scholarly journals Interferon-complement loop in transplant-associated thrombotic microangiopathy

2020 ◽  
Vol 4 (6) ◽  
pp. 1166-1177 ◽  
Author(s):  
Sonata Jodele ◽  
Mario Medvedovic ◽  
Nathan Luebbering ◽  
Jenny Chen ◽  
Christopher E. Dandoy ◽  
...  
Keyword(s):  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Mononuclear Cells ◽  
Transcriptional Regulatory Network ◽  
Tissue Injury ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Endothelial Injury ◽  
Hematopoietic Stem ◽  
Complement Pathways

Abstract Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

scholarly journals Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Hiroshi Okamura ◽  
Hirohisa Nakamae ◽  
Takero Shindo ◽  
Katsuki Ohtani ◽  
Yoshihiko Hidaka ◽  
...  
Keyword(s):  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Genetic Variants ◽  
Rare Variants ◽  
Alternative Pathway ◽  
Plasma Concentrations ◽  
Predictive Biomarker ◽  
Rare Allele ◽  
Complement Factor ◽  
Hematopoietic Stem

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation via the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA.

Similar Levels of Complement Activation in Both Patients with Thrombotic Thrombocytopenic Purpura and Atypical Hemolytic Uremic Syndrome: The Report from the Korean TTP Registry

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4195-4195
Author(s):  
Doyeun Oh ◽  
Ji Young Huh ◽  
So Young Chong ◽  
In-Ho Kim ◽  
Soo-Mee Bang ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Complement Activation ◽  
Conflicts Of Interest ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Healthy Controls ◽  
Adamts13 Activity ◽  
Newly Diagnosed ◽  
Thrombocytopenic Purpura ◽  
Complement Pathways

Abstract Background: Uncontrolled complement activation has a major role in the pathogenesis of atypical HUS (aHUS) and the restraint of this process by eculizumab is life saving. However, the evidence of complement dysregulation in the pathogenesis of Thrombotic Thrombocytopenic Purpura (TTP) is still unclear. In this study we examined the presence of complement activation biomarkers in patients with aHUS and TTP and the levels were compared to normal healthy controls . Patients and Methods: Patients with thrombotic microangiopathic thrombocytopenia diagnosed either as TTP with low ADAMTS13 activity less than 10% or aHUS with impaired renal function, Cr> 2mg/dL and normal ADAMTS13 activity were chosen from the Korean TTP registry from February 2012 to June 2014. Prospective plasma and serum samples prior to intervention were collected from newly diagnosed patients with TTP (n=20), aHUS (n=20), and 20 healthy controls and frozen at -700C. Complement activation products (C3a, Bb as alternative pathway; C4d as classic pathway; C5a, C5b-9; terminal pathway) were measured by ELISA. Results: Significantly increased levels of Bb and C5b-9 were observed in TTP (median [range], ng/mL; Bb, 1220 [540.0 – 16560], p=0.048; C5b - 9, 390.1 [238.5 - 938.7], p<0.0001) when compared with controls (Bb, 870.0 [630.0 - 2070]; C5b - 9, 190.8 [77.96 - 458.9]). Increased levels of C3a, C5a, C5b - 9, and Factor Bb were observed in HUS (C3a, 231.3 [80.70 - 791.8], p<0.0001; C5a, 21.38 [5.590 - 34.96], p= 0.006; C5b - 9, 0.49 [0.21 - 1.41], p<0.0001; Bb, 1490 [540.0 – 11800], p= 0.0003) as compared with controls (C3a, 108.7 [30.98 - 425.1]; C5a, 8.620 [2.660 - 26.93]; C5b - 9, 0.49 [0.21 - 1.41]; Bb, 870.0 [630.0 - 2070]). These suggested alternative and terminal complement pathways were activated in initial episodes of TTP or HUS. However levels of C4d were not different in HUS and TTP as compared with controls which suggested classic complement pathways were not important in this process. There were no significant differences in complement levels between TTP and HUS although levels of C3a, C4d, C5b - 9 in HUS (C3a, 231.3 [80.70 - 791.8]; C4d, 2140 [10.00 - 960.0]; C5b - 9, 488.4 [212.7 – 1414]) tended to be increased as compared with TTP (C3a, 134.5 [61.97 - 378.4]; C4d, 1330 [2.000 - 699.0]; C5b - 9, 390.1 [238.5 - 938.7]). Conclusion: Complement biomarkers are activated to a similar level in both newly diagnosed cases of TTP and aHUS. Complement activation product levels did not differentiate aHUS from TTP. Disclosures No relevant conflicts of interest to declare.

