Autoantibodies against laminin-521 are pathogenic in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against GBM components. Evidence from human inherited kidney diseases and animal models suggests that the α, ß, and γ chains of laminin-521 are all essential for maintaining the glomerular filtration barrier. We previously demonstrated that laminin-521 is a novel autoantigen within the GBM and that autoantibodies to laminin-521 are present in about one-third of patients. In the present study, we investigated the pathogenicity of autoantibodies against laminin-521 with clinical and animal studies. Herein, a rare case of anti-GBM disease was reported with circulating autoantibodies binding to laminin-521 but not to the NC1 domains of α1-α5(IV) collagen. Immunoblot identified circulating IgG from this patient bound laminin α5 and γ1 chains. A decrease in antibody levels was associated with improved clinical presentation after plasmapheresis and immunosuppressive treatments. Furthermore, immunization with laminin-521 in female Wistar-Kyoto rats induced crescentic glomerulonephritis with linear IgG deposits along the GBM, complement activation along with infiltration of T cells and macrophages. Lung hemorrhage occurred in 75.0% of the rats and was identified by the presence of erythrocyte infiltrates and hemosiderin-laden macrophages in the lung tissue. Sera and kidney-eluted antibodies from rats immunized with laminin-521 demonstrated specific IgG binding to laminin-521 but not to human α3(IV)NC1, while the opposite was observed in human α3(IV)NC1-immunized rats. Thus, our patient data and animal studies imply a possible independent pathogenic role of autoantibodies against laminin-521 in the development of anti-GBM disease.

Laminin-521 is a Novel Target of Autoantibodies Associated with Lung Hemorrhage in Anti-GBM Disease.

BACKGROUND: Antiglomerular basement membrane (anti-GBM) disease is characterized by GN and often pulmonary hemorrhage, mediated by autoantibodies that typically recognize cryptic epitopes within α345(IV) collagen-a major component of the glomerular and alveolar basement membranes. Laminin-521 is another major GBM component and a proven target of pathogenic antibodies mediating GN in animal models. Whether laminin-521 is a target of autoimmunity in human anti-GBM disease is not yet known. METHODS: A retrospective study of circulating autoantibodies from 101 patients with anti-GBM/Goodpasture's disease and 85 controls used a solid-phase immunoassay to measure IgG binding to human recombinant laminin-521 with native-like structure and activity. RESULTS: Circulating IgG autoantibodies binding to laminin-521 were found in about one third of patients with anti-GBM antibody GN, but were not detected in healthy controls or in patients with other glomerular diseases. Autoreactivity toward laminin-521 was significantly more common in patients with anti-GBM GN and lung hemorrhage, compared with those with kidney-limited disease (51.5% versus 23.5%, P=0.005). Antilaminin-521 autoantibodies were predominantly of IgG1 and IgG4 subclasses and significantly associated with lung hemorrhage (P=0.005), hemoptysis (P=0.008), and smoking (P=0.01), although not with proteinuria or serum creatinine at diagnosis. CONCLUSIONS: Besides α345(IV) collagen, laminin-521 is another major autoantigen targeted in anti-GBM disease. Autoantibodies to laminin-521 may have the potential to promote lung injury in anti-GBM disease by increasing the total amount of IgG bound to the alveolar basement membranes.

Four Ounces Can Move a Thousand Pounds: The Enormous Value of Nanomaterials in Tumor Immunotherapy.

The application of nanomaterials in healthcare has emerged as a promising strategy due to their unique structural diversity, surface properties, and compositional diversity. In particular, nanomaterials have found a significant role in improving drug delivery and inhibiting the growth and metastasis of tumor cells. Moreover, recent studies have highlighted their potential in modulating the tumor microenvironment (TME) and enhancing the activity of immune cells to improve tumor therapy efficacy. Various types of nanomaterials are currently utilized as drug carriers, immunosuppressants, immune activators, immunoassay reagents, and more for tumor immunotherapy. Necessarily, nanomaterials used for tumor immunotherapy can be grouped into two categories: organic and inorganic nanomaterials. Though both have shown the ability to achieve the purpose of tumor immunotherapy, their composition and structural properties result in differences in their mechanisms and modes of action. Organic nanomaterials can be further divided into organic polymers, cell membranes, nanoemulsion-modified, and hydrogel forms. At the same time, inorganic nanomaterials can be broadly classified as nonmetallic and metallic nanomaterials. The current work aims to explore the mechanisms of action of these different types of nanomaterials and their prospects for promoting tumor immunotherapy.

Clinical and immunological characteristics of patients with combined anti-glomerular basement membrane disease and IgA nephropathy.

