Quantitative assessment of glomerular basement membrane collagen IV α chains in paraffin sections from patients with focal segmental glomerulosclerosis and Alport gene variants.

Focal segmental glomerulosclerosis (FSGS) lesions have been linked to variants in COL4A3/A4/A5 genes, which are also mutated in Alport syndrome. Although it could be useful for diagnosis, quantitative evaluation of glomerular basement membrane (GBM) type IV collagen (colIV) networks is not widely used to assess these patients. To do so, we developed immunofluorescence imaging for collagen α5(IV) and α1/2(IV) on kidney paraffin sections with Airyscan confocal microscopy that clearly distinguishes GBM collagen α3α4α5(IV) and α1α1α2(IV) as two distinct layers, allowing quantitative assessment of both colIV networks. The ratios of collagen α5(IV):α1/2(IV) mean fluorescence intensities (α5:α1/2 intensity ratios) and thicknesses (α5:α1/2 thickness ratios) were calculated to represent the levels of collagen α3α4α5(IV) relative to α1α1α2(IV). The α5:α1/2 intensity and thickness ratios were comparable across all 11 control samples, while both ratios were significantly and markedly decreased in all patients with pathogenic or likely pathogenic Alport COL4A variants, supporting validity of this approach. Thus, with further validation of this technique, quantitative measurement of GBM colIV subtype abundance by immunofluorescence, may potentially serve to identify the subgroup of patients with FSGS lesions likely to harbor pathogenic COL4A variants who could benefit from genetic testing.

Short-chain fatty acids ameliorate experimental anti-glomerular basement membrane disease.

BACKGROUND: Short-chain fatty acids (SCFAs), as the link between gut microbiota and the immune system, had been reported to be protective in many autoimmune diseases by the modulation of T cell differentiation. The pathogenic role of autoreactive Th1 and Th17 cells and the protective role of Treg cells in the pathogenesis of anti-GBM disease have been fully demonstrated. Thus, the present study aimed to investigate the therapeutic effects of SCFAs in a rat model of anti-GBM disease. MATERIALS AND METHODS: Experimental anti-GBM disease was constructed by immunizing Wistar Kyoto rats with a nephrogenic T cell epitope α3127-148, and intervened by sodium acetate, sodium propionate, or sodium butyrate, 150 mM in the drinking water from day 0 to 42. Kidney injury was accessed by the biochemical analyzer, immunofluorescence, and immunohistochemistry. Antibody response was detected by ELISA. T cell clustering and proliferation were detected by flow cytometry. Human kidney 2 (HK2) cells were stimulated in vitro and cytokines were assessed by quantitative real-time PCR. RESULTS: Treatment with sodium acetate, sodium propionate, or sodium butyrate ameliorated the severity of kidney impairment in rats with anti-GBM glomerulonephritis. In the sodium butyrate-treated rats, the urinary protein, serum creatinine, and blood urea nitrogen levels were significantly lower; the percentage of crescent formation in glomeruli was significantly reduced; and the kidneys showed reduced IgG deposition, complement activation, T cell, and macrophage infiltration as well as the level of circulating antibodies against anti-α3(IV)NC1. The treatment of sodium butyrate reduced the α3127-148-specific T cell activation and increased the Treg cells differentiation and the intestinal beneficial bacteria flora. It also alleviated the damage of HK2 cells treated with inflammatory factors and complement. CONCLUSION: Treatment with SCFAs, especially butyrate, alleviated anti-GBM nephritis in rat model, indicating its potential therapeutic effects in clinical usage.

The protease inhibitor E64d might attenuate the development of experimental anti-glomerular basement membrane disease through regulating the activation of Th1 cells.

