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The ambiguous role of mannose-binding lectin (MBL) in human immunity

  • Namarta Kalia ORCID logo EMAIL logo , Jatinder Singh and Manpreet Kaur EMAIL logo
Published/Copyright: February 17, 2021
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Open Medicine
From the journal Open Medicine Volume 16 Issue 1

Abstract

Mannose-binding lectin (MBL) and lectin complement pathway have become targets of increasing clinical interest. Many aspects of MBL have been recently explored, including the structural properties that allow it to distinguish self from non-self/altered-self structures. Experimental evidences have declared the additional 5′- and 3′-variants that in amalgamation with well-known secretor polymorphisms change MBL function and concentration. Moreover, the current review highlights the differential behavior of MBL on exposure with extra/intracellular pathogens and in autoimmune diseases, stressing the fact that “high MBL levels can increase diseases susceptibility,” a paradox that needs justification. Attributable to these discrepancies, no absolute level of MBL deficiency could be defined so far and thus must be interpreted for specific diseases through case–control population-specific designs. Overall, it is evident that further research is needed about MBL and the lectin pathway of complement. Particularly, the transformative role of MBL over evolution is of interest and its role with regard to pathogenesis of different diseases and potential therapeutic targets within the respective pathways should be further explored. Apart from this, it is necessary to adopt an extensive locus-wide methodology to apprehend the clinical significance of MBL2 polymorphisms in a variety of infectious diseases by the future studies.

Keywords: infectious diseases; autoimmune diseases; single nucleotide polymorphisms; functional SNPs; 5′ near gene; 3′UTR; variants; phagocytosis and MBL patents

1 Introduction

Pathogens’ identification by the innate immune system is facilitated by the germ line-encoded host factors [1]. Pattern recognition receptors (PRRs) exemplify these factors, which recognize the conserved bio-molecular structures on the pathogens’ surface, designated as pathogen-associated molecular patterns (PAMPs). The ability to recognize PAMPs and differentiate the self from non-self/altered-self structures is the characteristic and fundamental definition of PRRs. This PRR–PAMP interaction further leads to the generation of immune responses against these pathogens, eventually leading to their clearance from the host [1]. C-type lectin receptors (CLRs) are the best emerging PRRs that are gaining attention because of their numerous functions. These multifunctional properties of CLRs include endocytosis, phagocytosis, complement activation, oxidative burst, immuno-modulation by activating pro-inflammatory and anti-inflammatory responses, immune cells’ recruitment, extravasations, linking innate with adaptive immunity, controlling adaptive immune responses, regulating and collaborating with other PRRs for the optimal immune response generation, clearance of altered self-cells, and so on [2].

CLRs are the collection of asymmetric molecules possessing one or more preserved structures, referred as carbohydrate-recognition domains (CRDs), which bind to the sugars in a Ca2+-dependent manner [3]. On the basis of their molecular structure, these Ca2+-dependent proteins are of two types, such as transmembrane CLRs and soluble CLR. The transmembrane CLRs are further divided into two categories, i.e., type I and II transmembrane proteins based on the number of CRD regions and N-terminal location. The soluble CLR has an oligomeric protein structure with multiple CRDs that binds to the repetitive carbohydrate structural arrangement present on the pathogens’ surface. This soluble CLR includes a liver-based mannose-binding lectin (MBL) protein, which is a significant constituent of the human innate immunity. However, its elevated levels in the liver cirrhosis patients suggested its extra-hepatic synthesis found in the small intestine, testis tissue, and restricted areas of the gastrointestinal and reproductive tracts [4]. MBL binds to the mannose-rich PAMPs with subsequent clearing of pathogens by complement activation and phagocytosis [5].

