Search

MBL is critical in activating the lectin pathway of the complement system. MBL deficiency remains a contentious issue in clinical practice, mainly because low MBL levels may present in completely asymptomatic individuals. However, in some cases, symptomatic patients may present with susceptibility to infections and even immune dysregulation. Infections may range from mild to severe, and may even be life-threatening and fatal. A significant number of patients may remain undiagnosed, merely because interrogating complement function is often postponed until after presumably more common immune problems have been excluded in patients with severe, recurrent or unusual infections. In addition, clinicians are less familiar with the clinical recognition and appropriate choice of special investigations necessary to diagnose MBL and other complement deficiencies. Our case report describes a young girl with a serious underlying inborn error of immunity. She initially presented with recurrent 'innocent' and mild infections. We illustrate that clinically relevant MBL deficiency, if undiagnosed, may have disastrous consequences. We also stress the importance of careful interpretation of MBL quantitative laboratory values and the urgent need for access to more specialised complement-component and genetic testing, especially for patients attending state healthcare facilities. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationships between serum mannan-binding lectin (MBL), B-cell activating factor of the tumor necrosis factor family (BAFF) and renal function and outcome of patients with phospholipase A2 receptor (PLA2R) -related idiopathic membranous nephropathy (IMN) . Methods Totally 103 patients with PLA2R-related IMN were selected as the observation group, and the patients with PLA2R-related IMN were divided into the non-remission group (n=44) and the remission group (n=59) according to the therapeutic efficacy； and another 67 cases of healthy physical examination volunteers were selected as the control group during the same period. Relevant data were collected； serum MBL, BAFF, and 24 h urine protein were detected by ELISA, blood creatinine was detected by PA rate microplate assay kit, and the estimated glomerular filtration rate (eGFR) was calculated. Spearman correlation method was used to analyze the correlation between serum MBL and BAFF levels and renal function indexes in patients with PLA2R-related IMN； multifactorial Logistic regression was used to analyze the factors affecting the efficacy of patients with PLA2R-related IMN, and the receiver operating characteristic (ROC) curve was used to analyze the predictive value of serum MBL and BAFF for the unremitted treatment in patients with PLA2R-related IMN. Results Serum MBL, BAFF levels and 24 hurine protein were higher in the observation group than in the control group, and eGFR was lower than that in the control group (all P<0. 05) . Serum MBL and BAFF levels in patients with PLA2R-related IMN were negatively correlated with eGFR (r=-0. 777, -0. 760, respectively； all P<0. 05) and were positively correlated with 24 h urinary protein (r=0. 883, 0. 828, respectively； all P<0. 05) . Albumin and eGFR were lower in the non-remission group than in the remission group, and 24 h urinary protein, MBL and BAFF were higher than those in the remission group (all P<0. 05) . There were no statistically significant differences in the gender, age, blood creatinine, blood uric acid, blood urea nitrogen, total cholesterol, triglycerides, IgG, complement 3 or PLA2R antibody titer between the two groups (all P＞0. 05) . Elevated albumin and eGFR were independent protective factors affecting the outcome of patients with PLA2R-related IMN (all P<0. 05), and elevated 24-hour urinary protein, MBL, and BAFF were independent risk factors (all P<0. 05) . The area under the curve of serum MBL and BAFF in prediction of unremitted treatment in patients with PLA2R-related IMN (0. 880) was greater than that of either alone (0. 791, 0. 787), with statistically significant difference (Z=2. 694, 2. 613 respectively； both P<0. 05) . Conclusion Elevated serum MBL and BAFF levels are associated with reduced renal function and poor outcome in patients with PLA2R-related IMN, the combined detection of the two has a higher value in predicting the unrelieved treatment of PLA2R-related IMN patients. [ABSTRACT FROM AUTHOR]

Mannose-binding lectin (MBL) binds to SARS-CoV-2, inhibits infection of susceptible cells, and activates the complement system via the lectin pathway. In this study, we investigated the association of MBL2 polymorphisms with the risk of hospitalization and clinical worsening in patients with COVID-19. A total of 550 patients with COVID-19 were included (94 non-hospitalized and 456 hospitalized). Polymorphisms in MBL2 exon 1 (codons 52, 54 and 57) and promoter region (−550, −221, and +4) were determined by real-time PCR. MBL and complement proteins were measured by Luminex. A higher frequency of the H/H genotype and the HYPA haplotype was observed in non-hospitalized patients when compared to hospitalized. In addition, critically ill patients carrying haplotypes associated with high MBL levels (HYPA/HYPA + HYPA/LYPA + HYPA/LYQA + LYPA/LYQA + LYPA/LYPA + LYQA/LYQA + LXPA/HYPA + LXPA/LYQA + LXPA/LYPA) were protected against lower oxygen saturation levels (P = 0.02), use of invasive ventilation use (P = 0.02, OR 0.38), and shock (P = 0.01, OR 0.40), independent of other potential confounders adjusted by multivariate analysis. Our results suggest that variants in MBL2 associated with high MBL levels may play a protective role in the clinical course of COVID-19.

