IgM Deposits Research Articles

Co-Deposition of IgM and C3 May Indicate Unfavorable Renal Outcomes in Adult Patients with Primary Focal Segmental Glomerulosclerosis

Background/Aims: We aimed to investigate the effects of glomerular IgM and C3 deposition on outcomes of adult patients with primary focal segmental glomerulosclerosis (FSGS). Methods: In this retrospective analysis, 86 consecutive adult patients with biopsy-proven primary FSGS were stratified into 3 groups according to their histopathological features: IgM– C3–, IgM+ C3–, and IgM+ C3+. Primary outcome was defined as at least a 50% reduction in baseline estimated glomerular filtration rate (eGFR) or development of kidney failure, while complete or partial remission rates were secondary outcomes. Results: Glomerular IgM deposits were found in 44 (51.1%) patients, 22 (25.5%) of which presented with accompanying C3 deposition. Patients in IgM+ C3+ group had higher level of proteinuria (5.6 g/24 h [3.77–8.5], p = 0.073), higher percentage of segmental glomerulosclerosis (20% [12.3–27.2], p = 0.001), and lower levels of eGFR (69 ± 37.2 mL/min/1.73 m2, p = 0.029) and serum albumin (2.71 ± 0.85 g/dL, p = 0.045) at the time of diagnosis. Despite 86.3% of patients in IgM+ C3+ group (19/22) received immunosuppressive treatment, the primary outcome was more common in patients in the IgM+ C3+ group compared with patients in IgM+ C3– and IgM– C3– groups (11 [50%] vs. 2 [9%] and 11 [26.1%] respectively [p = 0.010]). Complete or partial remission rates were lower in patients in the IgM+ C3+ group (5/22, 22.7%), as well (p = 0.043). Multivariate Cox regression analysis revealed that IgM and C3 co-deposition was an independent risk factor associated with primary outcome (hazard ratio 3.355, 95% CI 1.349–8.344, p = 0.009). Conclusions: Glomerular IgM and C3 co-deposition is a predictor of unfavorable renal outcomes in adult patients with primary FSGS.

Direct Immunofluorescence Studies in Lichen Planus.

Lichen planus is a common, usually intensely pruritic, symmetrical, papulosquamous dermatosis. Direct immunofluorescence studies in patients with lichen planus shows deposition of multiple immunoglobulins and fibrin at the dermoepidermal junction and in the colloid bodies. Histopathological features were analysed in 100 cases of lichen planus which were sent for routine histology. Direct immunofluorescence studies were done in 22 out of the 100 cases and the features were analysed. Clinical data was recorded from patient files. Positive direct immunofluorescence was seen in 78.5% of the cases. Deposits at the dermoepidermal junction and colloid bodies were detected in 88% and 40% of the cases respectively. IgG, IgM and C3 deposition was seen in 88%, 70% and 24% respectively. IgA was negative in all the cases. The linear and shaggy deposition of immunoreactants in a discontinuous form along the dermoepidermal junction and in the colloid bodies were indicators in support of lichen planus along with the characteristic histopathological findings. In lupus erythematosus, linear and granular deposition of immunoglobulins in a continuous form is found along the dermoepidermal junction. Direct immunofluorescence studies are of immense help in disease differentiation in cases of interface dermatitis with no specific histological or clinical characteristics and in cases with ambiguous features.

Activation of B-1 Cells Promotes Tumor Cell Killing in the Peritoneal Cavity.

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the antitumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer-induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B-cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice, restored MPL/TDCM-induced protection in mice with B-cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell-produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases. SIGNIFICANCE: This work identifies a critical antitumor role for innate-like B cells localized within the peritoneal cavity and demonstrates a novel strategy to activate their tumor-killing potential.See related commentary by Tripodo, p. 5.

Analysis of the relationship between Oxford classification, IgM deposition and multiple indexes and the adverse prognosis of patients with primary IgA nephropathy and related risk factors.

