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Transplant-associated thrombotic microangiopathy (TA-TMA) is an endotheliopathy complicating up to 30% of allogeneic hematopoietic stem cell transplants (alloHSCT). Positive feedback loops among complement, pro-inflammatory, pro-apoptotic, and coagulation cascade likely assume dominant roles at different disease stages. We hypothesized that mannose-binding lectin-associated serine protease 2 (MASP2), principal activator of the lectin complement system, is involved in the microvascular endothelial cell (MVEC) injury characteristic of TA-TMA through pathways that are susceptible to suppression by anti-MASP2 monoclonal antibody narsoplimab. Pre-treatment plasmas from 8 of 9 TA-TMA patients achieving a complete TMA response in a narsoplimab clinical trial activated caspase 8, the initial step in apoptotic injury, in human MVEC. This was reduced to control levels following narsoplimab treatment in 7 of the 8 subjects. Plasmas from 8 individuals in an observational TA-TMA study, but not 8 alloHSCT subjects without TMA, similarly activated caspase 8, which was blocked in vitro by narsoplimab. mRNA sequencing of MVEC exposed to TA-TMA or control plasmas with and without narsoplimab suggested potential mechanisms of action. The top 40 narsoplimab-affected transcripts included upregulation of SerpinB2, which blocks apoptosis by inactivating procaspase 3; CHAC1, which inhibits apoptosis in association with mitigation of oxidative stress responses; and pro-angiogenesis proteins TM4SF18, ASPM, and ESM1. Narsoplimab also suppressed transcripts encoding pro-apoptotic and pro-inflammatory proteins ZNF521, IL1R1, Fibulin-5, aggrecan, SLC14A1, and LOX1, and TMEM204, which disrupts vascular integrity. Our data suggest benefits to narsoplimab use in high-risk TA-TMA and provide a potential mechanistic basis for the clinical efficacy of narsoplimab in this disorder. Transplant-associated thrombotic microangiopathy (TA-TMA) complicates up to 30% of allogeneic stem cell transplants and is a significant cause of mortality. Positive feedback loops among complement, pro-inflammatory, pro-apoptotic, and coagulation cascades are involved in the endotheliopathy underlying this condition, with MASP2 and the lectin pathway a major component. Utilizing RNAseq and ex vivoand in vitromodels with patient plasmas, we identified a plausible mechanism by which the MASP2 inhibitor narsoplimab could protect against endothelial cell injury in TA-TMA, as illustrated in this figure. [ABSTRACT FROM AUTHOR]

Mannose-binding lectin-associated serine proteases (MASP) are among of the key components in the lectin pathway (LP) of the complement activation. MASP-2 is the most studied agent among specific enzymes activating both mannose-binding lectin (MBL) and ficolins, pattern-recognition proteins involved in the elimination of pathogenic microorganisms through LP complement activation. There are some mutations in MASP2, with the most significant identified as rs72550870 (p.D120G). The homozygous GG rs72550870 is associated with congenital MASP-2 deficiency and characterized by a total lack of serum protease activity, which leads to impaired binding to lectins. This, in turn, results in severe course of infectious diseases with a high risk of adverse outcome. There seem to be some marked populational differences in the genotype and haplotype prevalence in MASP2 gene polymorphisms. To date, no data are available on the genotype distribution for the MASP2 gene in the indigenous populations of the Russian Arctic regions. The aim of the work was to study the prevalence and ethnic specificity in the distribution of allelic variants of MASP2 rs72550870 in the populations of the Taymyr Dolgan-Nenets District of the Krasnoyarsk Territory (Nenets, Dolgans, Nganasans) as well as the city of Krasnoyarsk (Russians). MASP2 genotyping was performed by using real-time PCR. The frequencies of the AG genotype associated with low MASP-2 level was 6.6% for ethnic Russian newborns in the Eastern Siberia. The prevalence of the AG genotype was significantly lower in newborns of the Arctic populations than in the Russians, being 0.3% and 0.9% for the Nenets and the Dolgan-Nganasans, respectively, which is close to the prevalence values identified for Asian and African populations (0%). No homozygous GG rs72550870 associated with congenital MASP-2 deficiency in newborns of the indigenous populations of the Taymyr Dolgan-Nenets region of Krasnoyarsk Territory (Nenets and Dolgan-Nganasans) and ethnic Caucasian subjects of the Krasnoyarsk city was detected. The frequency of the rare allelic variant G rs72550870 in ethnic Russian subjects was 3.3%, being close to the frequencies in the European populations of the world (4.0%), whereas it was 0.5% in the indigenous inhabitants of the Arctic Region. We have suggested that isolated Arctic populations encounter some intracellular infections historically later and, as contrasted with Caucasoid populations, retained a high activity in the lectin pathway of the complement activation established at the early stage of human evolution.