MBL is critical in activating the lectin pathway of the complement system. MBL deficiency remains a contentious issue in clinical practice, mainly because low MBL levels may present in completely asymptomatic individuals. However, in some cases, symptomatic patients may present with susceptibility to infections and even immune dysregulation. Infections may range from mild to severe, and may even be life-threatening and fatal. A significant number of patients may remain undiagnosed, merely because interrogating complement function is often postponed until after presumably more common immune problems have been excluded in patients with severe, recurrent or unusual infections. In addition, clinicians are less familiar with the clinical recognition and appropriate choice of special investigations necessary to diagnose MBL and other complement deficiencies. Our case report describes a young girl with a serious underlying inborn error of immunity. She initially presented with recurrent 'innocent' and mild infections. We illustrate that clinically relevant MBL deficiency, if undiagnosed, may have disastrous consequences. We also stress the importance of careful interpretation of MBL quantitative laboratory values and the urgent need for access to more specialised complement-component and genetic testing, especially for patients attending state healthcare facilities. [ABSTRACT FROM AUTHOR]

Nanotechnology enables investigations of single biomacromolecules, but technical challenges have limited the application in liquid biopsies, for example, blood plasma. Nonetheless, tools to characterize single molecular species in such samples represent a significant unmet need with the increasing appreciation of the physiological importance of protein structural changes at nanometer scale. Mannose-binding lectin (MBL) is an oligomeric plasma protein and part of the innate immune system through its ability to activate complement. MBL also serves a role as a scavenger for cellular debris, especially DNA. This may link functions of MBL with several inflammatory diseases in which cell-free DNA now appears to play a role, but mechanistic insight has been lacking. By making nanoparticle tracking analysis possible in human plasma, we now show that superoligomeric structures of MBL form nanoparticles with DNA. These oligomers correlate with disease activity in systemic lupus erythematosus patients. With the direct quantification of the hydrodynamic radius, calculations following the principles of Taylor dispersion in the blood stream connect the size of these complexes to endothelial inflammation, which is among the most important morbidities in lupus. Mechanistic insight from an animal model of lupus supported that DNA-stabilized superoligomers stimulate the formation of germinal center B cells and drive loss of immunological tolerance. The formation involves an inverse relationship between the concentration of MBL superoligomers and antibodies to double-stranded DNA. Our approach implicates the structure of DNA-protein nanoparticulates in the pathobiology of autoimmune diseases.

Mannan-binding lectin (MBL) is a pattern-recognition molecule that plays a crucial role in innate immunity. MBL deficiency correlates with an increased risk of chronic kidney disease (CKD). However, the molecular mechanisms are not fully defined. Here, we established a CKD model in wild-type (WT) and MBL-deficient (MBL−/−) mice via unilateral ureteral obstruction (UUO). The result showed that MBL deficiency aggravated the pathogenesis of renal fibrosis in CKD mice. Strikingly, the in vivo macrophage depletion investigation revealed that macrophages play an essential role in the MBL-mediated suppression of renal fibrosis. We found that MBL limited the progression of macrophage-to-myofibroblast transition (MMT) in kidney tissues of UUO mice. Further in vitro study showed that MBL−/− macrophages exhibited significantly increased levels of fibrotic-related molecules compared with WT cells upon transforming growth factor beta (TGF-β) stimulation. We demonstrated that MBL inhibited the MMT process by suppressing the production of matrix metalloproteinase 9 (MMP-9) and activation of Akt signaling. In summary, our study revealed an expected role of MBL on macrophage transition during renal fibrosis, thus offering new insight into the potential of MBL as a therapeutic target for CKD.

Yunzhi Liu,1,2,&ast; Na Zhao,3,&ast; Qishan Xu,1,2 Fan Deng,1 Ping Wang,1,2 Lijun Dong,1,2 Xiao Lu,2 Lihua Xia,3 Mingyong Wang,4 Zhengliang Chen,2 Jia Zhou,2 Daming Zuo1,5 1Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 2Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 3Department of Medical Laboratory, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, Guangdong, 510399, People’s Republic of China; 4Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China; 5Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jia Zhou, Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Tel +86-20-61648220, Fax +86-20-61648221, Email yuguomm@smu.edu.cn Daming Zuo, Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Tel +86-20-61648552, Fax + 86-20-61648221, Email zdaming@smu.edu.cnObjective: Mannan-binding lectin (MBL), a soluble pattern recognition molecule of the innate immune system, is primarily synthesized in the liver and secreted into the circulation. Low serum level of MBL has been reported to be related to an increased risk of lung diseases. Herein, we aimed to investigate the function of MBL in silicosis-associated pulmonary inflammation.Methods: Serum collected from silicosis patients was tested for correlation between serum MBL levels and Th17 immunity. In vitro studies were performed to further demonstrated the effect of MBL on Th17 polarization. Silica was intratracheally injected in wild type (WT) or MBL-deficient (MBL–/–) mice to induce silicosis-associated lung inflammation and fibrosis. Th17 response was evaluated to explore the effect of MBL on silicosis in vivo.Results: Silicosis patients with high serum MBL levels displayed ameliorative lung function. We demonstrated that serum MBL levels negatively correlated to Th17 cell frequency in silicosis patients. MBL protein markedly reduced expression of IL-17 but enhanced expression of Foxp3 in CD4+ T cells in vitro when subjected to Th17 or Treg polarizing conditions, respectively. The presence of MBL during Th17 cell polarization significantly limited aryl hydrocarbon receptor (AhR) expression and suppressed the signal transducer and activator of transcription 3 (STAT3) phosphorylation. Treatment with the AhR antagonist abolished the effect of MBL on Th17 response. Strikingly, MBL directly bound to AhR and affected its nuclear translocation. Furthermore, MBL–/– mice displayed elevated Th17 cell levels compared with WT mice in response to the silica challenge. The CD4+ T lymphocytes from silica-administrated MBL–/– mice exhibited more AhR expression than the wild-type counterparts.Conclusion: Our study suggested that MBL limited the Th17 immunity via controlling the AhR/STAT3 pathway, thus providing new insight into silicosis and other inflammatory diseases in patients with MBL deficiency.Keywords: silicosis, mannan-binding lectin, aryl hydrocarbon receptor, signal transducer and activator of transcription 3, Th17 cell