The genetic polymorphisms of MBL and its varying serum levels are the hot topics of research in many clinical studies. However, the discrepancies observed in describing the normal and abnormal MBL levels could not provide a precision regarding the MBL’s role in health and disease. Therefore, in the current article, an effort has been made to examine the potential clarifications for the so far muddled and ambiguous discoveries reported on MBL’s function in host immunity. It first outlines the role of MBL as a prototypical PRR and the associated roles it plays in human immunity. Further, it explains and strengthens the need of more extensive locus-wide approach by future association studies to apprehend the clinical significance of MBL2 polymorphisms, apart from the standard ones, in a variety of infectious diseases. Finally, we discussed MBL as a friend and foe in different diseases, a paradox that needs to be resolved.

2 MBL structure

The functional MBL is an extracellular circulatory protein, which is mainly expressed and produced by the liver cells. It is a bouquet-like complex that ranges from minimum two to maximum six sets of homo-trimers formed of monomers of 32 kDa protein as shown in Figure 1 [6]. This 32 kDa MBL monomer is a protein of 248 amino acids, translated from MBL2 gene mapped to 10q11.2-q21. The monomer constitutes cysteine-rich domain, 18–20 tandem repeats of Gly-Xaa-Yaa in a collagen-like region, α-helical neck region, and a CRD from N → C terminal [7]. Owing to the triple helix nature of collagen, three monomers present with their collagen-like region in close proximity creases toward N-terminal resulting tri-meric structural subunit (the homo-trimer) with triple helix and three CRDs at C-terminal [8]. The inter-chain disulfide bonds linking tri-meric subunits further form and stabilize the high order functional oligomers found predominantly in the extracellular fluid [9]. These high order oligomers consist of multiple CRDs that allow concurrent binding of functional MBL with numerous repetitive PAMPs present on the pathogens’ surface ensuring high avidity comparative to the low binding affinity (10−3 M) of individual CRD–PAMP contact [10].

Figure 1 Structure and assembly of MBL (modified from ref. [113]).
Figure 1

Structure and assembly of MBL (modified from ref. [113]).

3 MBL, an ideal PRR

Structural studies revealed low affinity (10−3 M) interaction between individual CRD and PAMP residues. However, binding of MBL oligomer to pathogen as a whole has been shown of high affinity (10 × 1010 M) [11]. For these high affinity interactions, it is necessary that the ligand makes a proper geometry by spanning 45 Å in three dimensions of MBL, which is only possible in the case of repetitive carbohydrate structural patterns mainly found on the pathogen surfaces, but hidden inside the self-glycoproteins [12]. The sugar specificity is secured within the Glu-Pro-Asn amino acid sequence of CRD that favors the Ca2+-dependent binding with the 3′- and 4′-hydroxyl groups of carbohydrates including mannose, N-acetyl-d-glucosamine, glucose, fucose and their derivatives, but do not allow binding to galactose and the terminal sialic acid of oligosaccharide chains present on the host cell surface [13,14]. In addition, abnormal glycosylation occurs in the cancerous cells because of oncogenic transformation that leads to the exposure of sufficient sugar ligands in fitting pattern, allowing their recognition and binding by MBL [15]. Besides this, MBL recognizes apoptotic cells with exposed hidden repetitive sugar pattern [16]. Thus, MBL can also recognize altered self-structure and mediates cytotoxicity and clearance by phagocytosis. Therefore, three structural properties, i.e., (i) blocking of oligosaccharide chains with terminal sialic acid residues, (ii) inadequately exposed sugar ligands to allow precise binding configuration, and (iii) hidden repetitive sugar pattern inside glycoproteins, allow MBL to distinguish self from the non-self and altered-self structures, making it an ideal PRR. This prototypical PRR has been shown to bind diverse range of fungal, bacterial, parasitic, and viral species, thereby generating required immune responses [17,18,19,20,21,22].

4 The receptor-mediated effector functions of MBL

The receptor-mediated effector functions of MBL include complement (C) system activation, direct opsono-phagocytosis, MBL-dependent cell-mediated cytotoxicity, apoptosis, pro-inflammatory cytokines release, and ROS production. These are described herewith.

