Mannose-Binding Lectin: Clinical Implications for Infection, Transplantation, and Autoimmunity

doi:10.1016/j.humimm.2006.02.030

Human Immunology

Volume 67, Issues 4–5, April–May 2006, Pages 247-256

https://doi.org/10.1016/j.humimm.2006.02.030 Get rights and content

Abstract

Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL variant alleles have been described in the coding region of the MBL gene, which are associated with low MBL serum concentration and impaired MBL structure and function. Both high and low serum levels of functional MBL have been associated with a variety of diseases and disease complications. Functioning as double-edged sword, low MBL serum levels have been shown to enhance the risk for infections. On the other hand, high MBL serum levels and high MBL activity have been associated with inflammatory diseases, transplant rejection, and diabetic nephropathy. Underscoring the Jekyll-and-Hyde character of MBL, both high and low serum MBL levels are associated with several aspects of autoimmune diseases. This review provides a general outline of the genetic and molecular characteristics of MBL and discusses MBL–disease association and its consequence in infection, transplantation, and autoimmunity.

Section snippets

Mannose Binding Lectin

The ability to vastly counteract a great variety of pathogenic microorganisms is of eminent importance for immunological homeostasis. As the most rudimentary part of immunity, the innate immune system is composed of molecules that can recognize a restricted array of structures in a broad range of microorganisms, the so-called pathogen-associated molecular patterns. Mannose-binding lectin, also referred to as mannan-binding lectin or mannan-binding protein, is a recognition molecule of the

MBL History

The first case of an association of MBL deficiency and disease dates back to 1968. A small girl suffering from severe dermatitis, diarrhea, and recurrent bacterial infections indifferent to antibiotic and steroid therapy was reported. Hematological examination revealed a defect in the phagocytosis of yeast particles from Saccharomyces cerevisiae, rice starch, and Staphylococcus aureus by polymorphonuclear leukocytes. This defect was serum dependent. Infusion of fresh plasma corrected the

MBL Characteristics

Mannose-binding lectin is a C-type serum lectin and is primarily produced by the liver [4]. MBL is made up of 96-kDa structural units, which in turn are composed of three identical 32-kDa primary subunits. The subunits consist of an N-terminal cross-linking region, a collagen-like domain, and a C-terminal carbohydrate-recognition domain (CRD) [5]. Circulating MBL is composed of higher-order oligomeric structures, which include dimers, trimers, tetramers, pentamers, and hexamers of the

MBL Polymorphisms and Serum MBL

Exon 1 of the mbl-2 gene, which is located on chromosome 10, contains three functional single nucleotide polymorphisms (SNPs) at codon 52 (CGT to TGT; Arg → Cys, referred to as allele “D”), codon 54 (GGC to GAC: Gly → Asp, allele “B”), and codon 57 (GGA to GAA; Gly → Glu, allele “C”) (Figure 1) [13]. These SNPs of exon 1 result in altered collagenous regions and, as a consequence, interfere with the formation of high-order oligomers. This impairment of polymerization causes low serum levels of

MBL Epidemiology

A great variety of allele frequencies in various ethnic groups worldwide has been described. B allele frequencies have been reported as high as 0.80 in certain South American Indian groups with C allele frequencies as high as 0.32 in West Africans. In contrast, no variant alleles were found in the Aboriginal Australian population and C or D alleles were absent in Eskimos and in certain South American populations (reviewed in [21]). The high frequency of MBL variant alleles in different ethnic

MBL and Associated Diseases

MBL has been studied in a great diversity of diseases. Both decreased and elevated serum levels of MBL and different SNPs of the mbl2 gene and its promoter have been associated with a variety of diseases, reflecting the Jekyll-and-Hyde character of MBL. To structure the discussion of this double-edged sword phenomenon, involvement of MBL in different diseases will be discussed according to the etiology.

MBL and Infection

When the adaptive immune response is either immature or compromised, the innate immune system constitutes the principle defense against infection. A logical consequence of impaired MBL function would be an enlarged susceptibility to infectious disease. The phenomenon of an increased incidence of infectious disease in MBL-deficient patients has been shown in pediatric patients and in immune-compromised patients. However, it also has been shown that adult patients with recurrent infectious

MBL and transplantation

Tissue damage and impaired organ function resulting from ischemia/reperfusion (I/R) injury still remain enormous predicaments in solid-organ transplantation. The hypoxic state to which an organ is subjected during organ harvesting, transport, and implantation activates various immunological events [53, 54, 55, 56, 57]. The complement system plays an important role in mediating tissue injury after oxidative stress. Activation and deposition of complement on the vascular endothelium following