Idiopathic pulmonary fibrosis (IPF) is a type of idiopathic interstitial pneumonia with a poor clinical prognosis. Increasing evidence has demonstrated that epithelial-mesenchymal transition (EMT) contributes to the production of pathogenic myofibroblasts and plays a pivotal role in the development of pulmonary fibrosis. Mannan-binding lectin (MBL) is a soluble calcium-dependent complement molecule. Several studies have reported associations between serum MBL levels and lung diseases; however, the effect of MBL on IPF remains unknown. The present study observed aggravated pulmonary fibrosis in bleomycin-treated MBL−/− mice compared with their wild-type counterparts. Lung tissues from bleomycin-treated MBL−/− mice displayed a more severe EMT phenotype. In vitro studies determined that MBL inhibited the EMT process through attenuating store-operated calcium entry (SOCE) signaling. It was further demonstrated that MBL promoted the ubiquitination of Orai1, an essential component of SOCE, via pyruvate dehydrogenase kinase 1 (PDK1)-serum glucocorticoid-regulated kinase 1 signaling. PDK1 inhibition abolished the MBL-mediated regulation of SOCE activity and the EMT process. Notably, biochemical analysis showed that MBL interacted with PDK1 and contributed to PDK1 ubiquitination. In summary, the present findings suggested that MBL limited the EMT phenotype in human alveolar epithelial cells through regulation of SOCE, and MBL could be recognized as a potential therapeutic target for IPF.

Fanping Wang,1,2 Yonghui Yang,1,3 Zhixin Li,1,2 Yan Wang,1,4 Zhenchao Zhang,2,5 Wei Zhang,2,5 Yonghui Mu,2,5 Jingwen Yang,1,2 Lili Yu,2,5 Mingyong Wang1,2 1Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 2Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang, 453003, People’s Republic of China; 3Henan Center for Disease Control and Prevention, Zhengzhou, Henan, 450000, People’s Republic of China; 4Department of Laboratory Medicine, Luoyang Oriental Hospital, Luoyang, Henan, 471000, People’s Republic of China; 5School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of ChinaCorrespondence: Mingyong Wang; Lili Yu, Email wmy118@126.com; merrys222@126.comBackground: Mannan-binding lectin (MBL) is a key molecule in innate immunity and activates the lectin complement pathway, which plays an important role in resisting Candida albicans (C. albicans) infection. However, the underlying mechanism of this resistance to infection remains unclear.Methods: In this study, we investigated how MBL regulates the differentiation of CD4+ T cells into T helper type 17 (Th17) and T regulatory (Treg) cells against C. albicans in mice, as well as the underlying mechanisms. We generated MBL double-knockout (KO) mice and infected them with C. albicans by intraperitoneal injection.Results: Compared with that in wild-type (WT) mice, the percentage of Th17 cells increased in MBL-null mice, whereas Treg cells decreased, indicating that MBL might regulate the Th17/Treg balance. In addition, in MBL-null mice, the expression levels of interleukin (IL)-17A, IL-21, and the master transcription factor of Th17 cells, RORγt, significantly increased. Conversely, IL-10, IL-2, and the Treg-specific transcription factor, Foxp3, decreased. Moreover, we found that the levels of TGF-β and IL-6 upregulated in MBL-null mice. Mechanistically, we found that MBL regulated the TGF-β/SMAD pathway through the inhibition of p-SMAD2 and promotion of p-SMAD3, and mediated the JAK/STAT pathway through the inhibition of p-JAK2 and p-STAT3 and promotion of p-JAK3 and p-STAT5. MBL double-KO mice showed a more severe inflammatory response and significantly lower survival rates with C. albicans infection.Conclusion: These results suggest that MBL regulates the Th17/Treg cell balance to inhibit inflammatory responses, possibly via IL-6- and TGF-β-mediated JAK/STAT and TGF-β/SMAD signaling, and play an important role in anti-C. albicans infection.Keywords: mannan-binding lectin, Th17/Treg axis, JAK/STAT, TGF-β/SMAD, Candida albicans