4.1 Activation of complement (C) system

The C system involves the interactions of distinct plasma proteins that opsonize the pathogens and initiates a series of inflammatory reactions for the ultimate clearance of pathogens [23]. Activation of C system on the pathogen surfaces involves three pathways, i.e., the classical, lectin, and alternative, involving different initiatory molecules that eventually converge to produce similar molecules [23]. MBL binding to the pathogen surface activates the so-called MBL-mediated lectin complement pathway. There is a family of serine proteases that bind to MBL and get activated when the complex is associated with the pathogen. These MBL-associated serine proteases (MASPs) include MASP-1 to -3 along with the truncated version of MASP-2 currently named as MAP-2 (also known as Map19 or sMAP), of which MASP-2 has been shown to play an important role in the C system activation [23,24,25,26,27,28]. Following activation, MASP-2 results in the consecutive cleavage of C4 and C2, generating C4b and C2a fragments that interact with each other to form C3 convertase (C4bC2a complex) that will eventually converge with the other C3 convertases produced from both the alternative and the classical pathways. These C3 convertases then start the C cascade activity generating the terminal components of C system that gather to form membrane attack complex and damage the pathogen. Lectin pathway also generates opsonic C3b and other C fragments, which further enhance the phagocytosis as well as activate and infiltrate the additional phagocytes to the spot of C activation.

4.2 Direct opsonophagocytosis by MBL

Besides causing indirect opsonization because of the C components (opsonins) generated as a result of MBL pathway, MBL can directly act as an opsonin, independent of C system activation [29,30,31]. This direct opsonophagocytosis by MBL has been shown to be facilitated by the receptors present on the surface of phagocytic cells (monocytes and neutrophils) [32,33]. Other than this, several other intracellular and extracellular receptors have been defined in the literature, which directly bind to the MBL, although their function is not completely understood. These receptors include cC1qR (calreticulin), C1qRp, complement receptor 1 (CR1), alpha-2-beta-1 integrin, and α-2-macroglobulin receptor (CD91) [34,35,36,37,38,39,40]. This imperative property explains why the low levels of MBL has ultimately been suggested to be responsible for opsonic defects found in the children with recurrent infections, which was earlier thought to be occurring because of the deficiency of other opsonins [41,42].

4.3 MBL-dependent cell-mediated cytotoxicity

Researchers have detected MBL binding to the aberrant carbohydrate structures expressed by the cancerous cells and mediating cytotoxic activity, which was referred as MBL-dependent cell-mediated cytotoxicity [43,44]. It is important to note that this activity was shown by the mutated MBL protein with no opsonic and complement activation activity, suggesting the un-described cytotoxic role of MBL, whose relative importance in tumor immunology is currently not known.

4.4 Role in apoptosis

As mentioned above, MBL can directly bind to the apoptotic cells with exposed repetitive sugar pattern, thereby permitting their recognition and the ultimate clearance of apoptotic cells by phagocytes [16,45]. Low MBL levels have been suggested to be associated with defective apoptotic cell clearance [46].

4.5 Pro-inflammatory cytokine release

MBL has been shown to trigger the release of pro-inflammatory cytokines from the monocytes [47,48]. A study by Jack et al. [49] depicted the elevated production of the pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α from the monocytes at low MBL levels (4 μg/mL). However, the inflammatory production reduces at high MBL concentrations, suggesting the complex role of MBL in modulating the release of pro-inflammatory cytokines with unexplained mechanisms.

4.6 Reactive oxygen species (ROS) production

Other than the above-mentioned functions, MBL mediates ROS production including superoxide and H2O2 from human neutrophils [30,33,50].