scholarly journals Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome

2017 ◽  
Vol 29 (3) ◽  
pp. 1020-1029 ◽  
Author(s):  
Martina Gaggl ◽  
Christof Aigner ◽  
Dorottya Csuka ◽  
Ágnes Szilágyi ◽  
Zoltán Prohászka ◽  
...  
Keyword(s):  
Thrombotic Microangiopathy ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Intrauterine Fetal Death ◽  
Renal Outcome ◽  
Close Monitoring ◽  
Complement Alternative Pathway ◽  
Ckd Stage ◽  
Life Threatening ◽  
Stage 1

Atypical HUS (aHUS) is a disorder most commonly caused by inherited defects of the alternative pathway of complement, or the proteins that regulate this pathway, and life-threatening episodes of aHUS can be provoked by pregnancy. We retrospectively and prospectively investigated 27 maternal and fetal pregnancy outcomes in 14 women with aHUS from the Vienna Thrombotic Microangiopathy Cohort. Seven pregnancies (26%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by infection, bleeding, and curettage, and three individuals were considered to have preeclampsia/HELLP syndrome before the definitive diagnosis of p-aHUS was made. Mutations in genes that encode the complement alternative pathway proteins or the molecules that regulate this pathway were detected in 71% of the women, with no relationship to pregnancy outcome. Twenty-one pregnancies (78%) resulted in a live birth, two preterm infants were stillborn, and four pregnancies resulted in early spontaneous abortions. Although short-term renal outcome was good in most women, long-term renal outcome was poor; among the 14 women, four had CKD stage 1–4, five had received a renal allograft, and three were dialysis-dependent at study end. We prospectively followed nine pregnancies of four women and treated six of these pregnancies with prophylactic plasma infusions (one pregnancy resulted in p-aHUS, one intrauterine fetal death occurred, and seven pregancies were uneventful). Our study emphasizes the frequency of successful pregnancies in women with aHUS. Close monitoring of such pregnancies for episodes of thrombotic microangiopathy is essential but, the best strategy to prevent these episodes remains unclear.

scholarly journals Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy

Blood ◽  
2013 ◽  
Vol 122 (12) ◽  
pp. 2003-2007 ◽  
Author(s):  
Sonata Jodele ◽  
Christoph Licht ◽  
Jens Goebel ◽  
Bradley P. Dixon ◽  
Kejian Zhang ◽  
...  
Keyword(s):  
Thrombotic Microangiopathy ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Alternative Pathway ◽  
Cell Transplant ◽  
Treatment Interventions ◽  
Hematopoietic Stem ◽  
Novel Treatment ◽  
Key Points ◽  
Alternative Pathway Of Complement

Key Points Genetic variations in the alternative pathway of complement may be associated with thrombotic microangiopathy in children receiving HSCT. These findings may guide the development of novel treatment interventions for this poorly understood transplant complication.

scholarly journals Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD

Blood ◽  
2017 ◽  
Vol 130 (10) ◽  
pp. 1259-1266 ◽  
Author(s):  
Nicholas J. Gloude ◽  
Pooja Khandelwal ◽  
Nathan Luebbering ◽  
Dana T. Lounder ◽  
Sonata Jodele ◽  
...  
Keyword(s):  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Endothelial Injury ◽  
Neutrophil Recovery ◽  
Key Points