Background & Aims: Liver fibrosis represents a hallmark of most chronic liver diseases (CLD) triggered by recurrent liver injury and subsequent myofibroblast transdifferentiations of resident hepatic stellate cells (HSCs). Mannan-binding lectin (MBL) is potentially involved in hepatic fibrosis in CLD through unclear mechanisms. Therefore, we investigated the crosstalk between MBL and HSCs, and the consequent effects on fibrosis progression. Methods: Samples from patients with liver cirrhosis were collected. MBL deficiency (MBL-/-) and wild-type (WT) C57BL/6J mice were used to construct a CCl4-induced liver fibrosis model. Administration of MBL-expressing, liver-specific, adeno-associated virus was performed to restore hepatic MBL expression in MBL-/- mice. The human HSC line LX-2 was used for in vitro experiments. Results: MBL levels in patients with liver cirrhosis were correlated with disease severity. In the CCl4-induced liver fibrosis model, MBL-/- mice showed severer liver fibrosis accompanied by reduced senescent activated HSCs in liver tissue compared with WT mice, which could be inhibited by administering MBL-expressing, liver-specific, adeno-associated virus. Moreover, depleting senescent cells with senolytic treatment could abrogate these differences owing to MBL absence. Furthermore, MBL could interact directly with calreticulin associated with low-density lipoprotein receptor-related protein 1 on the cell surface of HSCs, which further promotes senescence in HSCs by up-regulating the mammalian target of rapamycin/p53/p21 signaling pathway. Conclusions: MBL as a newfound senescence-promoting modulator and its crosstalk with HSCs in the liver microenvironment is essential for the control of hepatic fibrosis progression, suggesting its potential therapeutic use in treating CLD associated with liver fibrosis.

IntroductionAccumulating evidence support that mannan-binding lectin (MBL) is a promising prognostic biomarker for risk-stratification of diabetic micro- and macrovascular complications. Serum MBL levels are predominately genetically determined and depend on MBL genotype. However, Type 1 diabetes (T1D) is associated with higher MBL serum levels for a given MBL genotype, but it remains unknown if this is also the case for patients with T2D. In this study, we evaluated the impact of MBL genotypes on renal function trajectories serum MBL levels and compared MBL genotypes in newly diagnosed patients with T2D with age- and sex-matched healthy individuals. Furthermore, we evaluated differences in parameters of insulin resistance within MBL genotypes.MethodsIn a cross-sectional study, we included 100 patients who were recently diagnosed with T2D and 100 age- and sex-matched individuals. We measured serum MBL levels, MBL genotype, standard biochemistry, and DEXA, in all participants. A 5-year clinical follow-up study was conducted, followed by 12-year data on follow-up biochemistry and clinical status for the progression to micro- or macroalbuminuria for the patients with T2D.ResultsWe found similar serum MBL levels and distribution of MBL genotypes between T2D patients and healthy individuals. The serum MBL level for a given MBL genotype did not differ between the groups neither at study entry nor at 5-year follow-up. We found that plasma creatinine increased more rapidly in patients with T2D with the high MBL expression genotype than with the medium/low MBL expression genotype over the 12-year follow-up period (p = 0.029). Serum MBL levels did not correlate with diabetes duration nor with HbA1c. Interestingly, serum MBL was inversely correlated with body fat percentage in individuals with high MBL expression genotypes both at study entry (p=0.0005) and 5-years follow-up (p=0.002).DiscussionContrary to T1D, T2D is not per se associated with increased MBL serum level for a given MBL genotype or with diabetes duration. Serum MBL was inversely correlated with body fat percentage, and T2D patients with the high MBL expression genotype presented with deterioration of renal function.

[Display omitted] • Involvement of mannan-binding lectin in oxidative stress-induced regulation of senescence. • Mannan-binding lectin ameliorates oxidative stress-induced senescence, mitigates oxidative damage, and inflammation. • Mannan-binding lectin inhibits p38 phosphorylation induced by oxidative stress. • The NAD+/Sirt1 pathway is required for mannan-binding lectin to retard oxidative stress-induced senescence. Prolonged or excessive oxidative stress can lead to premature cellular and body aging. Mannan-binding lectin (MBL) is synthesized by the liver and plays an important role in innate immunity, anti-inflammation, and anti-oxidation, and has a positive impact on health and longevity. To date, few studies investigated the role of MBL in attenuating oxidative stress-induced senescence. In this study, we evaluated the role of MBL in oxidative stress-induced premature aging and explored its underlying mechanism in C57BL/6 mice and mouse embryonic fibroblasts (NIH/3T3). First, we established an oxidative premature senescence model induced by D-galactose in C57BL/6 mice. We found that MBL-deficient mice had a marked aging-like appearance, reduced learning and spatial exploration abilities, severe liver pathological damage, and significantly upregulated expression of Senescence-associated proteins (p53 and p21), inflammatory kinesins (IL-1β and IL-6), and the senescence β-galactosidase (SA-β-Gal) positive rate as compared with WT mice. In the H 2 O 2 -induced oxidative senescence model of NIH/3T3 cells, consistent results were obtained after MBL intervention. In addition, MBL effectively inhibited G1 phase arrest, ROS levels, DNA damage, and mitochondrial dysfunction in premature senescent cells. Mechanistically, we found that oxidative stress inhibited the nicotinamide adenine dinucleotide (NAD+)/ silent information regulator 1 (Sirt1) signaling pathway, while MBL activated the NAD+/Sirt1 signaling pathway inhibited by oxidative stress. In addition, MBL could activate the NAD+/Sirt1 pathway by upregulating NAMPT, which in turn inhibited p38 phosphorylation by activating the NAD+/Sirt1 pathway. In conclusion, MBL inhibits oxidative aging, which may facilitate the development of therapeutics to delay oxidative aging. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease mediated by host immune responses. Plasmacytoid dendritic cells (pDC) and interferon (IFN)‐α secreted by pDC are involved in the initiation of psoriasis. Mannan‐binding lectin (MBL), a vital component of the complement pathway, plays a critical role in innate immune defense and the inflammatory response. Our previous study found that MBL could exacerbate skin inflammation in psoriatic mice, but the effect of MBL on pDC remains unstudied. Herein, we revealed that the circulating level of MBL was elevated in patients with psoriasis compared with the healthy controls. Moreover, the MBL level was positively correlated with disease severity, relative inflammatory cytokine levels, and peripheral blood (PB) pDC frequency in psoriasis. An in vitro study determined that the MBL protein could promote the differentiation of human pDC and upregulate the production of relative inflammatory cytokines and chemokines. Additionally, MBL‐deficient (MBL−/−) mice exhibited decreased accumulation of pDC in lymph nodes, spleens, and skin lesions with reduced secretion of pDC‐related cytokines compared with wild‐type (WT) mice in the preliminary stage of psoriasis induced by imiquimod. Notably, the differentiation of pDC from bone marrow (BM) cells derived from MBL−/− mice was weakened compared with that from WT mice upon Fms‐like tyrosine kinase 3 ligand (Flt3L) incubation. Mechanistic research indicated that the signal transducer and activator of transcription 3 (STAT3)–interferon regulatory factor 8 (IRF8) axis was responsible for MBL‐modulated pDC differentiation. In summary, these results suggest that MBL exacerbates the severity of psoriasis by enhancing pDC differentiation and pDC‐related cytokine secretion via the STAT3–IRF8 axis, thus providing a new target for psoriasis treatment. [ABSTRACT FROM AUTHOR]