BACKGROUND: Cathepsins have been recently identified as a regulator in the activation of Th1 and Th17 cells, which play an important role in the pathogenesis of anti-glomerular basement membrane (GBM) disease. Whether cathepsins contribute to the development of anti-GBM disease through regulating the activation of CD4+ T cell is still unclear. METHODS: Rats with experimental anti-GBM disease was established by immunization with the nephritogenic T cell epitope α3127-148. E64d, a cysteine cathepsin inhibitor, was administered in vitro and vivo to evaluate the effect of cathepsins on regulating the activation of antigen specific T cells and the development of anti-GBM disease. RESULTS: In rats with experimental anti-GBM diseases, E64d treatment not only reduced the levels of proteinuria, serum creatinine and anti-GBM antibody, but also ameliorated the kidney injury with less glomerular IgG deposition, a lower percentage of crescents and less infiltration of CD4+ T cells, CD8+ T cells and macrophages, as well as a lower percentage of splenic Th1 cells. In vitro, E64d treatment could significantly reduce the production of IFN-γ in the supernatant which might be produced by the activation of Th1 cells after being recalled with the autoantigen α3127-148. We also found the CD4+ T cells of rats with anti-GBM disease had an increased expression of cathepsin L (Cts-L), and the percentage of CD4+ T cells with extracellular expression of Cts-L was obviously higher, indicating it as a potential key regulator. CONCLUSIONS: E64d might attenuate the development of anti-GBM disease by participating in the activation of Th1 cells, indicating it as a potential drug for anti-GBM disease in the future.

THE EFFECT OF INTERNAL LIMITING MEMBRANE PEELING ON THE INNER RETINAL LAYERS IN PATIENTS WITHOUT MACULAR PATHOLOGIC CONDITION.

BACKGROUND: To examine the effect of internal limiting membrane peeling on the inner retinal layers in patients without macular pathological condition. METHODS: A prospective nonrandomized trial of patients undergoing pars plana vitrectomy with internal limiting membrane peeling for pathologic condition outside the macula was performed. Optical coherence tomography including macular ganglion cell layer, inner plexiform layer, and peripapillary retinal nerve fiber layer imaging was performed before surgery, 1, 3, and 6 months postoperatively, and at the end of follow-up (ranges between 4 and 17 months). Patients with any macular pathological condition on optical coherence tomography before surgery were excluded. The main outcome measure was change in thickness of the ganglion cell layer and inner plexiform layer. RESULTS: Ten patients who underwent pars plana vitrectomy with internal limiting membrane peeling for macula-on retinal detachment were included in the analysis. The mean age was 55 years, and the mean follow up was 10.8 months. All patients completed at least two postoperative follow-up visits that included an optical coherence tomography as per the protocol (range 2-6 months). There was an immediate reduction in the global (G), inferotemporal, superotemporal, and superior (S) ganglion cell layer thickness at the first follow up as compared with the preoperative state ( P = 0.028, P = 0.027, P = 0.026, and P = 0.027 respectively). From the first follow-up visit onward until the final follow-up, the thinning persisted, although there was no further statistically significant thinning. CONCLUSION: Peeling of the internal limiting membrane causes significant ganglion cell layer thinning in maculae without pathologic condition before surgery. At up to 17 months of follow-up, this effect seems to be immediate and nonprogressive.

Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours.

An effective nanotherapeutic transport from the vasculature to the tumour is crucial for cancer treatment with minimal side effects. Here we demonstrate that, in addition to the endothelial barrier, the tumour vascular basement membrane surrounding the endothelium acts as a formidable mechanical barrier that entraps nanoparticles (NPs) in the subendothelial void, forming perivascular NP pools. Breaking through this basement membrane barrier substantially increases NP extravasation. Using inflammation triggered by local hyperthermia, we develop a cooperative immunodriven strategy to overcome the basement membrane barrier that leads to robust tumour killing. Hyperthermia-triggered accumulation and inflammation of platelets attract neutrophils to the NP pools. The subsequent movement of neutrophils through the basement membrane can release the NPs entrapped in the subendothelial void, resulting in increased NP penetration into deeper tumours. We show the necessity of considering the tumour vascular basement membrane barrier when delivering nanotherapeutics. Understanding this barrier will contribute to developing more effective antitumour therapies.

Recurrent atypical antiglomerular basement membrane nephritis in the kidney transplant.