Key Points dsDNA production peaks 14 days after HSCT, likely a result of IL-8–driven neutrophil recovery. dsDNA production may serve as a mechanistic link between endothelial injury, TA-TMA, and GVHD.

scholarly journals Monomeric C-reactive protein inhibits renal cell-directed complement activation mediated by properdin

2016 ◽  
Vol 310 (11) ◽  
pp. F1308-F1316 ◽  
Author(s):  
Joseph O'Flynn ◽  
Pieter van der Pol ◽  
Karen O. Dixon ◽  
Zoltán Prohászka ◽  
Mohamed R. Daha ◽  
...  
Keyword(s):  
Complement Activation ◽  
Tissue Injury ◽  
Alternative Pathway ◽  
Fluorescent Microscopy ◽  
Jurkat Cells ◽  
C Reactive Protein ◽  
Tubular Cells ◽  
Reactive Protein ◽  
Renal Tubular Cells ◽  
Renal Tubular

Previous studies have shown that complement activation on renal tubular cells is involved in the induction of interstitial fibrosis and cellular injury. Evidence suggests that the tubular cell damage is initiated by the alternative pathway (AP) of complement with properdin having an instrumental role. Properdin is a positive regulator of the AP, which can bind necrotic cells as well as viable proximal tubular epithelial cells (PTECs), inducing complement activation. Various studies have indicated that in the circulation there is an unidentified inhibitor of properdin. We investigated the ability of C-reactive protein (CRP), both in its monomeric (mCRP) and pentameric (pCRP) form, to inhibit AP activation and injury in vitro on renal tubular cells by fluorescent microscopy, ELISA, and flow cytometry. We demonstrated that preincubation of properdin with normal human serum inhibits properdin binding to viable PTECs. We identified mCRP as a factor able to bind to properdin in solution, thereby inhibiting its binding to PTECs. In contrast, pCRP exhibited no such binding and inhibitory effect. Furthermore, mCRP was able to inhibit properdin-directed C3 and C5b-9 deposition on viable PTECs. The inhibitory ability of mCRP was not unique for viable cells but also demonstrated for binding to necrotic Jurkat cells, a target for properdin binding and complement activation. In summary, mCRP is an inhibitor of properdin in both binding to necrotic cells and viable renal cells, regulating complement activation on the cell surface. We propose that mCRP limits amplification of tissue injury by controlling properdin-directed complement activation by damaged tissue and cells.

scholarly journals Primer komplementdefektusok által okozott atípusos haemolyticus uraemiás szindróma

2018 ◽  
Vol 159 (23) ◽  
pp. 929-936 ◽  
Author(s):  
György Reusz
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Critical Role ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Genetic Diagnostics ◽  
Activation Process ◽  
Phagocytic Cells ◽  
Uremic Syndrome ◽  
The Complement System

Abstract: Complement is one of the most archaic parts of the innate immune system, which enhances the ability of antibodies and phagocytic cells to clear cell debris, and microorganisms. The complement system promotes inflammation and attacks the pathogen’s plasma membrane. Malfunction of the system may lead to the development of autoimmunity or uncontrolled infections. Further, dysregulation of the tightly controlled complement activation process may lead to thrombotic microangiopathies with consequent multiorgan involvement. The present paper gives a short overview of the different pathways of complement activation. It focuses on primary genetic defects of components of the alternative pathway that result in dysregulation as well as on pathomechanism, classification, diagnostics and treatment of atypical hemolytic uremic syndrome (aHUS) based on the most recent international recommendations and guidelines. Finally the critical role of complement in host immunity and genetic diagnostics of complement deficiencies are illustrated with two cases of aHUS. Orv Hetil. 2018; 159(23): 929–936.