This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for ~5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disorders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning. [ABSTRACT FROM AUTHOR]

Mannan-binding lectin (MBL) is a vital element in the host innate immune system, which is primarily produced by the liver and secreted into the circulation. Low serum level of MBL is reported to be associated with an increased risk of arthritis. However, the underlying mechanism by which MBL contributes to the pathogenesis of arthritis is poorly understood. In this study, we investigated the precise role of MBL on the course of experimental murine adjuvant-induced arthritis (AIA). MBL-deficient (MBL−/−) AIA mice showed significantly increased inflammatory responses compared with wild-type C57BL/6 AIA mice, including exacerbated cartilage damage, enhanced histopathological features and high level of tartrate-resistant acid phosphatase (TRAP)-positive cells. MBL protein markedly inhibited the osteoclast formation from human blood monocytes induced by receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in vitro. Mechanistic studies established that MBL inhibited osteoclast differentiation via down-regulation of p38 signaling pathway and subsequent nuclear translocation of c-fos as well as activation of nuclear factor of activated T-cells c1 (NFATc1) pathway. Importantly, we have provided the evidence that concentrations of MBL correlated negatively with the serum levels of amino-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (β-CTX), serum markers of bone turnover, in patients with arthritis. Our study revealed an unexpected function of MBL in osteoclastogenesis, thus providing new insight into inflammatory arthritis and other bone-related diseases in patients with MBL deficiency.

Mannose-binding lectin (MBL) binds to SARS-CoV-2, inhibits infection of susceptible cells, and activates the complement system via the lectin pathway. In this study, we investigated the association of MBL2 polymorphisms with the risk of hospitalization and clinical worsening in patients with COVID-19. A total of 550 patients with COVID-19 were included (94 non-hospitalized and 456 hospitalized). Polymorphisms in MBL2 exon 1 (codons 52, 54 and 57) and promoter region (-550, -221, and +4) were determined by real-time PCR. MBL and complement proteins were measured by Luminex. A higher frequency of the H/H genotype and the HYPA haplotype was observed in non-hospitalized patients when compared to hospitalized. In addition, critically ill patients carrying haplotypes associated with high MBL levels (HYPA/HYPA + HYPA/LYPA + HYPA/LYQA + LYPA/LYQA + LYPA/LYPA + LYQA/LYQA + LXPA/HYPA + LXPA/LYQA + LXPA/LYPA) were protected against lower oxygen saturation levels ( P  = 0.02), use of invasive ventilation use ( P  = 0.02, OR 0.38), and shock ( P  = 0.01, OR 0.40), independent of other potential confounders adjusted by multivariate analysis. Our results suggest that variants in MBL2 associated with high MBL levels may play a protective role in the clinical course of COVID-19., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Rodrigo Feliciano do Carmo reports financial support was provided by Foundation for Support of Science and Technology of Pernambuco State. Rodrigo Feliciano do Carmo reports financial support was provided by Coordination of Higher Education Personnel Improvement. Anderson da Costa Armstrong reports financial support was provided by Secretaria Estadual de Saúde de Pernambuco. Associate editor at Heliyon - RFC., (© 2023 The Authors. Published by Elsevier Ltd.)

