Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53

The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1α (DD1α), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1α appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1α-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1α thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses

Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy

Solid state NMR/Biophysical Organic Chemistr

Angiogenesis and chronic kidney disease

The number of patients requiring renal replacement therapy due to end-stage renal disease (ESRD) is increasing worldwide. The prevalence of chronic kidney disease (CKD), and the importance of CKD as a risk factor in development of ESRD and in complicating cardiovascular disease (CVD) have been confirmed. In recent years, the involvement of angiogenesis-related factors in the progression of CKD has been studied, and the potential therapeutic effects on CKD of modulating these factors have been identified. Vascular endothelial growth factor (VEGF)-A, a potent pro-angiogenic factor, is involved in the development of the kidney, in maintenance of the glomerular capillary structure and filtration barrier, and in the renal repair process after injury. VEGF-A is also involved in the development of early diabetic nephropathy, demonstrated by the therapeutic effects of anti-VEGF-A antibody. Angiopoietin (Ang)-1 induces the maturation of newly formed blood vessels, and the therapeutic effects of Ang-1 in diabetic nephropathy have been described. In experimental models of diabetic nephropathy, the therapeutic effects of angiogenesis inhibitors, including angiostatin, endostatin and tumstatin peptides, the isocoumarin NM-3, and vasohibin-1, have been reported

Textkritische Untersuchungen zum altbabylonischen „Rat des Šuruppak“

Im Zentrum der Untersuchungen steht der sumerische Weisheitstext „Rat des Šuruppak“. Anhand dieser Komposition werden die unterschiedlichen Textzeugen der altbabylonischen Version hinsichtlich ihrer Varianz analysiert. Dabei wird deutlich, dass die unterschiedlichen Textzeugen signifikante Abweichungen voneinander aufweisen, welches die Rekonstruktion einer Fassung, die repräsentativ für alle Textzeugen steht, schier unmöglich macht. Ferner wird sich der Frage nach dem Tradierungsprozess vom „Rat des Šuruppak“ gewidmet, indem die Abweichungen qualitativ bestimmt werden

Relevance of Complement C4 Deposits Localized to Distinct Vascular Compartments in ANCA-Associated Renal Vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis affecting multiple organ systems, including the kidney. Small vessels in the kidney include small-sized arteries, capillaries, and venules. Intrarenal C4 deposits are now increasingly recognized as a potential marker and pathogenic mechanism of autoantibody-mediated tissue damage in ANCA-associated renal vasculitis. We here describe the relevance of complement C4 deposits localized to distinct vascular compartments in a cohort of biopsy-proven ANCA-associated renal vasculitis. A cohort of 43 biopsy-proven cases of ANCA-associated renal vasculitis with myeloperoxidase (MPO) or proteinase 3 (PR3) seropositivity were retrospectively enrolled in a single-center observational study. Univariate and multivariate regression analysis was performed to identify parameters associated with intrarenal C4 deposits in ANCA-associated renal vasculitis. We here show that C4 deposits localize to distinct vascular compartments in ANCA-associated renal vasculitis, and provide evidence for an association with better short-term survival (p = 0.008), implicating that this subgroup had a superior response to remission induction therapy. Second, C4 deposits in interlobular arteries were associated with eosinophilic infiltrates in renal vasculitis with MPO-ANCA seropositivity (p = 0.021). In renal vasculitis positive for MPO-ANCA, the absence of C4 deposits in the glomerular tuft was associated with sclerotic class ANCA-associated renal vasculitis (p < 0.001), and tubular RBC casts (p = 0.024). Fourth, complement C4 in interlobular arteries is associated with tubular atrophy specifically in renal vasculitis with PR3-ANCA seropositivity (p = 0.006). Finally, complement C4 deposits in peritubular capillaries associated specifically with hyaline casts in cases positive for PR3-ANCA (p = 0.025), implicating a role in tubular injury. Interestingly, C4 deposits were localized to distinct vascular compartments independent of the systemic activation of the complement system, reflected by the consumption of respective serum complement molecules in ANCA-associated renal vasculitis. In summary, we here show that C4 deposits localize to distinct vascular compartments in ANCA-associated renal vasculitis, and provide evidence for an association with survival and distinct histopathological lesions. Considering recent advances in AAV therapy with the emergence of new therapeutics that inhibit complement activation, we here provide novel insights into complement C4 as a potential marker to identify patients who may benefit most from these drugs. Thus, our results may contribute to a more personalized treatment approach of AAV depending on the relevance of distinct intrarenal complement deposits

Molecular signatures of intrarenal complement receptors C3AR1 and C5AR1 correlate with renal outcome in human lupus nephritis