Atypical antiglomerular basement membrane (anti-GBM) nephritis can be defined as linear GBM staining for monotypic or polytypic immunoglobulin (Ig) by immunofluorescence (IF) without a diffuse crescentic pattern. We describe the clinicopathologic features of 6 patients (18 biopsies) in this first series of recurrent atypical anti-GBM nephritis after kidney transplantation. Recurrent glomerulonephritis occurred at a mean of 3.8 months posttransplant (range 1-7 months). Three index biopsies were for clinical indication, and 3 were protocol biopsies. Glomerular histologic changes were mild, with 2 showing segmental endocapillary hypercellularity, 1 focal glomerular microangiopathy, and the others no significant glomerular histologic changes. All 6 allografts showed monotypic linear glomerular Ig staining by IF: IgG kappa (n = 2), IgG lambda, IgA kappa, IgA lambda, and IgM lambda. Follow-up biopsies were available for 5 patients and showed similar histologic and IF findings without evidence of significant progression. No patients had detectable serum anti-GBM antibody or monoclonal proteins. The mean serum creatinine level on follow-up (24-62 months posttransplant) was 1.8 (range 0.93-2.77) mg/dL; no grafts were lost to recurrent disease. This series demonstrates that monotypic atypical anti-GBM recurs in the allograft and supports the idea that this disease is due to a circulating monoclonal protein.

Characterization of retinal hemorrhages delimited by the internal limiting membrane.

Clinically, hemorrhages at the vitreoretinal interface have been termed as 'pre-retinal' in location. However, there is a careful distinction to be made between sub-hyaloid and sub-internal limiting membrane (ILM) planes of blood collection. In the past half-century, a body of literature has accrued on sub-internal limiting membrane hemorrhage. We characterize the etiopathological, clinical, anatomical, and imaging characteristics of this entity (often misconstrued as sub-hyaloid hemorrhage). Management decisions are briefly described, and a unifying term of sub-internal limiting membrane macular hemorrhage is proposed to aid in further research.

Laminin-521: a novel target for pathogenic autoantibodies in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is typically characterized by autoimmunity against the α3 chain of type IV collagen. Rarely, circulating autoantibodies are not detected. These atypical cases follow a more indolent clinical course, and underlying mechanisms, including alternative target antigens, require investigation. In this issue of Kidney International, Kuang et al. describe a case of anti-GBM disease with autoantibodies against the GBM component laminin-521 and demonstrate that laminin-521 is pathogenic in a rat model of anti-GBM glomerulonephritis.

The Immunobiological Agents for Treatment of Antiglomerular Basement Membrane Disease.

Combination therapy with glucocorticoids, cyclophosphamide, and plasmapheresis is recommended as the standard treatment for anti-glomerular basement membrane (anti-GBM) disease, but the prognosis of this disease remains poor. Several immunobiological agents have been administered or are expected to be useful for anti-GBM disease in light of refractory disease or the standard treatments' tolerability. Many data regarding the use of biologic agents for anti-GBM disease have accumulated, verifying the effectiveness and potential of biologic agents as a new treatment option for anti-GBM disease. Tumor necrosis factor (TNF) inhibitors were shown to be useful in animal studies, but these agents have no clinical use and were even shown to induce anti-GBM disease in several cases. Although the efficacy of the TNF-receptor antagonist has been observed in animal models, there are no published case reports of its clinical use. There are also no published reports of animal or clinical studies of anti-B-cell-activating factor, which is a member of the TNF family of agents. Anti-interleukin (IL)-6 antibodies have been demonstrated to have no effect on or to exacerbate nephritis in animal models. Anti-C5 inhibitor was observed to be useful in a few anti-GBM disease cases. Among the several immunobiological agents, only rituximab has been demonstrated to be useful in refractory or poor-tolerance patients or small uncontrolled studies. Rituximab is usually used in combination with steroids and plasma exchange and is used primarily as an alternative to cyclophosphamide, but there is insufficient evidence regarding the efficacy of rituximab for anti-GBM disease, and thus, randomized controlled studies are required.

A case report and literature study on Alport syndrome featuring nephrotic syndrome as its primary manifestation.