Psoriasis is a chronic, relapsing inflammatory skin disorder. Numerous experimental evidence and therapeutic evidence have shown that the innate immune response is critical for the pathogenesis and development of psoriasis. Mannan‐binding lectin (MBL), a prototypic pattern recognition molecule of the innate immune system, plays an essential role in the host defense against certain infections and also appears to be a major regulator of inflammation. In this study, we investigated the function of MBL on the course of experimental murine imiquimod (IMQ)‐induced psoriasis. Our data showed that MBL‐deficient (MBL−/−) mice exhibited attenuated skin damage characterized by greatly decreased erythema compared with wild‐type control mice during the early stages of IMQ‐induced psoriasis‐like skin inflammation. The reduced skin inflammation in MBL−/− mice was associated with the decreased infiltration of neutrophils. Furthermore, we have determined that MBL deficiency limited the chemokine CXCL1 production from skin keratinocytes upon IMQ stimulation, which might be responsible for the impaired skin recruitment of neutrophils. Additionally, we have provided the data that MBL protein promotes the IMQ‐induced expression of CXCL1 and activation of MAPK/NF‐κB signalling pathway in human keratinocyte HaCaT cells in vitro. In summary, our study revealed an unexpected role of MBL on keratinocyte function in skin, thus offering a new insight into the pathogenic mechanisms of psoriasis. [ABSTRACT FROM AUTHOR]

Mannan-binding lectin (MBL) is a vital element in the host innate immune system, which is primarily produced by the liver and secreted into the circulation. Low serum level of MBL is reported to be associated with an increased risk of arthritis. However, the underlying mechanism by which MBL contributes to the pathogenesis of arthritis is poorly understood. In this study, we investigated the precise role of MBL on the course of experimental murine adjuvant-induced arthritis (AIA). MBL-deficient (MBL−/−) AIA mice showed significantly increased inflammatory responses compared with wild-type C57BL/6 AIA mice, including exacerbated cartilage damage, enhanced histopathological features and high level of tartrate-resistant acid phosphatase (TRAP)-positive cells. MBL protein markedly inhibited the osteoclast formation from human blood monocytes induced by receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in vitro. Mechanistic studies established that MBL inhibited osteoclast differentiation via down-regulation of p38 signaling pathway and subsequent nuclear translocation of c-fos as well as activation of nuclear factor of activated T-cells c1 (NFATc1) pathway. Importantly, we have provided the evidence that concentrations of MBL correlated negatively with the serum levels of amino-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (β-CTX), serum markers of bone turnover, in patients with arthritis. Our study revealed an unexpected function of MBL in osteoclastogenesis, thus providing new insight into inflammatory arthritis and other bone-related diseases in patients with MBL deficiency. [ABSTRACT FROM AUTHOR]

Background: C4d deposition is defined as the footprint of immune injury and it is associated with unfavorable renal outcomes in patients with IgA nephropathy. We searched whether mesangial C4d deposition is associated with poor renal survival in patients with primary focal segmental glomerulosclerosis (FSGS). Methods: Biopsy specimens were stained with anti-C4d antibody. Patients were classified based on mesangial C4d deposition as C4d-negative and C4d-positive. Groups were compared according to baseline and follow-up clinical variables. Factors that predict renal progression and treatment failure were determined using Cox-regression and multivariate logistic regression models, respectively. Results: Forty-one FSGS patients were followed for a mean of 67.7 ± 40.8 months. C4d-positive group included 18 patients while remaining 23 patients were C4d-negative. Urinary protein excretion and serum creatinine levels at baseline were comparable between groups. Fifteen patients reached the composite primary endpoint which included serum creatinine increasing > 30% from the baseline and reaching > 1.5 mg/dl, and/or evolution to end-stage renal disease (36.6%). In multivariate regression analysis, baseline eGFR (OR 0.71, 95% CI 0.53–0.94; p = 0.016) and mesangial C4d deposition (OR 10.5, 95% CI 1.51–73.18; p = 0.018) were independently associated with treatment failure rates. Mesangial C4d deposition was independently associated with the progression to the primary endpoint (HR 6.54, 95% CI 1.49–28.7, p = 0.013). Conclusion: We showed for the first time that mesangial C4d deposition is an independent predictor of disease progression and treatment failure in patients with primary FSGS. [ABSTRACT FROM AUTHOR]

Mannan‐binding lectin (MBL) acts as a soluble pattern recognition molecule in the innate immune system, which is primarily produced by the liver. MBL deficiency occurs with high frequency in the population and is reported to be associated with susceptibility to several liver diseases. In the present study, we investigated the pathophysiological role of MBL in acetaminophen (APAP)‐induced hepatotoxicity. After APAP treatment, MBL‐deficient (MBL−/−) mice had significantly higher mortality and aggravated hepatic necrosis as well as elevated serum lactate dehydrogenase and alanine aminotransferase levels compared to control mice. The enhanced hepatotoxicity in MBL−/− mice was associated with increased concentration of APAP toxic metabolisms. Furthermore, we demonstrated here that genetic ablation of MBL resulted in excessive reactive oxygen species (ROS) production and enhanced c‐Jun N‐terminal kinase (JNK) activation, leading to up‐regulated specificity protein 1 (SP1) nuclear expression, thus promoted CYP2E1 hepatic expression and consequently exacerbated APAP‐induced liver injury in mice. Importantly, we have validated that MBL protected against APAP toxicity in human HepaRG cells in vitro with the same mechanism. Our study revealed an unexpected function of MBL in drug metabolism, thus providing new insight into the drug‐induced liver injury in patients with MBL deficiency. Mannan‐binding lectin (MBL) inhibits acetaminophen (APAP)‐induced ROS generation in hepatocytes, subsequently suppresses JNK activation and SP1 nuclear expression, resulting in a decreased level of hepatic CYP2E1. Reduced CYP2E1 activity thus limits APAP metabolism and consequent liver damage. [ABSTRACT FROM AUTHOR]

