Mannose binding lectin gene (MBL2) functional polymorphisms are associated with systemic lupus erythematosus in southern Brazilians

doi:10.1016/j.humimm.2011.03.007

Human Immunology

Volume 72, Issue 6, June 2011, Pages 516-521

https://doi.org/10.1016/j.humimm.2011.03.007 Get rights and content

Abstract

Susceptibility to systemic lupus erythematosus (SLE) has been associated with immunologic, environmental, and genetic factors. To uncover a possible association between MBL2 gene polymorphisms and SLE, we analyzed functional polymorphisms in the promoter and first exon of the MBL2 gene in 134 Brazilian SLE patients and 101 healthy controls. Genotype and allele frequencies of MBL2 A/O polymorphism were significantly different between patients and controls, and the O allele was associated with an increased risk of SLE. An association between low mannose binding lectin (MBL) producer combined genotypes and increased risk for SLE was also reported. Furthermore, when stratifying SLE patients according to clinical and laboratory data, an association between the A/O genotype and nephritic disorders and between the X/Y genotype and antiphospholipid syndrome was evident. Combined genotypes responsible for low MBL production were more frequently observed in SLE patients with nephritis. Our results indicate MBL2 polymorphisms as possible risk factors for SLE development and disease-related clinical manifestations.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs, displaying a complex spectrum of clinical and immunologic manifestations. SLE is characterized by a breakdown of self-tolerance and an activation of auto-reactive lymphocytes against several nuclear and cytoplasm self-antigens. SLE pathogenesis is multifactorial; susceptibility to this disease has been associated with genetic, hormonal, immunologic, and environmental factors [1].

The ever-increasing information concerning the association of various genes with autoimmune disorders emphasized the contribution of certain alleles of the innate and adaptive immune response genes [2], and this is likely to be the case also in SLE [3].

Mannose binding lectin (MBL) is a molecule that plays an important role in the innate immunity. MBL2 gene, located at chromosome 10 (10q11.2-21) encodes human MBL. Three functional single nucleotide polymorphisms (SNPs) in exon 1 at codons 52 (C>T, rs5030737), 54 (G>A, rs1800450), and 57 (G>A, rs1800451), known as D, B, and C variant, respectively (collectively designated as O alleles, whereas A is the common nonmutated allele) have been associated with differential MBL production. Mutant alleles result in considerable reduction or complete absence of functional MBL protein, when present, respectively in heterozygosis and in homozygosis [4]. Homozygous combinations (O/O) of mutant MBL alleles have been observed in approximately 1–10% of Europeans, and are associated with an increased rate of infections both in immunocompetent children and in patients with immunodeficiency or infectious disorders [5], [6]. In addition, polymorphisms in the promoter region of the MBL2 gene, including SNPs located at positions –550 (G>C, rs11003125, H/L variant) and –221 (C>G, rs7096206, X/Y variant), are also known to play an important role in determining MBL serum levels [7]. Promoter and exon 1 polymorphisms are in linkage and combine into haplotypes/combined genotypes that are responsible for different protein levels [4], [8], [9].

Previous studies have suggested that deficiency or low MBL serum levels, determined by MBL2 functional SNPs, could be associated with the occurrence of autoimmune diseases [8], [10]. Several studies have investigated and in some case also disclosed a possible association between MBL, MBL2 polymorphisms, and SLE development as well as clinical features; controversial results have sometimes been obtained [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23].

Because MBL2 has been reported as a potential candidate gene for SLE susceptibility, we performed a replica study investigating the possible association between polymorphisms in exon 1 and promoter region of MBL2 gene in southern Brazilian SLE patients. Moreover, we also evaluated the possible involvement of MBL2 in clinical features of SLE patients.

Section snippets

Patients and controls

DNA samples were obtained from 134 SLE patients (127 female and 7 male; 17–70 years of age; mean, 39.8 years; SD, 11.6 years) who were followed up at the Division of Clinical Immunology, University Hospital of the School of Medicine of Ribeirão Preto, University of São Paulo, Brazil. SLE diagnosis was performed according to the American College of Rheumatology Classification Criteria.