Thus, MBL is one of the best examples of a single molecule with multiple functions ranging from an ideal PRR, activation of C system, direct and indirect opsonization, altered self-cells clearance, pro-inflammatory cytokines release to ROS production. These important functional activities explain why the defect in MBL has been shown to be associated with different infectious diseases such as malaria, human immunodeficiency virus (HIV) infection, leprosy, leishmaniasis, schistosomiasis, trypanosomiasis, tuberculosis, systemic lupus erythematosus, rheumatoid arthritis, recurrent vulvovaginal infections (RVVI), filariasis, etc. [51,52,53,54,55,56,57,58].

5 MBL2 structure

Humans have two MBL genes, MBL1 and MBL2, of which MBL1 is a pseudogene, leaving only one functional gene MBL2 that encodes for MBL protein [59]. MBL2 comprises 7,461 bases, between 5,27,65,380 and 5,27,72,841 bp region of chromosome no. 10 (10q11.2-q21) (NC_000010.11, NCBI), translating into MBL protein of 248 amino acid (NCBI accession number XP_011538118.1) via a 3,570 bp long mRNA (NCBI accession number NM_000242.21). The gene structure of MBL2 is same as that of other eukaryotic genes with each element contributing to the specific function in gene expression. MBL2 comprises four exons and three introns. The exons determine the structure of proteins with exon 1 encoding signal peptide, a cysteine-rich domain, and a portion of glycine-rich collagenous region. Exon 2 encodes the other portion of the collagenous domain, whereas α-helical “neck” region and CRD are encoded by exons 3 and 4, respectively (Figure 2). In addition, the promoter and 3′UTR region of the MBL2 contain various elements that have been shown to regulate MBL2 expression [60,61,62,63].

Figure 2 Structure of MBL2 (modified from ref. [114]).
Figure 2

Structure of MBL2 (modified from ref. [114]).

6 MBL2 genetics (SNPs with validated functional consequences)

An acute phase protein is the commonly referred term used for MBL accredited to the elevated serum levels’ subsequent infection and under aberrant body changes [64]. However, MBL is not a typical acute phase protein, because its response is generally demonstrated by the individuals’ MBL levels and genetic variations [65,66,67]. Single nucleotide polymorphisms (SNPs) in exon 1 and promoter region of MBL2 have been functionally characterized in regulating serum MBL (sMBL) levels. SNPs in exon 1 include rs5030737/codon 52, rs1800450/codon 54, and rs1800451/codon 57, jointly referred as MBL2 structural variations [68]. SNPs including rs1800450 and rs1800451 involve the glycine replacement with the di-carboxylic acids. In contrast, SNP rs5030737 involves arginine replacement with cysteine in the MBL monomers’ collagenous region consequently forming the variant subunits [69,70]. These variant monomers further impede the synthesis of high order MBL oligomers because of the distortion created in the triple helix collagenous region by codon 54 and 57 variations. Besides this, the additional disulfide bonds that are formed as a result of extra cysteine residues added by codon 52 variation also impede the MBL oligomers synthesis. These structural changes dramatically lower the synthesis, circulating levels, and functional activity of high order MBL oligomers [69,70,71,72,73,74]. Apart from these structural variations, promoter polymorphisms including rs11003125; L/H, rs7096206; Y/X, and rs7095891; P/Q regulate promoter activity of the gene subsequently modulating the MBL protein levels. From this, the biological implication of the genetic variations can be explicated in regard to the MBL2 transcription and translation [75,76,77]. MBL2 promoter and structural polymorphisms are in strong linkage disequilibrium (LD) forming the seven haplotypes, universally referred as secretor haplotypes involving LYPA, HYPA, LXPA, LYQA, LYPB, LYQC, and HYPD. The haplotypes involving HYPA, LYQA, and LYPA confer the high sMBL levels, whereas haplotypes involving LXPA, LYPB, LYQC, and HYPD confer the low sMBL levels [78]. Apart from the seven standard ones, the other haplotypes counting HYQA, HXPA, LXPB, LYQB, and LYPD have been reported by different population-specific studies [79,80,81]. This suggests the emergence of novel haplotypes besides the standard ones, owing to the heterogeneity found in the genetic pool of the various populations and the observed discerning advantage because of the ecological pressures like infections or demographics [82].