MBL and Autoimmunity

The role of the adaptive immune system in autoimmunity is well established and interest in the role of the innate immune system in the immunopathogenesis of autoimmune diseases is mounting. Evidence that the innate immune system could lead to autoimmunity, either by priming or by promoting aggressive immune responses, is growing [71, 72]. A major current pathophysiological concept of autoimmunity is impaired apoptotic cell clearance. MBL has been demonstrated to facilitate the clearance of

Concluding Remarks

Since the first report of the clinical implications of MBL deficiency almost four decades ago [2], our knowledge of the lectin pathway has expanded tremendously. At present, MBL replacement therapy is being studied in phase I, II, and III studies [94, 95, 96]. Infusing serum MBL in MBL-deficient subjects could potentially induce negative effects, for example autoimmune processes. However, no adverse clinical or laboratory changes have been reported upon repetitive MBL infusion. Furthermore, no

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA-directed therapy with eculizumab, a complement C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the MASP-2 effector enzyme of the lectin pathway, has been studied in adults with TA-TMA as first-line therapy with a response rate of 61%. Although there are limited data on narsoplimab use as a second-line agent in children, we hypothesized, that complement pathways proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children. In this single-center study, children were enrolled on single-patient, Institutional Review Board-approved compassionate use protocols for narsoplimab treatment. Clinical complement lab tests were obtained at the discretion of the treating physician, although all patients were also offered participation in a companion biomarker study. Research blood samples were obtained at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first narsoplimab dose. Single ELISA kits were used to measure markers of complement activation according to the manufacture's instructions. Five children with rTA-TMA received narsoplimab; 3 were in multiorgan failure and 2 had worsening multiorgan dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS; n = 3), viral infection (n = 3), and steroid-refractory stage 4 lower gut grade IV acute graft-versus-host disease (aGVHD, n = 3). Two infants with concurrent SOS and no aGVHD had resolution of organ dysfunction; 1 also developed transfusion-independence (complete response), and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence but had no improvement in organ manifestations (partial response), and 2 patients treated late in the course of disease had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to provide additional research blood samples. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with subsequent declines in Ba, Bb, C3a, and C5a and increases in C3 in both clinical and research lab tests. Otherwise, there was no clear pattern of other complement markers, including MASP-2 levels, after therapy. In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefited from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid-refractory aGVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful for monitoring lectin pathway activation and inhibition.
Lack of association between Mannose Binding Lectin-2 gene polymorphisms and periodontitis: A meta-analysis
2020, Meta Gene
The aim of this study was to perform a meta-analysis to verify whether MBL-2 gene polymorphisms (rs1800450 and rs1800451) are associated with susceptibility to periodontitis. A search of the literature was performed for studies published before 2, March 2020 in various databases. Calculations of Odds Ratio (OR) with 95% of Confidence Intervals (CI) and heterogeneity (I²) were assessed and publication bias was calculated by Begg’ and Egger's test. The value of P < .05 was considered as significant. As results, eight articles composed the results which non-significant associations were found for all included comparisons (P > .05). Neither the mutant allele in rs1800450 polymorphisms nor the mutant allele in rs1800451 polymorphisms was associated with periodontitis (OR = 1.11, CI: 0.90–1.38, P = .33; OR = 1.01, CI: 0.75–1.35, P = .96, respectively) with no interference of I² in these evaluations (I² = 0%, P = .75 and I² = 0%, P = .65, respectively) as well as in all calculations. The stratified analyses were composed by Ethnicity in Caucasian and Mixed populations and genotyping methods. In conclusion, this meta-analysis showed a non-significant association among the rs1800450 and 1,800,451 polymorphism in MBL-2 gene and periodontitis in the overall evaluation, Caucasian group and Mixed population.
Mannose binding lectin 2 gene polymorphisms in patients after renal transplantation with acute graft rejection
2019, Transplant Immunology
Mannose binding lectin 2 (MBL2) is one of the pattern-recognition soluble receptors and is responsible for complement activation via the lectin pathway, so it plays an important role in kidney transplantation.
The aim of the study was to examine the association between MBL2 gene polymorphisms and acute rejection of the kidney allograft. This study enrolled 266 Caucasian deceased-donor renal transplant recipients – 69 with diagnosed acute graft rejection, 197 with stable graft function.
A 969 bp DNA fragment, from chromosome 10, including promoter region and exon 1 of MBL2 gene was sequenced. The DNA fragment obtained contained 122 SNPs accordingly to the NCBI dbSNP database. Of this number only nine showed variation within our population (rs36014597, rs5030737, rs1800450, rs7095891, rs11003123, rs7096206, rs7084554, rs11003124, rs11003125), and only these were subjected to further analysis.
Among the studied polymorphisms in the MBL2 gene only rs1800450 polymorphism was statistically significantly associated with kidney allograft rejection. The AA genotype was significantly associated with an increased risk of acute kidney allograft rejection. (AA vs GA+GG: OR=9.29 (95%CI: 1.83–47.17), p=0.005).
The results of our study indicate that MBL2 gene rs1800450 polymorphism may be associated with the risk of acute kidney allograft rejection. The AA genotype, associated with lower MBL2 expression, may be associated with an increased risk of acute kidney allograft rejection.
Impact of MBL2 gene polymorphisms on the risk of infection in solid organ transplant recipients: A systematic review and meta-analysis
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Mannose-binding lectin (MBL) is a soluble pattern recognition molecule involved in complement activation. Single nucleotide polymorphisms (SNPs) in the MBL2 gene have been associated with susceptibility to infection, although data in solid organ transplant recipients remains inconclusive. This meta-analysis was primarily aimed at investigating the association between posttransplant bacterial and fungal infection and variant alleles of MBL2 gene SNPs in the promoter/5’ untranslated region and exon 1. Cytomegalovirus (CMV) infection and/or disease were considered secondary outcomes. PubMed, EMBASE, and Web of Knowledge were searched for relevant articles up to August 2018. Eleven studies (comprising 1858 patients) were included, with liver transplant (LT) recipients accounting for 80.4% of the pooled population. As compared to high-MBL expression haplotypes (YA/YA, YA/XA), any MBL-deficient haplotype was associated with an increased risk of posttransplant bacterial and fungal infections (risk ratio [RR]: 1.30; P = .04). Low/null-MBL expression haplotypes (XA/O, O/O) also increased the risk of primary outcome (RR: 1.51; P = .008) and CMV events (RR: 1.50; P = .006). No effect was observed for individual promoter SNPs. In conclusion, MBL-deficient haplotypes are associated with a significant, albeit moderate, increase in the risk of posttransplant infection, with this association being mainly restricted to LT recipients.
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Mannose-Binding Lectin: Clinical Implications for Infection, Transplantation, and Autoimmunity