Objective Lupus nephritis is one of the most common and serious complications of systemic lupus erythematosus (SLE). Lupus nephritis is a major cause of kidney failure in patients with SLE, attributed to increased morbidity and mortality. The in situ deposition of intrarenal immune complexes promotes the accumulation of inflammatory cells and causes kidney injury. Methods We here extracted transcriptome array datasets for expression of complement molecules in human lupus nephritis. Furthermore, we performed gene set enrichment analysis to identify molecular signatures associated with follow-up kidney function in lupus nephritis. Results Within the glomerular compartment, intrarenal mRNA expression levels of C3AR1 (p=0.0333) and C5AR1 (p=0.0167) correlated with treatment success reflected by kidney function recovery specifically in class III lupus nephritis, while no such association was observed in class II or class IV lupus nephritis. Interestingly, mRNA expression levels of either glomerular C3AR1 or C5AR1 resulted in identical gene set and signalling pathways enrichments in human lupus nephritis, including interferon signalling and signalling by interleukins. Direct comparison of C3AR1 and C5AR1 confirmed a strong association between glomerular mRNA expression levels of both complement receptors (r=0.8955, p<0.0001). Conclusions This study provides additional insights into signalling pathways associated with intrarenal synthesis of complement components in lupus nephritis that might be also affected by targeted therapy of the complement system. These results require confirmation but may contribute to a personalised treatment approach in distinct classes of human lupus nephritis.Göttingen Universit

AB0400 Urinary Albumin-To-Creatinine Ratio Indicates Necrotizing and Crescentic Glomerulonephritisin Anca-Associated Vasculitis

Background: Renal involvement is a common and severe complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) as it can cause acute kidney injury (AKI), end-stage renal disease (ESRD) or death. Objectives: We have previously reported that elevated urinary albumin-to-creatinine ratio (uACR) correlates with rapid deterioration of kidney function in ANCA GN. Therefore, we here aimed to describe the association between proteinuric findings and histopathological diagnosis of necrotizing and crescentic ANCA GN in 50 urinary samples at admission and corresponding renal biopsies of patients with AAV. Methods: A total number of 50 urinary samples at admission and corresponding renal biopsies with confirmed renal involvement of AAV were retrospectively included between 2015 till 2020 in a single-center observational study. Results: Renal involvement of AAV revealed variable proteinuria ranging from low-range to nephrotic syndromes, however most patients presented with subnephrotic proteinuria. Severe deterioration of kidney function requiring RRT within 30 days after admission was associated with elevated levels of nonselective proteinuria, mostly attributed to albuminuria (uACR). Because we have previously shown that histologically confirmed ANCA GN with glomerular crescents and necrosis is associated with AKI and requirement of RRT during short-term disease course and elevated uACR levels were equally associated with AKI and requirement of RRT during the short-term course after disease onset, we next analyzed the association between uACR measurements at admission and histopathological findings within renal biopsies performed thereafter. Severely increased uACR levels >300 mg/g correlated with reduction of normal glomeruli, attributed to increased glomerular crescents and necrosis. By contrast, no such association was observed for global sclerotic glomeruli, revealing that uACR reflects crescentic ANCA GN rather than adaptive glomerular hyperfilitration in chronic sclerosing stage. Since uACR levels could reflect both, either a specific renal involvement with necrotizing and crescentic ANCA GN or severity of systemic AAV disease, we next correlated uACR levels assessed at admission with extrarenal disease manifestation. We observed no association between uACR levels and extrarenal manifestation of AAV disease including pulmonary hemorrhage, skin involvement and BVAS assessment, suggesting that uACR levels reflected specific renal involvement in AAV. These observations were further confirmed by survival analysis for cumulative incidence of RRT during the short-term course of disease. Conclusion: Early identification of patients who mostly benefit from aggressive immunosuppressive therapy is of clinical importance. Our observation that uACR levels at disease onset predict necrotizing and crescentic ANCA GN requires further investigation for therapeutic decision especially in patients with severe deterioration of kidney function. Disclosure of Interests: None declaredBackground: Renal involvement is a common and severe complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) as it can cause acute kidney injury (AKI), end-stage renal disease (ESRD) or death. Objectives: We have previously reported that elevated urinary albumin-to-creatinine ratio (uACR) correlates with rapid deterioration of kidney function in ANCA GN. Therefore, we here aimed to describe the association between proteinuric findings and histopathological diagnosis of necrotizing and crescentic ANCA GN in 50 urinary samples at admission and corresponding renal biopsies of patients with AAV. Methods: A total number of 50 urinary samples at admission and corresponding renal biopsies with confirmed renal involvement of AAV were retrospectively included between 2015 till 2020 in a single-center observational study. Results: Renal involvement of AAV revealed variable proteinuria ranging from low-range to nephrotic syndromes, however most patients presented with subnephrotic proteinuria. Severe deterioration of kidney function requiring RRT within 30 days after admission was associated with elevated levels of nonselective proteinuria, mostly attributed to albuminuria (uACR). Because we have previously shown that histologically confirmed ANCA GN with glomerular crescents and necrosis is associated with AKI and requirement of RRT during short-term disease course and elevated uACR levels were equally associated with AKI and requirement of RRT during the short-term course after disease onset, we next analyzed the association between uACR measurements at admission and histopathological findings within renal biopsies performed thereafter. Severely increased uACR levels >300 mg/g correlated with reduction of normal glomeruli, attributed to increased glomerular crescents and necrosis. By contrast, no such association was observed for global sclerotic glomeruli, revealing that uACR reflects crescentic ANCA GN rather than adaptive glomerular hyperfilitration in chronic sclerosing stage. Since uACR levels could reflect both, either a specific renal involvement with necrotizing and crescentic ANCA GN or severity of systemic AAV disease, we next correlated uACR levels assessed at admission with extrarenal disease manifestation. We observed no association between uACR levels and extrarenal manifestation of AAV disease including pulmonary hemorrhage, skin involvement and BVAS assessment, suggesting that uACR levels reflected specific renal involvement in AAV. These observations were further confirmed by survival analysis for cumulative incidence of RRT during the short-term course of disease. Conclusion: Early identification of patients who mostly benefit from aggressive immunosuppressive therapy is of clinical importance. Our observation that uACR levels at disease onset predict necrotizing and crescentic ANCA GN requires further investigation for therapeutic decision especially in patients with severe deterioration of kidney function. Disclosure of Interests: None declare