The risk and influencing factors of prognosis in patients with primary IgA nephropathy (IgAN) were explored. One hundred and twenty-four patients who were diagnosed with IgA nephropathy in West China Hospital of Sichuan University were selected as the study subjects. The baseline data were recorded. All patients were followed up for 3 years. Patients with poor prognosis were defined as poor prognosis group, and the patient with no adverse prognosis was defined as a good prognosis group during the follow-up period. The risk factors that may affect the prognosis of patients with IgAN were analyzed by single factor analysis. The influence of all factors that were statistically significant on the prognosis of the patients was further evaluated by multifactor Cox regression. The single factor analysis and multivariate Cox proportional hazard model showed that patients with 24 h urinary protein, pathological type, Oxford classification (T1+T2), Lee (grade IV) and mesangial IgM deposition were independent factors of patients, and the difference was statistically significant, their P-values were 0.041, 0.046, 0.037, 0.043, and 0.028, respectively. Patients with 24 h urinary protein, pathological type, Oxford classification (T1+T2), Lee (grade IV) and mesangial IgM deposition can be used as independent factors affecting poor prognosis in primary IgAN patients. It provides evidence for early detection of high-risk IgA nephropathy.

DYSPNEA IN THE CONGO LINE

SESSION TITLE: Lung Pathology 1 SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Amyloidosis is a spectrum of diseases characterized by the extracellular infiltration of fibrillar proteins into various tissues of the body. Organs typically involved include the heart and kidneys, but other organs can be affected as well. Amyloidosis isolated to the lungs is reported rarely in the literature. CASE PRESENTATION: We present a case of a 45-year-old male who presented to the pulmonary clinic for an abnormal CT scan of his chest. His medical history included latent tuberculosis, Sjogren’s syndrome, testicular cancer, and chronic kidney disease with a renal biopsy showing mesangial IgM deposition. He reported a 30-pack year smoking history. His exam was remarkable only for poor dentition. CT of his chest revealed multiple cysts and nodules, and his pulmonary function tests showed only borderline air trapping. He was counseled on smoking cessation. Six months later, he began to experience dyspnea and fatigue, and PFTs revealed a new mild obstructive pattern. Repeat chest CT demonstrated enlarging nodules and ground glass opacities. PET CT showed avidity of a cystic lesion in the left lung as well as asymmetry in parotid gland avidity. Bronchoscopy discovered diffuse mucosal friability and endobronchial lesions at the right middle lobe takeoff as well as the left lower lobe. Endobronchial biopsy results described amorphous material with Congo red staining consistent with amyloidosis. Bone marrow biopsy, echocardiogram, and fat pad biopsy were all negative for evidence of systemic disease. Parotid gland biopsy revealed marginal zone lymphoma. Treatment with bedamustine and rituximab resulted in symptom and imaging stabilization. DISCUSSION: Amyloidosis is characterized by apple-green birefringence under polarized light after Congo red staining. Disease can be localized or systemic, hereditary or acquired, and primary or secondary. Amyloidosis affecting the lung is usually associated with systemic disease, but localized forms can also occur. These localized forms tend to be of the tracheobronchial subtype as opposed to nodular or alveolar-septal types and composed of AL fibril proteins. Most case reports of tracheobronchial amyloidosis in the literature describe middle-aged patients with a slight predilection for males. Symptoms generally include dyspnea, cough, wheezing, and hemoptysis. CT scan of the chest is important for identifying abnormalities but endobronchial tissue sampling is necessary for diagnosis. Interestingly, nodular AL pulmonary amyloidosis, which is generally associated with systemic disease, has been associated with MALT lymphoma. Localized tracheobronchial amyloidosis in the setting of MALT lymphoma appears to be less frequently described but has been associated with Sjogren’s disease. CONCLUSIONS: Recognition of atypical presentations of amyloidosis can lead to earlier interventions and diagnosis of associated systemic disease. Reference #1: Khoor, A., & Colby, T. V. (2017). Amyloidosis of the Lung. Archives of Pathology & Laboratory Medicine, 141(2), 247–254. https://doi.org/10.5858/arpa.2016-0102-RA DISCLOSURES: No relevant relationships by Audrey Haywood, source=Web Response

Role of Direct Immunofluorescence in Cutaneous Small-Vessel Vasculitis: Experience From a Tertiary Center.