Background: The combination of anti-glomerular basement membrane (GBM) disease and immunoglobulin A nephropathy (IgAN) has been well documented in sporadic cases, but lacks overall assessment in large collections. Herein, we investigated the clinical and immunological characteristics and outcome of this entity. Methods: Seventy-five consecutive patients with biopsy-proven anti-GBM disease from March 2012 to March 2020 were screened. Among them, patients with concurrent IgAN were identified and enrolled. The control group included biopsied classical anti-GBM patients during the same period, excluding patients with IgAN, other glomerular diseases or tumors, or patients with unavailable blood samples and missing data. Serum IgG and IgA autoantibodies against GBM were detected by enzyme-linked immunosorbent assay, as were circulating IgG subclasses against GBM. Results: Fifteen patients with combined anti-GBM disease and IgAN were identified, accounting for 20% (15/75) of all patients. Among them, nine were male and six were female, with an average (± standard deviation) age of 46.7 ± 17.3 years. Thirty patients with classical anti-GBM disease were enrolled as controls, with 10 males and 20 females at an average age of 45.4 ± 15.3 years. Patients with combined anti-GBM disease and IgAN had restricted kidney involvement without pulmonary hemorrhage. Compared with classical patients, anti-GBM patients with IgAN presented with significantly lower levels of serum creatinine on diagnosis (6.2 ± 2.9 vs 9.5 ± 5.4 mg/dL, P = .03) and less occurrence of oliguria/anuria (20%, 3/15 vs 57%, 17/30, P = .02), but more urine protein excretion [2.37 (1.48, 5.63) vs 1.11 (0.63, 3.90) g/24 h, P = .01]. They showed better kidney outcome during follow-up (ESKD: 47%, 7/15 vs 80%, 24/30, P = .03). The autoantigen and epitope spectrum were comparable between the two groups, but the prevalence of circulating anti-α3(IV)NC1 IgG1 (67% vs 97%, P = .01) and IgG3 (67% vs 97%, P = .01) were lower in patients with IgAN. Conclusions: Concurrent IgAN was not rare in anti-GBM disease. Patients showed milder kidney lesions and better recovery after immunosuppressive therapies. This might be partly explained by lower prevalence of anti-GBM IgG1 and IgG3 in these patients.

The Prevalence and Characteristics of Circulating IgA Anti-Glomerular Basement Membrane Autoantibodies in Anti-Glomerular Basement Membrane Disease.

Introduction: In some cases, immunoglobulin (IgA)-mediated antiglomerular basement membrane (anti-GBM) disease has been reported. Whether circulating IgA anti-GBM antibodies affect the clinico-pathologic characteristics and outcome of typical anti-GBM disease deserves further study. Methods: Circulating IgA anti-α3(IV)NC1 antibodies were examined by enzyme-linked immunosorbent assay (ELISA) using recombinant human α3(IV)NC1 as solid phase antigens in 107 patients with anti-GBM disease and 115 controls. Clinical, pathological, and follow-up data of patients were retrospectively analyzed. Results: Circulating IgA anti-α3(IV)NC1 antibodies were found in 18.7% (20/107) of patients with anti-GBM disease but were not detected in healthy controls or in patients with other glomerular diseases. The positivity of circulating IgA anti-α3(IV)NC1 antibodies was not associated with whether the patient was with combined IgA nephropathy or other glomerulonephritis. Kidney immunofluorescence showed no statistical difference in IgA deposition between patients with circulating IgA anti-α3(IV)NC1 antibodies and patients without (30.0% vs. 40.4%, P = 0.725). The titers of circulating immunoglobulin G (IgG) anti-α3(IV)NC1 antibodies in patients with circulating IgA anti-α3(IV)NC1 antibodies were significantly higher than those without (200 [183.3, 200] vs. 161 [85.5, 200] U/ml, P = 0.005). There were no significant differences in kidney outcome and mortality between the 2 groups. Conclusion: Circulating IgA anti-α3(IV)NC1 antibodies occurred in 18.7% (20/107) of patients with anti-GBM in our center and were specific to anti-GBM disease. Patients with circulating IgA anti-α3(IV)NC1 antibodies showed a higher levels of serum IgG anti-α3(IV)NC1 antibodies than those without.

Clinical-Pathological Features and Outcome of Atypical Anti-glomerular Basement Membrane Disease in a Large Single Cohort.

Background: Atypical cases of anti-glomerular basement membrane (GBM) disease had absent circulating antibodies but linear IgG deposits along GBM in the kidneys. Herein, we reported the clinical-pathological features and outcome of these rare cases. Methods: Linear IgG deposit along GBM were examined by immunofluorescence on renal specimens, with exclusion of diabetic kidney disease. Circulating anti-GBM antibodies were tested by commercial ELISA assay. Clinical, pathological and follow-up data were retrospectively analyzed. Results: From 2013 to 2018, a total of 60 patients were diagnosed as atypical anti-GBM disease. They had a male predominance, with an average age of 51.7 ± 15.6 years. Three (5.0%) patients had alveolar hemorrhage. Forty five percent of them presented with acute kidney disease. All patients had linear IgG deposit along GBM, some in addition on tubular basement membrane and/or Bowmans' capsules. C3 deposition was found in 65.0% of the patients. 41.7% (25/60) of the patients showed crescent formation and the percentage of crescent was (34.7 ± 23.5)% in those patients. They had higher prevalence of hematuria and C3 deposit, higher levels of serum creatinine, worse renal and patient survival than those without crescent (P < 0.05). During the follow-up of 35.7 ± 21.4 months, 14 (23.3%) patients progressed to ESRD. The serum creatinine on diagnosis [per 200 µmol/L increase, HR (95% CI): 2.663 (1.372, 5.172), P = 0.004], serum C3 [per 0.1 g/L increase, HR (95% CI): 0.689(0.483, 0.984), P = 0.040] and the intensity of kidney C3 staining [per 1+ increase, HR (95% CI): 2.770 (1.115, 6.877), P = 0.028] were independent predictive factors for kidney outcome. Nine (15.0%) patients died of all causes. Conclusions: Atypical anti-GBM disease manifested milder kidney injury and scarce pulmonary hemorrhage compared to the classical cases. Though heterogeneous, a substantial number of the patients had complement activation and crescent formation. Patients having crescents presented with more severe clinical course and worse outcomes. The poor kidney and patient prognosis emphasize prompt interventions from physicians. The immunosuppressive intervention was not associated with kidney or patient outcome. Further studies are needed to address the optimal therapeutic regimen.