Neutrophils associate with Bowman’s capsule rupture specifically in PR3-ANCA glomerulonephritis

Background!#!Renal involvement is a common and severe complication of ANCA (antineutrophil cytoplasmic antibody) associated vasculitis (AAV) potentially resulting in a pauci-immune necrotizing and crescentic antineutrophil cytoplasmic antibody (ANCA) glomerulonephritis (GN) with acute kidney injury (AKI), end-stage renal disease (ESRD) or death. We recently described that Bowman's capsule rupture links glomerular damage to tubulointerstitial inflammation in ANCA-associated glomerulonephritis. Herein we provide a comprehensive histological subtyping of immune cell infiltrates in association with Bowman's capsule rupture in ANCA GN.!##!Methods!#!A total of 44 kidney biopsies with ANCA GN were retrospectively included in a single-center observational study. Within a renal biopsy specimen, each glomerulus was scored separately for the presence of extensive and focal Bowman's capsule rupture in injured glomeruli. Infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the area of total cortical inflammation.!##!Results!#!Extensive Bowman's capsule rupture was associated with tubulointerstitial inflammation containing infiltrates of neutrophils, eosinophils and plasma cells. A similar association was observed for the presence of focal Bowman's capsule rupture, correlating with tubulointerstitial inflammation containing neutrophils, eosinophils and plasma cells. Multiple logistic regression confirmed that extensive Bowman's capsule rupture correlated with tubulointerstitial inflammation containing neutrophils, and focal Bowman's capsule rupture correlated with neutrophil and plasma cell infiltration. Furthermore, this association was specifically observed in PR3-ANCA GN.!##!Conclusion!#!To our knowledge, this is the first report linking Bowman's capsule rupture directly to tubulointerstitial inflammation by immune cell subtypes. This underscores a pathomechanistic link between tubulointerstitial and glomerular lesions in ANCA GN and needs further investigation

C-Reactive Protein Levels Are Associated with Complement C4 Deposits and Interstitial Arteritis in ANCA-Associated Renal Vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis in case of kidney involvement, representing a major denominator of AAV mortality. Innate immunity with complement system activation is increasingly recognized in the pathogenesis of AAV and as an attractive therapeutic target. Although C-reactive protein (CRP) was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self-determinants. Elevated baseline CRP at disease onset of AAV has already been described as a determinant of poor long-term outcomes. However, its clinical implications at disease onset of AAV, with respect to vasculitis manifestations and complement system activation that might also affect long-term outcomes, remain elusive. CRP levels were retrospectively analyzed in 53 kidney-biopsy-confirmed cases of ANCA-associated renal vasculitis; a total of 138 disease controls were also evaluated. Univariate and multivariate regression analysis was performed on clinicopathological parameters associated with CRP levels in ANCA-associated renal vasculitis. Results: Compared to disease controls, CRP elevation was common in ANCA-associated renal vasculitis and associated with de novo disease (p = 0.0169), critical illness (p = 0.0346), and severe deterioration of kidney function (p = 0.0167), independent of extrarenal disease manifestations. As confirmed by multiple regression analysis, CRP levels were correlated with active lesions predominated by interstitial arteritis in renal vasculitis, specifically with MPO-ANCA seropositivity (p = 0.0017). Based on analysis of systemic complement system activation and intrarenal complement deposits, CRP elevation was correlated specifically with complement C4 deposits in interstitial arteries in the subgroup with myeloperoxidase (MPO)-ANCA seropositivity (p = 0.039). Finally, this association was independent of systemic complement system activation, as reflected by the consumption of respective complement components. Here, we expand our current understanding of CRP in ANCA-associated renal vasculitis not only as an inflammatory marker, but potentially also as being involved in the pathogenesis of kidney injury by interaction with the complement system.Else-Kröner research programGöttingen UniversityOpen-Access-Publikationsfonds 202