scholarly journals Factor H Autoantibodies and Complement-Mediated Diseases

2020 ◽  
Vol 11 ◽  
Author(s):  
Yuzhou Zhang ◽  
Nicolo Ghiringhelli Borsa ◽  
Dingwu Shao ◽  
Arthur Dopler ◽  
Michael B. Jones ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Alternative Pathway ◽  
Phenotypic Variability ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Fluid Phase ◽  
Factor H ◽  
Regulatory Function ◽  
Regulators Of Complement Activation ◽  
Uremic Syndrome ◽  
Genetic Deletion

Factor H (FH), a member of the regulators-of-complement-activation (RCA) family of proteins, circulates in human plasma at concentrations of 180–420 mg/L where it controls the alternative pathway (AP) of complement in the fluid phase and on cell surfaces. When the regulatory function of FH is impaired, complement-mediated tissue injury and inflammation occur, leading to diseases such as atypical hemolytic uremic syndrome (a thrombotic microangiopathy or TMA), C3 glomerulopathy (C3G) and monoclonal gammopathy of renal significance (MGRS). A pathophysiological cause of compromised FH function is the development of autoantibodies to various domains of the FH protein. FH autoantibodies (FHAAs) are identified in 10.9% of patients with aHUS, 3.2% of patients with C3G, and rarely in patients with MGRS. The phenotypic variability of FHAA-mediated disease reflects both the complexity of FH and the epitope specificity of FHAA for select regions of the native protein. In this paper, we have characterized FHAA epitopes in a large cohort of patients diagnosed with TMA, C3G or MGRS. We explore the epitopes recognized by FHAAs in these diseases and the association of FHAAs with the genetic deletion of both copies of the CFHR1 gene to show how these disease phenotypes are associated with this diverse spectrum of autoantibodies.

P0403INNATE DEFECTS OF COMPLEMENT ALTERNATIVE PATHWAY AMONG LUPUS PATIENTS WITH AND WITHOUT THROMBOTIC MICROANGIOPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Cai Yue ◽  
Quexian Cui ◽  
Xuemei Li
Keyword(s):  
Lupus Erythematosus ◽  
Thrombotic Microangiopathy ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Malignant Hypertension ◽  
Complement Alternative Pathway ◽  
College Hospital ◽  
Medical College ◽  
Significant Difference ◽  
Uremic Syndrome

Abstract Background and Aims Thrombotic microangiopathy (TMA) is a rare and severe complication of systemic lupus erythematosus (SLE). The pathogenesis of TMA among lupus patients is not fully understood yet. The aim of the study was to evaluated innate complement alternative pathway (AP) defects among patients with SLE-TMA. Method 15 consecutive lupus patients with clinically or pathologically diagnosed TMA from Peking Union Medical College Hospital through Jan 2017 to Dec 2019 were enrolled. Lupus patients with TMA secondary to antiphospholipid antibodies, ADAMTS13 inhibitor, overlap syndrome, infection, malignant hypertension and medications were excluded. The exonic regions of 13 genes including CFH, CFI, CFB, C3, CFHR1-5, MCP, THBD, DGKE, PLG were analysed with next generation sequencing. Mutations were interpreted according to ACMG 2015 guideline. Patients with atypical hemolytic uremic syndrome (aHUS) (n=2), lupus nephritis (LN) without TMA (n=8), and malignant hypertension (n=6) were set as control. Results Six AP mutations rated as VUS or likely pathogenic were detected among 5/15 (33.3%) patients with SLE-TMA, while three were detected among 3/8 (37.5%) of patients with LN, one among 1/6 (16.7%) patients with malignant hypertension, and three among 2/2 (100%) of patients with aHUS. There was no significant difference regarding mutation rate among the groups. Conclusion There is no significant difference regarding AP mutations among lupus patients with and without TMA. Mechanisms other than innate AP abnormality may be involved in the pathogenesis of TMA among lupus patients.

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