Abstract

Section snippets

Mannose Binding Lectin

MBL History

MBL Characteristics

MBL Polymorphisms and Serum MBL

MBL Epidemiology

MBL and Associated Diseases

MBL and Infection

MBL and transplantation

MBL and Autoimmunity

Concluding Remarks

Immunol Today

Lancet

Gastroenterology

Immunity

Mol Immunol

J Immunol Methods

Mol Immunol

Lancet

Lancet

Lancet

Lancet

Blood

Lancet

Lancet

Lancet

J Hepatol

Immunobiology

J Hepatol

Am J Pathol

Immunopharmacology

Am J Pathol

Am J Pathol

Am J Pathol

Am J Transplant

Gastroenterology

Biochem Biophys Res Commun

J Biol Chem

A familial, plasma associated defect of phagocytosis

Lancet

Mannose-binding lectinstructure, function, genetics and disease associations

Rev Immunogenet

Mannose-binding lectin engagement with late apoptotic and necrotic cells

Eur J Immunol

Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease

J Exp Med

A second serine protease associated with mannan-binding lectin that activates complement

Nature

Proteolytic activities of two types of mannose-binding lectin-associated serine protease

J Immunol

Distinct pathways of mannan-binding lectin (MBL)- and C1-complex autoactivation revealed by reconstitution of MBL with recombinant MBL-associated serine protease-2

J Immunol

Characterization of recombinant mannan-binding lectin- associated serine protease (MASP)-3 suggests an activation mechanism different from that of MASP-1 and MASP-2

J Immunol

The human mannose-binding protein gene. Exon structure reveals its evolutionary relationship to a human pulmonary surfactant gene and localization to chromosome 10

J Exp Med

Antibody-mediated activation of the classical pathway of complement may compensate for mannose-binding lectin deficiency

Eur J Immunol

Analysis of the relationship between mannose-binding lectin (MBL) genotype, MBL levels and function in an Australian blood donor population

Scand J Immunol

Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein

J Immunol

Different molecular events result in low protein levels of mannan-binding lectin in populations from southeast Africa and South America

J Immunol

Mannose-binding lectin and its genetic variants

Genes Immun

Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood

J Am Med Assoc

Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis

J Clin Invest

Impact of mannose-binding lectin on susceptibility to infectious diseases

Clin Infect Dis

Mannan-binding lectin (MBL) serum levels and post-operative infections

Biochem Soc Trans

Mannan-binding lectin and procalcitonin measurement for prediction of postoperative infection

Crit Care

Dual role of mannan-binding protein in infectionsanother case of heterosis?

Eur J Immunogenet