Clinical and laboratory data regarding the SLE patients were collected (Table 1): photosensitivity, serositis

MBL2 promoter and exon 1 polymorphisms

Table 2 shows the distribution of MBL2 promoter and exon 1 polymorphisms in SLE patients and controls. Alleles and genotypes frequencies were in Hardy–Weinberg equilibrium in both groups.

No significant differences in genotype or allele frequencies between patients and controls were evident for H/L and X/Y promoter variants.

The exon 1 O allele was significantly more frequent in SLE patients than in controls (32% vs 22%, p = 0.012) and thus associated with an increased risk of SLE (OR = 1.72, 95%

Discussion

MBL2 gene polymorphisms localized at codons 52 (D allele), 54 (B allele), and 57 (C allele) in exon 1 can lead to structural alterations that are responsible for reduced MBL plasma levels. Promoter polymorphisms at position –550 (alleles H/L), –221 (alleles X/Y), combined or not with SNPs found in exon 1, also correlates with MBL production [7], [8].

Previous studies have reported an association between MBL2 genetic variants and clinical and/or laboratories features of lupus, as well as disease

Acknowledgments

We acknowledge the financial support of FACEPE (APQ-1098-4.01/08) and FACEPE/CNPq (DCR-0089-2.02/08). LS is recipient of a fellowship grant (APQ-0020-4.01/08) from FACEPE. SC is recipient of a fellowship grant from European Project “Talents for an International House” within the framework of the 7th Research and Development Framework Programme PEOPLE – Marie Curie Actions–COFUND (Co-Funding of Regional, National and International Programmes).