However, there are studies that did not find the complete correlation of sMBL levels with the secretor haplotypes signifying the existence of other MBL2 regulating variants [20,78,83]. To reveal this, Bernig’s group in 2004 analyzed the complete MBL2 gene of 10.0 kbp by re-sequencing it and found a great degree of heterozygosity [84]. They further found that the LD pattern of complete MBL2 uncovers a plausible recombination hotspot of 1.6 kbp that lies in the coding region of exon 4 in the 3′ end of the gene. This hotspot divides the whole MBL2 into two separate haplotype blocks in which the markers within each block are in linkage with each other, while the markers of one block are not in linkage with the markers of other. They named these blocks as the 5′ and 3′ haplotype blocks or simply as 5′ and 3′ blocks of MBL2 gene [84]. Moreover, the structural SNPs of exon 1 along with the upstream promoter polymorphisms that form the “secretor haplotypes” were found to lie in the 5′ block and are part of its extended haplotypes, indicating the possibility of additional linked 5′ variants with the possible functional implications. To investigate this, Bernig’s group in another study analyzed both MBL2 blocks in the unrelated Dutch Caucasians [61]. The results of this study suggested that the other variants in 5′ as well as 3′ haplotype block may modify the protein functionality and serum levels (Table 1). To further confirm these findings, the same group presented the preliminary evidence authenticating that 3′UTR variants of MBL2 manipulate the MBL concentration and also interact with the haplotypes of 5′ block that might increase the risk of breast cancer in the African-American women [62]. Other studies by different groups also found that the combined 5′ and 3′ blocks of MBL2 alter sMBL levels and increase risk of postoperative myocardial infarction, colon cancer, and RVVIs in White-Americans, African-Americans, and Indians, respectively [54,55,63,85]. Because of these observed associations, Zanetti et al. [63] functionally characterized the 3′UTR haplotypes of 3′ block and found that the SNP rs10082466 in the 3′UTR haplotype generates a binding site for miR-27a with full complementarity to its seed region. This binding has been shown to hasten the mRNA degradation by microRNAs (miRNAs) resulting in reduced protein translation as depicted by a significant decrease found in the normalized luciferase activity of MBL2 [63]. Overall, this implicates the necessity to adopt an extensive locus-wide methodology by the future association studies to apprehend the clinical significance of MBL2 polymorphisms in a variety of infectious diseases.

Table 1

Functionally characterized polymorphisms of MBL2

dbSNP identifiera SNP position (5′ → 3′)b Chromosome positionb Secretorc Region Nucleotide change Effect Characterized function References
rs11003125 −618 5,27,72,254 L/H (aka −550) 5′ near gene C/G Variation in the promoter activity of MBL2 Alter transcriptional levels [75,76,77]
rs7096206 −289 5,27,71,925 Y/X (aka −221) 5′ near gene G/C
rs7095891 −65 5,27,71,701 P/Q (aka +4) 5′ near gene C/T
rs5030737 +152 5,27,71,482 A/D (codon 52) Exon 1 C/T Distortion in the triple helix collagenous region Dramatically reduce the formation of functional higher order oligomers [69,70,71,72,73,74]
rs1800450 +161 5,27,71,475 A/B (codon 54) Exon 1 G/A
rs1800451 +170 5,27,71,466 A/C (codon 57) Exon 1 G/A Formation of adventitious disulfide bonds
rs10082466 +4,455 5,27,66,862 — 3′UTR A/G Generates a binding site for miR-27a Hasten mRNA degradation by miR-27a with reduced protein translation [63]
  1. a

    NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/SNP).

  2. b

    NCBI contig accession number NT_030059.14 (NCBI build 142, locus ID 4153).