Skin is commonly affected by vasculitic process and often subjected to biopsy. Cutaneous vasculitis can be either primary or part of a systemic vasculitic process. This study was conducted to evaluate the diagnostic utility of direct immunofluorescence (DIF) in determination of etiology of cutaneous vasculitis. All histologically proven cases of cutaneous vasculitis over the past two and half years were retrospectively analyzed along with their clinical and DIF findings (IgG, IgA, IgM, and C3). Within this study period, a total of 198 cases of small-vessel vasculitis were diagnosed based on skin biopsy and DIF findings. The mean age of patients was 31.2 years (range 1-84 years) with slight male dominance (M:F ratio 1.06:1). Henoch-Schonlein purpura/IgA vasculitis was the commonest clinical diagnosis (31%), followed by urticarial vasculitis (11%) and others. Idiopathic vasculitis was suspected in 33% cases. Overall, DIF was positive in 60% (119/198) cases, with vascular deposition of IgA being commonest, followed by C3. The clinical diagnosis of Henoch-Schonlein purpura could be confirmed in 61.5% (40/65) cases by DIF, whereas another 20 unsuspected cases were picked up as IgA vasculitis based on DIF findings. DIF findings confirmed lupus vasculitis in 50% cases. Other cases showed variable nonspecific deposition of C3 and IgM in 42% cases. DIF can be highly useful to classify cutaneous vasculitis, with maximum efficacy for diagnosis of IgA vasculitis and lupus vasculitis. It can aid in the accurate diagnosis even when the histological changes are minimal. All cases of suspected cutaneous vasculitis should be subjected to DIF.

Comprehensive evaluation of the significance of immunofluorescent findings on clinicopathological features in IgA nephropathy.

The clinicopathological significance of immunofluorescent findings in IgA nephropathy remains controversial. The relations of the deposition of IgA, IgG, IgM, C3, C1q and fibrinogen (Fib) with pathological findings, baseline clinical findings, and renal outcome were evaluated in 688 patients with IgA nephropathy. Pathological features included cellular or fibrocellular crescents, endocapillary or mesangial hypercellularity, segmental or global glomerulosclerosis and the Oxford classification. The median age at biopsy was 30years. There were 289 men. With 74months median follow-up, 32% of patients received steroids. Twelve percent of patients developed end-stage renal disease (ESRD). The degree of IgA was closely related to the degree of C3, IgG and IgM deposition. The degree of IgA, C3, IgG and Fib deposition was significantly related to the percentage of glomeruli with crescent, endocapillary and mesangial hypercellularity. IgM deposition showed significant association with crescent, mesangial hypercellularity, segmental sclerosis, global glomerulosclerosis and tubular atrophy/interstitial fibrosis. In the patients treated with steroids, the risk for ESRD in patients with 2-3+ IgA deposition was significantly lower with reference of 1+ IgA deposition. We found the different roles of glomerular immune reactants' deposition in the inflammatory process from acute to chronic stage. IgA deposition together with IgG, Fib and C3 may produce acute inflammatory injury. IgM deposition might occur in the early stage of inflammation and remains until late sclerotic stage. The prominent deposition of IgA related to low risk for ESRD in patients who received steroids might suggest effectiveness of steroids in such patients.

Spontaneous remission of adult-onset minimal change nephrotic syndrome associated with influenza B infection: a case report

BackgroundWhile the majority of adult-onset minimal change nephrotic syndrome (MCNS) is a primary or an idiopathic form of disease, it can also occur as a secondary form. Reports on the spontaneous remission of MCNS are rare since the condition is typically treated with corticosteroids. We herein describe the spontaneous remission of adult-onset MCNS in a patient who developed nephrotic syndrome after type B influenza infection.Case presentationA 50-year-old woman experienced fever, cough, malaise, and low back pain, which had persisted for 6 days before she presented to our hospital, and edema of the face and limbs, which had persisted for 5 days before her presentation. She was diagnosed with type B influenza infection and later exhibited an exacerbation of facial edema, decreased urine output, and a high level of proteinuria. She was referred to our department after the diagnosis of nephrotic syndrome. On admission, her proteinuria level was 20.88 g/gCr and her selectivity index value was 0.13. The examination of a kidney biopsy specimen obtained on the fourth day of hospitalization under a light microscope revealed minor abnormalities. An immunofluorescence showed only nonspecific granular IgM deposits in the mesangium. Electron microscopy showed extensive foot process effacement without any immune complex deposits. Based on these findings, the patient was diagnosed with MCNS. After admission, the proteinuria decreased to 0.06 g/gCr with rest and sodium restriction (6 g/day) alone; a complete remission from nephrotic syndrome was observed at approximately 2 weeks after the onset of symptoms. There have been no signs of recurrence of nephrotic syndrome in the one years since.ConclusionWe experienced a rare case in which spontaneous remission of MCNS occurred within a short period of 2 weeks after influenza B infection. When patients present with nephrotic syndrome after an infection, it is necessary to consider MCNS in the differential diagnosis, which also includes post-infectious glomerulonephritis and the acute exacerbation of IgA nephropathy.