Lectins, being the main proteins of the lectin pathway activating the complement system, are encoded by polymorphic genes, wherein point mutations cause the protein conformation and expression to change, which turns out to have an effect on the functionality and ability to respond to the pathogen. In the current study, largescale data on the population genotype distribution of the genes for H-ficolin FCN3 rs28357092 and mannose-binding lectin-associated serine protease MASP2 rs72550870 among the indigenous peoples of the Russian Arctic regions (Nenets, Dolgans and Nganasans, a mixed population and Russians: a total sample was about 1000 newborns) have been obtained for the first time. Genotyping was carried out using RT-PCR. The frequency of the homozygous variant del/del FCN3 rs28357092 associated with the total absence of the most powerful activator of the lectin complement pathway, N-ficolin, was revealed; 0 % in the Nenets, 0.8 % in the Dolgans and Nganasans, and 3.5 % among the Russians ( p < 0.01). Analysis of the prevalence of the MASP2 genotypes has shown the predominance of the homozygous variant AA in all studied populations, which agrees with the available world data. The heterozygous genotype AG rs72550870 associated with a reduced level of protease was found to occur rarely in the Nenets, Dolgans and Nganasans compared to newborns of Caucasoid origin from Krasnoyarsk: 0.5 % versus 3.3 %, respectively. Moreover, among 323 examined Nenets, one AG carrier was identified, whereas in Russians, 16 out of 242 examined newborns were found to be AG carriers ( p < 0.001). A homozygous variant (GG) in total absence of protease with impaired binding of both MBL and ficolins was not detected in any of the 980 examined newborns. An additional analysis of infectious morbidity in Arctic populations allows one to find phenotypic characteristics related to a high functional activity of the lectin pathway of complement activation as an most important factor for the first-line of anti-infectious defense, including such new viral diseases as COVID-19.

Mannose binding lectin‐associated serine protease 2 (MASP2) is the effector part of mannose binding lectin (MBL) that activates the complement system in an antibody‐independent manner. We aimed to investigate the role of genetic polymorphisms in the MASP2 gene and susceptibility to HTLV‐1 infection. A total of 172 HTLV‐1 infected individuals and 170 healthy blood donors were analyzed in this case–control study. Nine single nucleotide polymorphisms (SNPs) encompassing different regions of the MASP2 gene were genotyped with a polymerase chain reaction‐sequence‐specific primer (PCR‐SSP) assay. The relation between the SNPs genotype and the susceptibility to HTLV‐1 infection was investigated with a χ2 test considering P < 0.05 as statistically significant. Two of nine tested SNPs were associated with the risk of HTLV‐1 infection. The genotype TT at rs17409276 decreased the risk of HTLV‐1 (P = 0.005, OR = 0.301, 95% CI = 0.124–0.728). The genotypes CC and CT at rs2273346 were also associated with a higher risk of HTLV‐1 acquisition (P = 0.004, OR = 2.225, 95% CI = 1.277–3.877). These findings highlight the importance of MASP2 genetic polymorphisms in the lectin pathway of complement activation and susceptibility to HTLV‐1 infection. [ABSTRACT FROM AUTHOR]