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Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis
2017, Clinical Immunology
Citation Excerpt :
The role of MBL in the lupus pathogenesis is potentially complex as high expression results in complement activation and tissue damage while low levels lead to defective apoptotic cell clearance [82,83]. Variants in the MBL2 gene result in MBL deficiency, predisposition to SLE, and increased risk of LN [84–86]. IgM is also involved in the opsonization and clearance of dying cells and low serum IgM levels have been reported in SLE patients [87].
Nephritis is one of the most severe complications of systemic lupus erythematosus (SLE). One key characteristic of lupus nephritis (LN) is the deposition of immune complexes containing nucleic acids and/or proteins binding to nucleic acids and autoantibodies recognizing these molecules. A variety of cell death processes are implicated in the generation and externalization of modified nuclear autoantigens and in the development of LN. Among these processes, apoptosis, primary and secondary necrosis, NETosis, necroptosis, pyroptosis, and autophagy have been proposed to play roles in tissue damage and immune dysregulation. Cell death occurs in healthy individuals during conditions of homeostasis yet autoimmunity does not develop, at least in part, because of rapid clearance of dying cells. In SLE, accelerated cell death combined with a clearance deficiency may lead to the accumulation and externalization of nuclear autoantigens and to autoantibody production. In addition, specific types of cell death may modify autoantigens and alter their immunogenicity. These modified molecules may then become novel targets of the immune system and promote autoimmune responses in predisposed hosts. In this review, we examine various cell death pathways and discuss how enhanced cell death, impaired clearance, and post-translational modifications of proteins could contribute to the development of lupus nephritis.
Complement in autoimmune diseases
2017, Clinica Chimica Acta
Citation Excerpt :
A deficiency status of MBL, though believed as an important risk factor for infections, is also considered a predisposing risk factor for the development of autoimmune conditions such as SLE [62]. Polymorphisms of MBL2 gene is considered as a risk factor for SLE [63,64]. Allele B and promoter region polymorphisms (especially at positions − 221 and − 550) are considered risk factors in SLE in a meta-analysis done including populations from Europe, Africa, and Asia [63].
The complement system is an ancient and evolutionary conserved element of the innate immune mechanism. It comprises of more than 20 serum proteins most of which are synthesized in the liver. These proteins are synthesized as inactive precursor proteins which are activated by appropriate stimuli. The activated forms of these proteins act as proteases and cleave other components successively in amplification pathways leading to exponential generation of final effectors. Three major pathways of complement pathways have been described, namely the classical, alternative and lectin pathways which are activated by different stimuli. However, all the 3 pathways converge on Complement C3. Cleavage of C3 and C5 successively leads to the production of the membrane attack complex which is final common effector.
Excessive and uncontrolled activation of the complement has been implicated in the host of autoimmune diseases. But the complement has also been bemusedly described as the proverbial “double edged sword”. On one hand, complement is the final effector of tissue injury in autoimmune diseases and on the other, deficiencies of some components of the complement can result in autoimmune diseases.
Currently available tools such as enzyme based immunoassays for functional assessment of complement pathways, flow cytometry, next generation sequencing and proteomics-based approaches provide an exciting opportunity to study this ancient yet mysterious element of innate immunity.
Mannose binding lectin 2 promotor-221 X/Y gene polymorphism in Egyptian systemic lupus erythematosus patients
2016, Egyptian Rheumatologist
Citation Excerpt :
No association was found between MBL2 genotype and pulmonary or GIT symptoms which is in accordance to the findings of another study on Chinese children [39]. There was no association between MBL2 genotype and autoimmune hemolytic anemia which is consistent with that of other studies carried out on different ethnicities [39,40,44]. In the current study the YY genotype was significantly associated only with the low serum complement level.
The present study was undertaken to determine whether mannose binding lectin-2 (MBL2) promotor-221X/Y gene polymorphism had a possible association with systemic lupus erythematosus (SLE) in Mansoura city.
We analyzed functional polymorphisms in the promoter of MBL2 gene in 106 Egyptian SLE patients and 99 healthy controls by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). SLE disease activity was evaluated using SLE Disease Activity Index (SLEDAI) and organ damage was evaluated using SLE International Collaborating Clinic Damage Index (SLICC/DI).
The patients were 95 females and 11 males with a mean age of 34.4 ± 10.2 years and disease duration of 4 ± 3.03 years. Genotype frequencies of MBL2 were significantly different between patients and controls. The YY genotype was significantly associated with SLE in 77 (72.6%) patients compared to the control in 59 (59.6%) (p = 0.048). The XY genotype was in 29 (27.4%) patients and in 40 (40.4%) control. An association was found between the XY genotype and alopecia (p = 0.048), central nervous system involvement (p = 0.03), vasculitis (p = 0.004) and anti-phospholipid syndrome (p = 0.001) while the YY genotype was associated with discoid rash, low serum complement level (C3; p = 0.014 and C4; p = 0.008) and with the presence of anticardiolipin antibodies (p = 0.032). MBL genotype did not show any correlation with SLEDAI or SLICC/DI.
Our results indicate that MBL2 promotor-221X/Y polymorphism is a possible key-player for SLE development as well as the occurrence of some clinical and laboratory features. Further longitudinal studies including other single nucleoproteins are needed to clarify the role of MBL2.