Clinical and prognostic significance of glomerular C1q deposits in primary MN

BackgroundAlthough complement activation is believed to be important in mediating PMN, the pathways involved and clinical consequences remain controversial. Many cases of idiopathic or primary membranous nephropathy (PMN) present with subepithelial C1q deposits along with IgG and C3 on glomerular capillary walls but without deposits of IgA or IgM (“full house”) by immunofluorescence or any causes of secondary MN. We sought to define the clinical and pathological significance of these C1q deposits in PMN by comparing a variety of clinical parameters, outcomes and other serum and urine factors in patients with and without significant glomerular C1q deposits. MethodsTwo-hundred eighty-eight patients with biopsy-proven PMN were enrolled. We compared the clinical and pathological features, treatment responses and kidney outcomes, between patients with and without C1q deposition. Circulating anti-PLA2R antibodies and complement components in plasma and urine were detected by ELISA. ResultsGlomerular C1q deposition was detected on capillary walls by immunofluorescence in 66/288 (22.9%) patients. C1q-positive patients presented with lower concentrations of serum IgG (5.3 ± 3.1 vs. 6.6 ± 3.5 g/l, p = 0.008), a higher frequency of IgA (37.9% vs. 15.8%, p < 0.001), IgM (48.5% vs. 31.5%, p = 0.011) and C3c (100% vs. 88.3%, p = 0.004) deposits in glomeruli and more stage III of MN (24.2% vs. 11.7%, p < 0.001) by pathologic criteria. Other features, including gender, age, anti-PLA2R antibody positivity and concentrations, proteinuria, albumin and serum creatinine, were not different between the patients with and without C1q deposition (p > 0.05). The IgG subclasses of anti-PLA2R antibodies in circulation or in glomeruli showed no difference (p > 0.05). C1q deposition, and C1q concentrations in circulation and urine had no apparent effect on the treatment responses or kidney outcomes (p > 0.05). ConclusionThe classical pathway of complement is activated in some patients with PMN, but may not play an essential role in mediating the kidney injury seen in this disease.

Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy

IntroductionCobalamin C (cblC) deficiency is the most common inborn error of vitamin B12 metabolism. Renal failure attributed to thrombotic microangiopathy (TMA) has occasionally been described in the late-onset presentation of cblC deficiency, but kidney lesions associated with cblC deficiency remain poorly defined. This study aims to describe the characteristics of kidney disease in cblC deficiency, and to provide a comparative histological analysis with cblC-independent renal TMA.MethodsWe performed a multicenter retrospective study including 7 patients with cblC deficiency and 16 matched controls with cblC-independent TMA. The patients included were aged 6 to 26 years at the time of the first manifestations. All patients presented with acute renal failure, proteinuria, and hemolysis; 5 patients required dialysis.ResultsThe histological study revealed arteriolar and glomerular TMA in all patients. After comparison with the cblC-independent TMA control group, a vacuolated aspect of the glomerular basement membrane and the intensity of glomerular capillary wall IgM deposits were more present in cblC deficiency patients than in controls. Six patients were treated with hydroxycobalamin. All of them improved, with disappearance of hemolysis, and 3 of the 4 patients requiring renal replacement therapy were weaned off dialysis.ConclusionThis study provides a precise description of kidney pathology in cblC deficiency. Due to major therapeutic implications, we suggest that patients with renal TMA be screened for cblC deficiency regardless of age, particularly when the kidney biopsy provides evidence of long-lasting TMA, including a vacuolated aspect of the glomerular basement membrane and glomerular capillary wall IgM deposition.

Intracapillary monoclonal deposits disease due to B-cell non-Hodgkin lymphoma: A case report and review of the literature

Intracapillary monoclonal deposits disease is a rare kidney disorder defined by the presence of intracapillary monoclonal IgM deposits that completely obstruct glomerular capillary lumina. It is typically associated with Waldenstrom macroglobulinemia and significant levels of circulating monoclonal IgM. We describe a patient that presented with nephrotic range proteinuria, rapidly rising serum creatinine, and low levels of biclonal IgM. Kidney biopsy showed intracapillary monoclonal deposits disease with a membranoproliferative pattern and focal crescent formation. Subsequent bone marrow biopsy revealed marginal zone lymphoma. Despite treatment, the patient rapidly progressed to end-stage renal disease. Patients with indolent lymphomas and low levels of circulating clonal IgM may present with aggressive renal disease due to IgM deposition.