Purpose: Immunoglobulin A (IgA) nephropathy (IgAN) is a common chronic glomerulonephritis and the main cause of end-stage renal diseases. Recent evidence suggests that mannan binding lectin associated serine proteases 2 (MASP2) is related to IgAN; therefore, we investigated the expression and significance of MASP2 in serum and urinary extracellular vesicles (UEVs) in patients with IgAN.Methods: Thirty-eight patients with IgAN and 17 healthy controls were enrolled in this study. UEVs were extracted by ultracentrifugation. The separation by ultra-high-speed centrifuge was verified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Candidate internal references (TSG101, CD9, flotillin, β-actin and GAPDH) were identified by western blotting in the control group, and the expression of MASP2 in the UEVs was compared. The levels of MASP2 in the serum and UEVs in the IgAN and control groups were determined by enzyme-linked immunosorbent assay (ELISA).Results: TEM and NTA results demonstrated that UEVs were successfully extracted. Western blotting results confirmed that TSG101 was suitable as an internal reference for this study. Compared with the control group, the IgAN group showed positive expression of MASP2. MASP2 levels in the UEVs, determined by ELISA, showed significant differences between IgAN and control groups, which were significantly positively correlated with the level of urinary microalbumin.Conclusions: The level of MASP2 in UEVs was related to IgAN and shows promise as a biomarker for evaluating the severity of renal injury and prognosis of IgAN, thereby helping to elucidate the role of MASP2 in the mannan-binding lectin pathway. [ABSTRACT FROM AUTHOR]

Purpose: Immunoglobulin A (IgA) nephropathy (IgAN) is a common chronic glomerulonephritis and the main cause of end-stage renal diseases. Recent evidence suggests that mannan binding lectin associated serine proteases 2 (MASP2) is related to IgAN; therefore, we investigated the expression and significance of MASP2 in serum and urinary extracellular vesicles (UEVs) in patients with IgAN., Methods: Thirty-eight patients with IgAN and 17 healthy controls were enrolled in this study. UEVs were extracted by ultracentrifugation. The separation by ultra-high-speed centrifuge was verified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Candidate internal references (TSG101, CD9, flotillin, β-actin and GAPDH) were identified by western blotting in the control group, and the expression of MASP2 in the UEVs was compared. The levels of MASP2 in the serum and UEVs in the IgAN and control groups were determined by enzyme-linked immunosorbent assay (ELISA)., Results: TEM and NTA results demonstrated that UEVs were successfully extracted. Western blotting results confirmed that TSG101 was suitable as an internal reference for this study. Compared with the control group, the IgAN group showed positive expression of MASP2. MASP2 levels in the UEVs, determined by ELISA, showed significant differences between IgAN and control groups, which were significantly positively correlated with the level of urinary microalbumin., Conclusions: The level of MASP2 in UEVs was related to IgAN and shows promise as a biomarker for evaluating the severity of renal injury and prognosis of IgAN, thereby helping to elucidate the role of MASP2 in the mannan-binding lectin pathway.

Lectins, being the main proteins of the lectin pathway activating the complement system, are encoded by polymorphic genes, wherein point mutations cause the protein conformation and expression to change, which turns out to have an effect on the functionality and ability to respond to the pathogen. In the current study, largescale data on the population genotype distribution of the genes for H-ficolin FCN3 rs28357092 and mannose-binding lectin-associated serine protease MASP2 rs72550870 among the indigenous peoples of the Russian Arctic regions (Nenets, Dolgans and Nganasans, a mixed population and Russians: a total sample was about 1000 newborns) have been obtained for the first time. Genotyping was carried out using RT-PCR. The frequency of the homozygous variant del/del FCN3 rs28357092 associated with the total absence of the most powerful activator of the lectin complement pathway, N-ficolin, was revealed; 0 % in the Nenets, 0.8 % in the Dolgans and Nganasans, and 3.5 % among the Russians ( p < 0.01). Analysis of the prevalence of the MASP2 genotypes has shown the predominance of the homozygous variant AA in all studied populations, which agrees with the available world data. The heterozygous genotype AG rs72550870 associated with a reduced level of protease was found to occur rarely in the Nenets, Dolgans and Nganasans compared to newborns of Caucasoid origin from Krasnoyarsk: 0.5 % versus 3.3 %, respectively. Moreover, among 323 examined Nenets, one AG carrier was identified, whereas in Russians, 16 out of 242 examined newborns were found to be AG carriers ( p < 0.001). A homozygous variant (GG) in total absence of protease with impaired binding of both MBL and ficolins was not detected in any of the 980 examined newborns. An additional analysis of infectious morbidity in Arctic populations allows one to find phenotypic characteristics related to a high functional activity of the lectin pathway of complement activation as an most important factor for the first-line of anti-infectious defense, including such new viral diseases as COVID-19., (Copyright © AUTHORS.)