BACKGROUND: Historically, due to the lack of distinct clinical symptoms, Alport syndrome, a hereditary kidney disease prevalent in children and a leading cause of kidney failure, has often been misdiagnosed as other kidney conditions. CASE DESCRIPTION: This article presents a comprehensive review and analysis of clinical data concerning a child diagnosed with Alport syndrome, where nephrotic syndrome served as the primary manifestation. The male child in this case exhibited symptoms starting at the age of 6, initially diagnosed as nephrotic syndrome. Consequently, oral steroid medication was administered, proving ineffective. Due to persistent proteinuria and microscopic hematuria, a renal biopsy was performed. Immunofluorescence staining revealed no abnormal expression of the α3, α4, and α5 chains of type IV collagen. Notably, electron microscopy revealed the basement membrane to be partially torn and arachnoid. Genetic testing indicated a hemizygous COL4A5 acceptor-splice-site mutation c.4707-1(IVS50)G > A, inherited from his mother. CONCLUSION: This specific mutated locus, being the first of its kind reported, adds valuable information to the existing gene mutation spectrum of Alport syndrome. Consequently, it emphasizes the importance for clinicians to deepen their understanding of rare kidney diseases, contributing to enhanced diagnostic accuracy and improved patient care.

360-degree pedicled inverted internal limiting membrane flap technique without face-down posturing for large idiopathic macular holes: a retrospective case series.

PURPOSE: This study aimed to determine closure rates of large idiopathic macular holes treated with pars plana vitrectomy and 360-degree pedicled inverted internal limiting membrane flap without face-down posturing and define visual improvement, types of macular hole closure, and external retina integrity as secondary outcomes. METHODS: This retrospective case series analyzed all patients who were treated by vitrectomy, 360-degree pedicled inverted internal limiting membrane flap, and gas tamponade, without face-down posturing postoperatively. Age, sex, time of visual acuity reduction, other ocular pathologies, and lens status were collected. The best-corrected visual acuity and optical coherence tomography results were recorded during pre- and postoperative follow-up examinations (15 days and 2 months after surgery). RESULTS: This study enrolled 20 eyes of 19 patients, and the mean age was 66 years. Optical coherence tomography performed 2 months after surgery revealed hole closure in 19 (95%) eyes. The median best-corrected visual acuity improved from +1.08 preoperatively to +0.66 LogMAR 2 months postoperatively (p<0.001), with a median of 20 letters of visual improvement (0.4 LogMAR) on the Early Treatment Diabetic Retinopathy Study chart. V (47.36%)- and U (52.63%)-types of closure were observed. CONCLUSION: The 360-degree pedicled inverted internal limiting membrane flap technique, without face-down posturing, provided a high closure rate (95%), external layer recovery, and V- and U-type foveal closure contours, in addition to visual improvement in most cases of large macular holes (even macular holes >650 µm). This technique may be a viable alternative to patients in whom traditional postoperative face-down positioning for large macular hole treatment is not possible.

A Hematopoietic Stem Cell Transplant Recipient with Nephrotic Syndrome and Immune Complex Deposits in Tubular Basement Membrane: A Rare Case Report.

Following allogenic hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) may develop which may affect several organs. Although the presence of nephrotic syndrome after HSCT is rare, sometimes it occurs in the setting of GVHD. The most common histological finding on kidney biopsy of patients with proteinuria owing to GVHD is membranous glomerulonephritis (MGN). However, reports of immune complex deposition in the tubular basement membrane (TBM) and glomerular basement membrane (GBM) are extremely rare. Herein we present a 65-year-old female with a history of HSCT at six years ago who was referred to Dr.Shariati Hospital in Tehran with nephrotic syndrome. Secondary serologic laboratory tests were all normal. The histopathologic study indicated diffuse GBM and TBM thickening, spike formation, infiltration of inflammatory mononuclear cells in tubulointerstitial area and acute tubular injury in light microscopy. Immunofluorescence staining showed immune complex deposits in GBM, mesangial cells, and TBM.  DOI: 10.52547/ijkd.7550.