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome

BackgroundBoth dysfunctional neuropeptide signaling and immune system activation are characteristic of complex regional pain syndrome (CRPS). Unknown is whether substance P (SP) or calcitonin gene-related peptide (CGRP) support autoantibody production and, consequently, nociceptive sensitization.MethodsThese experiments involved the use of a well-characterized tibia fracture model of CRPS. Mice deficient in SP expression (Tac1−/−) and CGRP signaling (RAMP1−/−) were used to probe the neuropeptide dependence of post-fracture sensitization and antibody production. The deposition of IgM in the spinal cord, sciatic nerves, and skin was followed using Western blotting, as was expression of the CRPS-related autoantigen cytokeratin 16 (Krt16). Passive serum transfer to B-cell-deficient muMT mice was used to assess the production of functional autoantibodies in CRPS model mice. The use of immunohistochemistry allowed us to assess neuropeptide-containing fiber distribution and Langerhans cell abundance in mouse and human CRPS patient skin, while Langerhans cell-deficient mice were used to assess the functional contributions of these cells.ResultsFunctional SP and CGRP signaling were required both for the full development of nociceptive sensitization after fracture and the deposition of IgM in skin and neural tissues. Furthermore, the passive transfer of serum from wildtype but not neuropeptide-deficient mice to fractured muMT mice caused enhanced allodynia and postural unweighting. Langerhans cells were increased in number in the skin of fracture mice and CRPS patients, and those increases in mice were reduced in neuropeptide signaling-deficient animals. Unexpectedly, Langerhans cell-deficient mice showed normal nociceptive sensitization after fracture. However, the increased expression of Krt16 after tibia fracture was not seen in neuropeptide-deficient mice.ConclusionsCollectively, these data support the hypothesis that neuropeptide signaling in the fracture limb of mice is required for autoantigenic IgM production and nociceptive sensitization. The mechanism may be related to neuropeptide-supported autoantigen expression.

Delayed cerebral thrombosis complicating pneumococcal meningitis: an autopsy study

BackgroundDelayed cerebral thrombosis (DCT) is a devastating cerebrovascular complication in patients with excellent initial recovery of pneumococcal meningitis. The aetiology is unknown, but direct bacterial invasion, activation of coagulation or post-infectious immunoglobulin deposition has been suggested.Methods We studied histopathology of 4 patients with pneumococcal meningitis complicated by DCT. Results were compared with 8 patients who died of pneumococcal meningitis without DCT and 3 non-meningitis control cases. Furthermore, we evaluated vascular immunoglobulin depositions (IgA, IgG and IgM) and the presence of pneumococcal capsules by immunofluorescence.Results Patients who died after pneumococcal meningitis showed inflammation in the meninges and blood vessels with extensive infarction and thrombosis. We did not observe gross differences between DCT and non-DCT patients, except that 2 of 4 DCT patients had a basilar artery aneurysm compared to none of the non-DCT patients. We observed high density of IgM and IgG deposition in meningitis cases as compared to controls, but no difference between DCT and non-DCT patients. Immunofluorescence staining of pneumococci demonstrated the presence of bacterial capsules in the meninges of all meningitis patients, even 35 days after the initiation of antibiotic treatment.ConclusionThe aetiology of DCT complicating pneumococcal meningitis seems to be of multifactorial aetiology and includes vascular inflammation, thromboembolism of large arteries and infectious intracranial aneurysms. Pneumococcal cell wall components can be observed for weeks after pneumococcal meningitis and may be a source of resurging inflammation after the initial immunosuppression by dexamethasone.

Abstract 176: Enhancing the Efficacy of Current Management of Ischemic Stroke Using Injury-Site Targeted Complement Inhibition - A Preclinical Study