Mannose binding lectin deposition in skin of lupus erythematosus patients: A case series
2014, Human Immunology
Mannose binding lectin (MBL) has been linked to predisposition to systemic lupus erythematosus (SLE) and to disease activity. Some studies found deposits of MBL in glomerular tissue of patients with lupus nephritis. There is no research about the deposition of MBL in skin.
Skin biopsies from lesional and non lesional skin of 4 discoid lupus erythematosus (DLE) and 10 SLE patients were submitted to immunofluorescence staining for IgG, IgA, IgM, C3, C4, C1q, C5b-9 and MBL. Charts were reviewed for demographic, clinical and serological data. Patients with SLE had disease activity measured by SLEDAI.
MBL was found only in SLE lesional skin and its presence showed an association trend towards higher disease activity. Deposition of C5b-9 occurred in vessels only in patients with SLE (70%) and in the two patients with kidney involvement.
MBL deposition was found in the lesional skin of SLE patients but not in SLE non lesional skin nor in DLE patients, and it seems to be less frequent and less strong than observed in the kidneys biopsies, suggesting that the complement participation in the pathophysiology of SLE process may not be the same in these two clinical manifestations.
Mannose-binding lectin 2 (MBL2) gene polymorphisms do not influence frequency of infections in chronic lymphocytic leukemia patients
2014, Revista Brasileira de Hematologia e Hemoterapia
Infectious complications represent the main cause of morbidity and mortality in chronic lymphocytic leukemia. It has been reported that polymorphisms of the mannose-binding lectin 2 (MBL2) genes are correlated with MBL protein serum levels and, consequently, are associated with the development of infectious diseases.
The purpose of this study was to investigate the possible association between MBL2 gene polymorphisms and risk of infection in chronic lymphocytic leukemia patients.
Peripheral blood samples from 116 chronic lymphocytic leukemia patients were collected; after genomic DNA extraction, real time polymerase chain reaction was used to determine the polymorphisms of the promoter region and exon 1 of the MBL2 gene.
A high frequency of Binet stage A (p-value = 0.005) and absence of splenomegaly (p-value = 0.002) were observed in patients with no infection; however, variant alleles/ genotypes and haplotypes of this gene had no impact on the risk of infection.
To the authors’ knowledge, this is the first study describing the association between MBL2 polymorphisms and infectious disease in chronic lymphocytic leukemia. Although it was not possible to demonstrate any influence of MBL2 polymorphisms as a genetic modulator of infection in chronic lymphocytic leukemia, the authors believe that the present data are clinically relevant and provide the basis for future studies.
© 2014 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. All rights reserved.
Low producer MBL genotypes are associated with susceptibility to systemic lupus erythematosus in Odisha, India
2013, Human Immunology
Citation Excerpt :
Further, combined analysis of MBL2 polymorphisms also revealed significant association between MBL low producer genotypes and low plasma MBL levels as a risk factor for SLE and AIHA possibly due to poor immune complex clearance. Association of MBL expression genotype with different clinical categories in SLE has been defined with regard to nephritis [22,24]. Interestingly, we observed a strong association of AIHA with low producer MBL genotype and not with other clinical manifestations.
Variants of MBL gene have been associated with autoimmune disorders. The aim of this study was to explore whether common polymorphisms in MBL gene are associated with susceptibility to systemic lupus erythematosus (SLE) and its clinical manifestations in a cohort from eastern India. A total of 108 female SLE patients and 105 age, sex, and ethnically matched healthy controls were enrolled in the study. MBL2 codon and promoter polymorphisms were genotyped by AS-PCR and dARMS PCR, respectively. Plasma level of MBL was quantified by ELISA. Higher frequency of BB genotype and minor allele (B) was observed in patients of SLE compared to healthy controls (BB genotype: P = 0.0002; OR = 5.75, 95% CI = 2.09–15.76, B allele: P < 0.0001; OR = 2.78, 95% CI = 1.66–4.64). MBL codon 54, H-550L, Y-221X polymorphisms and combined MBL genotypes contributed to plasma MBL levels. Prevalence of MBL low producer genotype (LXA/LYB, LYB/LYB and LXB/LXB) was significantly higher in SLE patients compared to healthy control. (P = 0.005; OR = 3.09, 95% CI = 1.38–6.91). On analysis of clinical manifestations, MBL low producer genotype was significantly associated with autoimmune haemolytic anaemia (P = 0.006; OR = 13.06). Results of the present study indicate MBL2 variants as possible risk factors for development of SLE and clinical manifestation in eastern India.

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Mannose binding lectin gene (MBL2) functional polymorphisms are associated with systemic lupus erythematosus in southern Brazilians

Abstract

Introduction

Section snippets

Patients and controls

MBL2 promoter and exon 1 polymorphisms

Discussion

Acknowledgments

Mol Immunol

Lancet

Hum Immunol

Autoimmun Rev

Clin Immunol

The role of mannose-binding lectin in systemic lupus erythematosus

Clin Rheumatol

Genetics of autoimmune diseases − disorders of immune homeostasis

Nat Rev Genet

Shared and unique gene expression in systemic lupus erythematosus depending on disease activity

Ann N Y Acad Sci

Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series

Br Med J

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 polymorphisms and susceptibility to infection in systemic lupus erythematosus

Arthritis Rheum

Association of mannose-binding lectin gene variation with disease severity and infections in a population-based cohort of systemic lupus erythematosus patients

Genes Immun

Mannose-binding lectin gene: Polymorphisms in Japanese patients with systemic lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome

Genes Immunol

Association of mannose binding lectin (MBL) gene polymorphism and serum MBL concentration with characteristics and progression of systemic lupus erythematosus

Ann Rheum Dis