The Role of MMP-9 in Regulating Degradation of the Splenic Microvascular Basement Membrane Induced by High Altitude Hypoxia / Rol de la MMP-9 en la Regulación de la Degradación de la Membrana Basal Microvascular Esplénica Inducida por Hipoxia de Altura

SUMMARY: To investigate changes of MMP-9 in the rat spleen and hypoxia-induced microvascular basement membrane under high altitude hypoxia. Thirty male specific pathogen-free Sprague Dawley rats were randomly divided into control and hypoxia groups, with 15 rats in each group. The rats in the control group were placed in Dingxi City, Gansu Province (2080 m above sea level) for 30 days. Rats in the hypoxia group were raised in a hypoxic environment in Maduo County, Qinghai Province (4300 m above sea level), for 30 days to establish a hypoxic rat model. Routine blood tests, MMP-9 mRNA, MMP-9 protein, and the spleen microvascular basement membrane were detected. (1) Compared with the control group, the red blood cell count, hemoglobin, and hematocrit levels of the rats in the hypoxia group were all increased; thus, a hypoxia model was successfully established. (2) Compared with the control group, the expression of MMP-9 mRNA and protein was significantly higher in the spleen of rats in the hypoxic group, and the difference was statistically significant (P <0.05). (3) Compared with the control group, the blood vessel basement membrane in the spleen of the hypoxia group was degraded. Under natural low air pressure and high altitude conditions, the expression of MMP-9 in rat spleen tissue increases and participates in the degradation of the microvascular basement membrane.

El objetivo de este trabajo fue investigar los cambios de la MMP-9 en el bazo de la rata y la membrana basal microvascular inducida bajo hipoxia a gran altura. Treinta ratas macho Sprague Dawley, libres de patógenos específicos, se dividieron aleatoriamente en dos grupos de 15 ratas cada uno, un grupo control y un grupo hipoxia. Durante 30 días las ratas del grupo control estuvieron en la ciudad de Dingxi, provincia de Gansu (2080 m sobre el nivel del mar). Las ratas del grupo de hipoxia se criaron en un entorno hipóxico en el condado de Maduo, provincia de Qinghai (4300 m sobre el nivel del mar), durante 30 días para establecer un modelo de rata hipóxica. Se realizaron análisis de sangre de rutina, ARNm de MMP-9, proteína MMP-9 y de la membrana basal microvascular del bazo. En comparación con el grupo control, el recuento de glóbulos rojos, la hemoglobina y los niveles de hematocrito de las ratas del grupo de hipoxia aumentaron; por lo tanto, se estableció con éxito un modelo de hipoxia. En comparación con el grupo control, la expresión de ARNm y proteína de MMP-9 fue significativamente mayor en el bazo de las ratas del grupo hipóxico, siendo la diferencia estadísticamente significativa (P <0,05). En comparación con el grupo control, la membrana basal de los vasos sanguíneos estaba degradada en el bazo del grupo hipoxia. En condiciones naturales de baja presión atmosférica y gran altitud, la expresión de MMP-9 en el tejido del bazo de la rata aumenta y participa en la degradación de la membrana basal microvascular.

Seronegative Atypical Anti-Glomerular Basement Membrane Glomerulonephritis Associated With Thrombotic Microangiopathy: Case Report and Literature Analysis.

Anti-glomerular basement membrane (GBM) antibody nephritis is defined by linear immunofluorescence staining of GBM by immunoglobulin G (IgG), typically associated with GBM rupture, fibrinoid necrosis, and crescent formation. Clinically, the patients present with rapidly worsening renal function, often with hematuria. Typical renal pathologic findings include necrotizing and crescentic glomerulonephritis. In contrast, thrombotic microangiopathy (TMA) is characterized by microvascular thrombosis, which can also lead to acute kidney injury. Thrombotic microangiopathy is associated with some systemic diseases and has characteristic clinical features of microangiopathic hemolytic anemia, platelet consumption, and multiple organ failure. Anti-GBM nephritis associated with TMA has rarely been reported. We describe an unusual case of atypical anti-GBM disease without crescent formation or necrosis but with light microscopic and ultrastructural features consistent with endothelial cell injury and glomerular-limited TMA.

Screening of hub inflammatory bowel disease biomarkers and identification of immune-related functions based on basement membrane genes.