Ischemia leads to the cellular expression of damage-associated molecular patterns (DAMPs), recognition of which by natural IgM antibodies (NIgM) results in activation of the complement system and the propagation of inflammation. We identified an IgM mAb, termed B4IgM, that recognizes a DAMP (annexin IV) and that reconstitutes cerebral ischemia reperfusion injury in otherwise protected antibody-deficient Rag1-/- mice. We took advantage of this injury recognition system by linking a complement inhibitor (Crry) to a B4IgM-derived single chain antibody (scFv) for site-targeted delivery of a therapeutic after stroke. Using a murine model of transient middle cerebral artery occlusion (MCAO), we show that a single dose of B4Crry administered IV up to 24 h after MCAO inhibited IgM and complement deposition in the ischemic brain and provided sustained neuroprotection up to 30 days. B4Crry treatment resulted in a significant reduction in cell death and tissue scarring (70% reduction, p&lt;0.01), and significant improvements in neurological deficit scores (p&lt;0.05), forelimb asymmetry (corner test, &lt;0.05), and spatial learning (Barnes maze, p&lt;0.05). We further investigated B4Crry treatment in the context of tissue-plasminogen activator (tPA) therapy using a microembolic model of ischemic stroke. A single dose of B4Crry administered at 2h, 4h, or 6h after ischemia demonstrated significant improvements in motor and cognitive recovery compared to vehicle with a comparable outcome to 2h t-PA therapy. However, administration of tPA at 4h or 6h was associated with increased risk of mortality and hemorrhage. Combination of B4Crry and tPA expanded the therapeutic window of tPA (more than 6 h) and reduced the incidence of post-stroke mortality and tPA-induced intracerebral hemorrhage. Combination therapy also showed an additive effect on motor and cognitive recovery measures over 30 days. Finally, we demonstrated that B4Crry does not increase the risk of post-stroke pneumonia in a mouse model, and demonstrate that B4Crry specifically targets the ischemic stroke hemisphere in both murine and human brains. These data indicate that B4Crry is a promising translational stroke therapeutic that can also augment the efficacy and safety profile of tPA therapy.

N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation.

Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFα S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue-destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body’s natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure therapies for chronic inflammation.

A case report of proliferative glomerulonephritis with monoclonal immunoglobulin M-kappa deposits without associated lymphoproliferative disorder or detectable paraproteinemia.

A 53-year-old man presented with proteinuria and hematuria. No significant abnormality was detected in his physical examination or laboratory tests, including evidence of paraprotein in serum and urine. Renal biopsy revealed mesangial proliferation, thickened glomerular basement membranes, and spike formation. Immunofluorescence revealed deposition of immunoglobulin (Ig) M heavy chain, kappa (κ) light chain, and complement component C3 along capillary walls in the glomeruli. Light chain staining indicated significant restriction, because only κ chain, not lambda chain, was present in glomeruli. Aggregated electron dense deposits were observed in the subepithelial area and within the lamina densa on electron-microscopic examination. Cryoglobulinemia and amyloidosis were ruled out. Clinically, steroid therapy was not initiated due to patient preference, and the only prescribed medication was an angiotensin II receptor blocker. At the approximately 3-year follow-up, estimated glomerular filtration rate had decreased very mildly. The present case demonstrates that deposition of monoclonal IgM-κ may be associated with membranoproliferative glomerulonephritis-like changes in the glomeruli. Although no underlying hematological abnormality or paraproteinemia was observed in this case within the range of limited clinical examination, the patient's condition is consistent with proliferative glomerulonephritis with monoclonal IgM deposits, similar to the recently established proliferative glomerulonephritis with monoclonal IgG deposits. Further elucidation of the pathophysiology and effective treatments of the disorder should be expected in the future through the accumulation of similar cases.

Focal segmental glomerulosclerosis in a patient with hypereosinophilic syndrome

Background: Renal complication in hypereosinophilic syndrome (HES) is rare, with literature scarcely reporting association of this syndrome with glomerular involvement. While the direct effect of eosinophilic infiltration in tissues has been linked to histological damage of the HES, other mechanisms may account for renal involvement too. Case Presentation: We present a case of a 17-year-old male patient, with progressive edema, contact reactive erythematous skin lesions, acute kidney injury, nephrotic syndrome and progressive eosinophilia. His bone marrow biopsy revealed moderate hyperplasia with severe eosinophilia and atypical lymphocytes. His renal biopsy revealed glomeruli, enlarged in volume with mesangial expansion and hypercellularity and segmental thickening of capillary loops. Likewise, some glomeruli showed peripheral hyalinosis with synechiae to Bowman’s capsule. Tubules showed cloudy swelling, mild tubular atrophy and hyaline cylinders. Interstitial area showed infiltrated lymphomononuclear cells, focal with no evidence of eosinophils. Blood vessels were unaltered. Immunofluorescence identified glomeruli with granular mesangial IgM deposition. After corticosteroid treatment, eosinophilia and creatinine values regress to normal range. Conclusions: While our case may suggest the coexistence of two unrelated diseases, further studies are required to assess the pathophysiology of glomerular involvement in HES. Given the possibility that mechanisms other than the direct effect of eosinophils are involved in certain patients

Value of immunofluorescence-mediated detection of Ig, C1q, C3, and FRA for the identification and diagnosis of atypical membranous nephropathy.