Noninfectious liver injury, including the effects of drugs and diet, is a major cause of liver diseases worldwide. The innate inflammatory response to hepatocyte death plays a crucial role in the outcome of liver injury. Mannan‐binding lectin (MBL) is a pattern recognition molecule of the innate immune system, which is primarily produced by liver. MBL deficiency occurs with high frequency in the population and is reported associated with predisposition to infectious diseases. We here observed that genetic MBL ablation strongly sensitizes mice to sterile liver injury induced by carbon tetrachloride (CCl4). Aggravated liver damage was shown in CCl4‐administrated MBL−/− mice, as evidenced by severe hepatocyte death, elevated serum alanine aminotransferase and lactate dehydrogenase activity, and enhanced production of inflammatory cytokines. Mechanistic studies established that MBL deficiency caused increased chemokine CXCL2 production from liver macrophages upon CCl4 stimulation, thereby promoting the hepatic recruitment of neutrophils and subsequent liver damage. Furthermore, MBL‐mediated protection from CCl4‐induced liver injury was validated by administration of an MBL‐expressing liver‐specific adeno‐associated virus, which effectively ameliorated the hepatic damage in CCl4‐treated MBL–/– mice. We propose that MBL may be exploited as a new therapeutic approach in the treatment of chemical‐induced sterile liver injury in patients with MBL deficiency. MBL may be exploited as a new therapeutic approach in the treatment of chemically‐induced sterile liver injury in patients with MBL deficiency. [ABSTRACT FROM AUTHOR]

Innate immunity plays an important role in orchestrating the immune response, and the complement cascade (ComC) is a major component of this ancient defense system, which is activated by the classical-, alternative-, or mannan-binding lectin (MBL) pathways. However, the MBL-dependent ComC-activation pathway has been somewhat underappreciated for many years; recent evidence indicates that it plays a crucial role in regulating the trafficking of hematopoietic stem/progenitor cells (HSPCs) by promoting their egress from bone marrow (BM) into peripheral blood (PB). This process is initiated by the release of danger-associated molecular patterns (DAMPs) from BM cells, including the most abundant member of this family, adenosine triphosphate (ATP). This nucleotide is well known as a ubiquitous intracellular molecular energy source, but when secreted becomes an important extracellular nucleotide signaling molecule and mediator of purinergic signaling. What is important for the topic of this review, ATP released from BM cells is recognized as a DAMP by MBL, and the MBL-dependent pathway of ComC activation induces a state of “sterile inflammation” in the BM microenvironment. This activation of the ComC by MBL leads to the release of several potent mediators, including the anaphylatoxins C5a and desArgC5a, which are crucial for egress of HSPCs into the circulation. In parallel, as a ligand for purinergic receptors, ATP affects mobilization of HSPCs by activating other pro-mobilizing pathways. This emerging link between the release of ATP, which on the one hand is an activator of the MBL pathway of the ComC and on the other hand is a purinergic signaling molecule, will be discussed in this review. This mechanism plays an important role in triggering defense mechanisms in response to tissue/organ injury but may also have a negative impact by triggering autoimmune disorders, aging of HSPCs, induction of myelodysplasia, and graft-versus-host disease after transplantation of histoincompatible hematopoietic cells.

Evidence has accumulated that the occurrence of psychiatric disorders is related to chronic inflammation. In support of this linkage, changes in the levels of circulating pro-inflammatory cytokines and chemokines in the peripheral blood (PB) of psychiatric patients as well as correlations between chronic inflammatory processes and psychiatric disorders have been described. Furthermore, an inflammatory process known as “sterile inflammation” when initiated directly in brain tissue may trigger the onset of psychoses. In this review, we will present the hypothesis that prolonged or chronic activation of the complement cascade (ComC) directly triggers inflammation in the brain and affects the proper function of this organ. Based on the current literature and our own work on mechanisms activating the ComC we hypothesize that inflammation in the brain is initiated by the mannan-binding lectin pathway of ComC activation. This activation is triggered by an increase in brain tissue of danger-associated molecular pattern (DAMP) mediators, including extracellular ATP and high-mobility group box 1 (HMGB1) protein, which are recognized by circulating pattern-recognition receptors, including mannan-binding lectin (MBL), that activate the ComC. On the other hand, this process is controlled by the anti-inflammatory action of heme oxygenase 1 (HO-1). In this review, we will try to connect changes in the release of DAMPs in the brain with inflammatory processes triggered by the innate immunity involving activation of the ComC as well as the inflammation-limiting effects of the anti-inflammatory HO-1 pathway. We will also discuss parallel observations that during ComC activation subsets of stem cells are mobilized into PB from bone marrow that are potentially involved in repair mechanisms.