BACKGROUND: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic, inflammatory, and autoimmune disease, but its specific etiology and pathogenesis are still unclear. This study aimed to better discover the causative basement membrane (BM) genes of their subtypes and their associations. METHODS: The differential expression of BM genes between CD and UC was analyzed and validated by downloading relevant datasets from the GEO database. We divided the samples into 3 groups for comparative analysis. Construction of PPI networks, enrichment of differential gene functions, screening of Lasso regression models, validation of ROC curves, nomogram for disease prediction and other analytical methods were used. The immune cell infiltration was further explored by ssGSEA analysis, the immune correlates of hub BM genes were found, and finally, the hub central genes were screened by machine learning. RESULTS: We obtained 6 candidate hub BM genes related to cellular immune infiltration in the CD and UC groups, respectively, and further screened the central hub genes ADAMTS17 and ADAMTS9 through machine learning. And in the ROC curve models, AUC > 0.7, indicating that this characteristic gene has a more accurate predictive effect on IBD. We also found that the pathogenicity-related BM genes of the CD and UC groups were mainly concentrated in the ADAMTS family (ADAMTS17 and ADAMTS9). Addition there are some differences between the two subtypes, and the central different hub BM genes are SPARC, POSTN, and ADAMTS2. CONCLUSIONS: In the current study, we provided a nomogram model of CD and UC composed of BM genes, identified central hub genes, and clarified the similarities and differences between CD and UC. This will have potential value for preclinical, clinical, and translational guidance and differential research in IBD.

Baseline reticular basement membrane morphology is related to subsequent spirometry deterioration in pediatric chronic airway inflammation: a follow-up study.

Reticular basement membrane (RBM) thickening may occur in children with allergic bronchial asthma (BA), cystic fibrosis (CF), and primary ciliary dyskinesia (PCD). Its functional consequences remain unknown. We investigated the relationship between baseline RBM thickness and subsequent spirometry. In our cohort follow-up study, patients aged 3-18 yr with BA, CF, and PCD and controls underwent baseline lung clearance index (LCI) measurement, spirometry, and endobronchial biopsy sampling. Total RBM and collagen IV-positive layer thickness were measured. Trends in forced vital capacity (FVC), forced expired volume in 1 s (FEV1), and FEV1/FVC were analyzed during follow-up, and their relationship to baseline characteristics was studied using univariate analysis and multiple regression models. Complete baseline data were available in 19 patients with BA, 30 patients with CF, 25 patients with PCD, and 19 controls. The RBM was thicker in patients with BA (6.33 ± 1.22 µm), CF (5.60 ± 1.39 µm), and PCD (6.50 ± 1.87 µm) than in controls (3.29 ± 0.55 µm) (all P < 0.001). The LCI was higher in patients with CF (15.32 ± 4.58, P < 0.001) and PCD (10.97 ± 2.46, P = 0.002) than in controls (7.44 ± 0.43). The median follow-up times were 3.6, 4.8, 5.7, and 1.9 years in patients with BA, CF, PCD, and controls, respectively. The z-scores of FEV1 and FEV1/FVC deteriorated significantly in all groups except in controls. In patients with CF and PCD, trends in FEV1 z-scores correlated with baseline LCI and RBM; in BA, it correlated with collagen IV. In multiple regression models, RBM morphology and ventilation inhomogeneity could predict up to 84.4% of variability in spirometry trends. In conclusion, baseline LCI value and RBM morphology may predict trends in subsequent spirometry.NEW & NOTEWORTHY This paper deals with the relationship between reticular basement membrane (RBM) morphology at baseline and follow-up spirometry in children with asthma, cystic fibrosis, and primary ciliary dyskinesia. For the first time, to our knowledge, the possibility to predict subsequent lung function development using selected baseline characteristics (reticular basement membrane morphology from endobronchial biopsy and ventilation inhomogeneity from nitrogen multiple breath washout test) is proposed. Corresponding predictive models are presented.

Tubular basement membrane amyloid deposition: is it an indicator of renal progression in light chain amyloidosis?

