of our eight cases, we discuss both options and limitations in the treatment of cicatricial pemphigoid and review new aspects of the pathogenesis of this disease.

We report on a 2-year-old girl with chronic bullous disease of childhood (CBDC). Concomitantly with a feverish gastrointestinal infection caused by Salmonella enteritidis, the child presented with lesions resembling impetigo contagiosa on the legs and face. Following antibiotic treatment with cephalosporins p.o. and flucloxacillin i.v. she developed typical symptoms of CBDC, i.e. tense blisters on erythematous skin in the perineal area, on the flexor aspects of the thighs and upper arms and on the face. Direct immunofluorescence revealed a linear IgA deposition along the basement membrane zone, confirming the diagnosis of CBDC. These lesions cleared rapidly after treatment with dapsone p.o. This case prompted us to consider new aspects of the pathogenesis, clinical entity and treatment of this rare bullous disease of childhood.

The inhibitory actions of thunberginol A on anti-allergic (type I-IV) activity were examined. Oral administration of thunberginol A 2 hr before the challenge significantly inhibited the PCA reaction (type I) in rats at a dose of more than 300 mg/kg and the ear PCA reaction in mice at a dose of more than 50 mg/kg. Thunberginol A at a dose of more than 300 mg/kg also significantly inhibited the allergic bronchoconstriction in rats. Thunberginol A concentration-dependently (10(7)-10(-4), 10(-5)-10(-4) M) inhibited the allergic contractions of rat trachea sensitized with IgE and those of the guinea pig lung preparation sensitized with IgG. It also inhibited the allergic histamine release from sensitized peritoneal exudate cells in a concentration-dependent manner (10(-5)-10(-4) M). Thunberginol A had anti-serotonic activity on the contraction of smooth muscle, and it increased the ear vascular permeability in mice. Thunberginol A significantly inhibited the primary response of contact dermatitis (type IV) in mice at 100 mg/kg from the day after immunization to the day before challenge, and it also inhibited the delayed type foot pad swelling in mice at a dose of more than 300 mg/kg at 0 and 8 hr after the challenge. These findings suggest that orally administered thunberginol A is effective against type I and type IV allergy.

Seven patients with Sjögren's syndrome (6 with primary and 1 with secondary form of the syndrome developing during SLE) were treated with TFX Polfa in ampoules of 10 mg during 6-12 month. Before the treatment, besides evaluation of the general clinical condition, the following immunological parameters were determined: IgG, IgA and IgM levels, absolute lymphocyte count, T-cell and B-cell counts, absolute neutrophil count, antinuclear antibodies, circulating immune complexes and skin tests with recall antigens (tuberculin and distreptase). The clinical condition of the patients was determined at monthly intervals and the immunological investigations were repeated after the treatment which lasted 6-12 months. In all patients alleviation was observed of the clinical manifestations of the disease with decreased proneness to infections. In some patients improvement was observed of the determined immunological parameters, in the first place, reversal of cutaneous tests from negative to positive.

Twelve Beagles were inoculated with concanavalin A, and after a mean ninefold increase in antibody titer, 1 mg of concanavalin A was infused into each renal artery of each dog to induce in situ immune complex glomerulonephritis. Starting 4 weeks after renal arterial infusion, 6 dogs were treated orally 3 times daily with 30 mg of 3-methyl-2 (3 pyridyl)-1-indolectanoic acid (CGS 12970)/kg of body weight, a thromboxane synthetase inhibitor, and 6 dogs (control group) received a gelatin capsule 3 times daily. Endogenous creatinine clearance and 24-hour urinary excretion of protein and thromboxane B2 were determined for each dog prior to renal arterial infusion, at the initiation of treatment and at 2, 4, 6, and 8 weeks after initiation of treatment. In addition, methyoxy-3H inulin clearance was determined at initiation of treatment and 4 and 8 weeks later. Renal specimens were examined histologically at the initiation of treatment and 4 and 8 weeks later. Glomerular mononuclear profiles/microns 3 were determined from at least 10 equatorially sectioned glomeruli from each dog. Paired t tests were used to compare mean values at the various time points to the respective mean baseline value and 2-sample t tests were used to evaluate differences between treatment groups. At the start of treatment (4 weeks after renal arterial infusion of concanavalin A), histologic evaluation of renal specimens revealed glomerular epithelial crescent formation, mononuclear cell proliferation, and infiltration of neutrophils. Mononuclear cell profiles and urinary excretion of protein and thromboxane B2 were significantly increased, but endogenous creatinine clearance values were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)