Mannan-binding lectin (MBL) is a pattern-recognition molecule that plays a crucial role in innate immunity. MBL deficiency correlates with an increased risk of chronic kidney disease (CKD). However, the molecular mechanisms are not fully defined. Here, we established a CKD model in wild-type (WT) and MBL-deficient (MBL -/- ) mice via unilateral ureteral obstruction (UUO). The result showed that MBL deficiency aggravated the pathogenesis of renal fibrosis in CKD mice. Strikingly, the in vivo macrophage depletion investigation revealed that macrophages play an essential role in the MBL-mediated suppression of renal fibrosis. We found that MBL limited the progression of macrophage-to-myofibroblast transition (MMT) in kidney tissues of UUO mice. Further in vitro study showed that MBL -/- macrophages exhibited significantly increased levels of fibrotic-related molecules compared with WT cells upon transforming growth factor beta (TGF-β) stimulation. We demonstrated that MBL inhibited the MMT process by suppressing the production of matrix metalloproteinase 9 (MMP-9) and activation of Akt signaling. In summary, our study revealed an expected role of MBL on macrophage transition during renal fibrosis, thus offering new insight into the potential of MBL as a therapeutic target for CKD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Innate immunity plays an important role in orchestrating the immune response, and the complement cascade (ComC) is a major component of this ancient defense system, which is activated by the classical-, alternative-, or mannan-binding lectin (MBL) pathways. However, the MBL-dependent ComC-activation pathway has been somewhat underappreciated for many years; recent evidence indicates that it plays a crucial role in regulating the trafficking of hematopoietic stem/progenitor cells (HSPCs) by promoting their egress from bone marrow (BM) into peripheral blood (PB). This process is initiated by the release of danger-associated molecular patterns (DAMPs) from BM cells, including the most abundant member of this family, adenosine triphosphate (ATP). This nucleotide is well known as a ubiquitous intracellular molecular energy source, but when secreted becomes an important extracellular nucleotide signaling molecule and mediator of purinergic signaling. What is important for the topic of this review, ATP released from BM cells is recognized as a DAMP by MBL, and the MBL-dependent pathway of ComC activation induces a state of "sterile inflammation" in the BM microenvironment. This activation of the ComC by MBL leads to the release of several potent mediators, including the anaphylatoxins C5a and desArgC5a, which are crucial for egress of HSPCs into the circulation. In parallel, as a ligand for purinergic receptors, ATP affects mobilization of HSPCs by activating other pro-mobilizing pathways. This emerging link between the release of ATP, which on the one hand is an activator of the MBL pathway of the ComC and on the other hand is a purinergic signaling molecule, will be discussed in this review. This mechanism plays an important role in triggering defense mechanisms in response to tissue/organ injury but may also have a negative impact by triggering autoimmune disorders, aging of HSPCs, induction of myelodysplasia, and graft-versus-host disease after transplantation of histoincompatible hematopoietic cells. [ABSTRACT FROM AUTHOR]

Evidence has accumulated that the occurrence of psychiatric disorders is related to chronic inflammation. In support of this linkage, changes in the levels of circulating pro-inflammatory cytokines and chemokines in the peripheral blood (PB) of psychiatric patients as well as correlations between chronic inflammatory processes and psychiatric disorders have been described. Furthermore, an inflammatory process known as "sterile inflammation" when initiated directly in brain tissue may trigger the onset of psychoses. In this review, we will present the hypothesis that prolonged or chronic activation of the complement cascade (ComC) directly triggers inflammation in the brain and affects the proper function of this organ. Based on the current literature and our own work on mechanisms activating the ComC we hypothesize that inflammation in the brain is initiated by the mannan-binding lectin pathway of ComC activation. This activation is triggered by an increase in brain tissue of danger-associated molecular pattern (DAMP) mediators, including extracellular ATP and high-mobility group box 1 (HMGB1) protein, which are recognized by circulating pattern-recognition receptors, including mannan-binding lectin (MBL), that activate the ComC. On the other hand, this process is controlled by the anti-inflammatory action of heme oxygenase 1 (HO-1). In this review, we will try to connect changes in the release of DAMPs in the brain with inflammatory processes triggered by the innate immunity involving activation of the ComC as well as the inflammation-limiting effects of the anti-inflammatory HO-1 pathway. We will also discuss parallel observations that during ComC activation subsets of stem cells are mobilized into PB from bone marrow that are potentially involved in repair mechanisms. [ABSTRACT FROM AUTHOR]

The pandemic influenza A (H1N1)pdm09 virus continues to be a threat to human health. Low doses of mannan-binding lectin (MBL) (<1 μg/mL) were shown not to protect against influenza A(H1N1)pdm09 infection. However, the effect of high doses of MBL has not been investigated. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) has been proposed as an alternative receptor for influenza A(H1N1)pdm09 virus. In this study, we examined the expression of DC- SIGN on DCs as well as on acute monocytic leukemia cell line, THP-1. High doses of recombinant or human MBL inhibited binding of influenza A(H1N1)pdm09 to both these cell types in the presence of complement derived from bovine serum. Further, anti- DC- SIGN monoclonal antibody inhibited binding of influenza A(H1N1)pdm09 to both DC- SIGN-expressing DCs and THP-1 cells. This study demonstrates that high doses of MBL can inhibit binding of influenza A(H1N1)pdm09 virus to DC- SIGN-expressing cells in the presence of complement. Our results suggest that DC- SIGN may be an alternative receptor for influenza A(H1N1)pdm09 virus. [ABSTRACT FROM AUTHOR]