In light chain amyloidosis (LA), the massive glomerular and vascular amyloid deposition leading to interstitial fibrosis/tubular atrophy (IFTA) is thought to be responsible for renal failure. The amyloid deposition in the interstitium and the tubular basement membrane (TBM) has received less attention in the study of LA. We, therefore, collected clinical and laboratory data on patients diagnosed with LA in our Nephrology Department and studied amyloid deposition in the TBM. Twelve LA patients were diagnosed by renal biopsy during a seven-year period. In 4 of the 12, amyloid deposition could also be detected in the TBM. In our first case of a patient with diabetes mellitus, non-amyloid fibrils resembling 'diabetic fibrillosis' were also seen by electron microscopy. Despite the double damage, IFTA was negligible, blood vessels were unaffected, and the glomerular deposition was segmental. In the other three cases, significant (>50%) IFTA and a severely reduced estimated glomerular filtration rate were already detected at the time of diagnosis and amyloid deposition was also observed in the blood vessels. These findings indicate the importance of TBM amyloid deposition in the progression of renal disease. This may represent a late-stage presentation of the disease with a heavy LC burden.

Basement membrane proteins in extracellular matrix characterize NF1 neurofibroma development and response to MEK inhibitor.

Neurofibromatosis type 1 (NF1) is one of the most common tumor-predisposing genetic disorders. Neurofibromas are NF1-associated benign tumors. A hallmark feature of neurofibromas is an abundant collagen-rich extracellular matrix (ECM) that constitutes more than 50% of the tumor dry weight. However, little is known about the mechanism underlying ECM deposition during neurofibroma development and treatment response. We performed a systematic investigation of ECM enrichment during plexiform neurofibroma (pNF) development and identified basement membrane (BM) proteins, rather than major collagen isoforms, as the most upregulated ECM component. Following MEK inhibitor treatment, the ECM profile displayed an overall downregulation signature, suggesting ECM reduction as a therapeutic benefit of MEK inhibition. Through these proteomic studies, TGF-ß1 signaling was identified as playing a role in ECM dynamics. Indeed, TGF-ß1 overexpression promoted pNF progression in vivo. Furthermore, by integrating single-cell RNA sequencing, we found that immune cells including macrophages and T cells produce TGF-ß1 to induce Schwann cells to produce and deposit BM proteins for ECM remodeling. Following Nf1 loss, neoplastic Schwann cells further increased BM protein deposition in response to TGF-ß1. Our data delineate the regulation governing ECM dynamics in pNF and suggest that BM proteins could serve as biomarkers for disease diagnosis and treatment response.

Basement membrane thickness helps to differentiate hypopigmented mycosis fungoides from clinical and pathological mimickers.

BACKGROUND: Hypopigmented mycosis fungoides (HMF) is a relatively rare subtype of mycosis fungoides (MF). The diagnosis of HMF can be quite challenging in case of insufficient diagnostic criteria due to the diverse conditions that present with hypopigmented lesions. This study aimed to evaluate the usefulness of the assessment of the basement membrane thickness (BMT) in the diagnosis of HMF. METHODS: A retrospective study was conducted on biopsy specimens of 21 HMF and 25 non-HMF cases who presented with hypopigmented lesions. The thickness of the basement membrane was evaluated in periodic acid-Schiff (PAS)-stained sections. RESULTS: The mean BMT was significantly higher in the HMF group than in the non-HMF group (P < 0.001). The best cut-off value of mean BMT for the detection of HMF verified in ROC analysis was 32.7 µm (P < 0.001) with a sensitivity of 85.7% and a specificity of 96%. CONCLUSION: Evaluation of BMT can be a useful tool to distinguish HMF from other causes of hypopigmented lesions in doubtful cases. We suggest the use of " BMT more than 33 µm" as a histopathologic criterion of HMF.

[Epithelial basement membrane corneal dystrophy: A case report]. / Distrofia de membrana basal epitelial corneal: a propósito de un caso.

Epithelial basement membrane corneal dystrophy is a rare entity, characterized by recurrent corneal erosions secondary to a disorder in the attachment of the corneal epithelium to the basement membrane. To date, mainly the ophthalmological aspect of cases has been reported, with little emphasis on the pathology of this lesion. Here we aim to describe the microscopy and discuss the clinical and therapeutic aspects of a case.