The present study was to investigate the value of immunofluorescence-mediated detection of Ig, C1q, C3, and FRA for the identification and diagnosis of atypical membranous nephropathy (AMN). Fifty-five patients with AMN and 135 patients with idiopathic membranous nephropathy (IMN) diagnosed by renal biopsy in our hospital were consecutively selected. The positive expressions of Ig, C1q, C3, and FRA by immunofluorescence were analyzed. We compared the levels of blood urea nitrogen, creatinine, cystatin C, and 24 h urine protein, and the levels of serum IgA, IgG, IgM, and C3. The differences were not significant (p>0.05). Proportionate increases in glomerular spiky projection formations in patients with AMN were observed by light microscopy, without observation of other pathologic changes. By immunofluorescence, AMN patients showed higher positive rates of deposition of IgA, IgM, C1q, and FRA compared with IMN patients. Comparison of the positive rates of deposition of IgG and C3 showed no differences. By electron microscopy, AMN patients showed higher percentages of mesangial cell and mesangial matrix proliferation. Deposition of electron dense granules was mostly found in subepithelium, inside basement membranes, and in the mesangial area. The comparisons between the two groups showed no differences. Immunofluorescence-mediated detection of Ig, C1q, C3, and FRA have important application value for the identification and diagnosis of AMN.

Effect of cobra venom factor on the immune function of the pig to monkey liver xeno-transplantation

Objective To explore the effect of high purity venom factor (CVF) and other factors on immune function after pig to monkey liver xeno-transplantation. Methods To establish the pig to monkey heterotopic auxiliary liver transplantation model, the occurrence of super acute rejection (HAR) and delayed rejection (DXR) was observed after liver transplantation while interfered by high purity CVF. The expression of IgG, IgM and C3 protein in liver tissues was detected by Western blotting at different time points. Results The donor liver used for the adsorption all occured HAR, respectively of 10, 12, 11, 9, 13 minutes, the average time was (11.00±1.41) minutes. The pathological findings were ischemic necrosis and thrombosis. After CVF and other multiple factors, all the recipient monkey liver did not observe HAR and DXR until death, the IgG, IgM and C3 protein deposition in liver tissue after the death of the receptor were lower than the donor liver used for the adsorption, which is statistically significant difference (P=0.026, 0.047, 0.032). Conclusion CVF and other multiple factors can effectively overcome the occurrence of HAR in pig to monkey liver xeno-transplantation, and has the potential to prevent or delay the DXR. Key words: Xenograft; Snake venom factor; Rejection

Clinical, histological, immunological presentations and outcomes of bullous systemic lupus erythematosus: 10 New cases and a literature review of 118 cases.

Bullous systemic lupus erythematosus (BSLE) is a rare blistering condition associated with systemic lupus erythematosus (SLE). We conducted a multi-center retrospective study and literature review in order to describe the clinical, immunological, and histological presentations and outcomes of BSLE. The skin biopsies were centrally reviewed, and sera obtained during a flare of BSLE were analyzed for identification of circulating anti-basement membrane zone antibodies. Ten patients (all women, median age at SLE diagnosis of 22 years) were included, as well as 118 cases from a systematic review of the literature. Lupus nephritis was associated in 50% of the cases. BSLE presented as tensed bullae on normal or erythematous skin, predominantly localized on the trunk, arms, head, and neck. Urticarial lesions were associated in 31% of the cases, and mucous membrane involvement was seen in 51%. Histological analyses displayed subepidermal detachment, dermal infiltration of polynuclear neutrophils, alignment of these cells at the basal membrane zone and leukocytoclasis. The direct immunofluorescence was polymorphic, showing linear and/or granular deposits of IgG, IgA, IgM, and/or C3. Anti-type VII collagen antibodies were detected in 69% of cases. Dapsone was efficacious in 90% of cases. BSLE is rather an autoimmune neutrophilic blistering disease associated with SLE than a cutaneous manifestation and may be associated with active extra-cutaneous manifestations of SLE. Dapsone is the first-choice option.