  3. c

    Designation extensively used in the literature is also followed in the present study, and these markers form the “secretor haplotypes.”

7 MBL in different diseases and MBL paradox

The important functions of MBL in immune defense led to the following implicit assumption: “High serum MBL (sMBL) levels provide protection and low levels risk to the diseases.” This assumption was initially documented in 1989, when the defect in opsonization because of MBL deficiency (i.e., low sMBL levels) was recognized as the reason of frequent inexplicable infections in children [42]. After this, the number of pediatric population-specific studies started emphasizing the importance of nonspecific innate immunity provided by MBL in the early life. The later was considered as the substitute for the defense offered by the adaptive immunity, which is suggested to be undeveloped in infants. Nonetheless, the studies based on the adults suggested the role of MBL throughout one’s life, emphasizing its role as a first line of defense against pathogens till the adaptive immunity starts responding [86]. A synopsis involving specific examples covering the mushrooming literature regarding MBL in different diseases is discussed below:

7.1 MBL in infectious diseases caused by extracellular pathogens and autoimmune diseases

Low sMBL levels (i.e., MBL deficiency) have been shown to be predisposing individuals to many infectious diseases specifically caused by the extracellular pathogens [87]. One of the earliest evidences in this regard was observed in the AIDS patients with MBL2 structural variant alleles. These patients were found to have a low survival rate attributed to their increased susceptibility to coinfections [88]. In addition, the number of studies have shown the MBL-deficient states in patients with hepatitis B or C indicating that the low sMBL levels increase susceptibility to this disease [89,90]. The same scenario was also observed in the autoimmune diseases where MBL deficiency was shown to predispose individuals to systemic lupus erythematosus [79] and rheumatoid arthritis [91]. In general, a surplus literature can be found vis-à-vis MBL2 genetic variations and their association with low sMBL levels in susceptibility to many diseases including tuberculosis, malaria, filariasis, systemic lupus erythematosus, trypanosomiasis, rheumatoid arthritis, HIV infection, RVVIs, and many more (as afore referred), not to mention the severe acute respiratory syndrome-coronavirus (SARS-CoV) infection.

It has been documented that MBL paucity upsurges the risk of SARS-CoV-1 infection [92] with a higher prevalence of low secretor haplotypes in SARS cases than controls. Of all the viral envelopes to which MBL can bind, both plasma-derived and recombinant human MBL have been shown to directly inhibit SARS-CoV spike (S) glycoprotein (SARS-S)-mediated viral infection [93]. Therefore, MBL binding to SARS-S may intrude the events necessary for the efficient viral entry. This further suggests a possible role of MBL in the coronavirus disease 2019 (COVID-19). In this respect, a recent study suggested that SARS-CoV-2 uses the mannose-rich S protein for binding the angiotensin-converting enzyme 2 (ACE2) receptor of host to mediate host-cell entry [94]. This provides an assumption that MBL may possibly bind and inhibit the S-ACE2 interaction in SARS-CoV-2, as it did for SARS-CoV-1. A recent pre-print by Gao et al. [95] strengthened this speculation, by suggesting the role of MASP-2-mediated complement over-activation on interaction with N protein dimers of SARS-CoV-2 that aggravates the lung injury. Moreover, a case–control study showed higher expression of MBL in the lungs of COVID-19 group than controls [96]. In contrast, comparable plasma MBL levels were found between COVID-19 cases and controls by another study [97]. These two case–control studies together provide the inclusive findings attributed to their underpower study design. Given the prevalence of this disease, it is very important that such case–control studies must be performed in the larger datasets of different populations, so that the role of MBL in COVID-19 can be elucidated. This is of utmost importance as the presence of symptomatic COVID appears to be dependent more on the host factors rather than on the pathogen itself. Therefore, the knowledge of MBL role in COVID-19 may help us devise an efficient immune-based therapy.

7.2 MBL in infectious diseases caused by intracellular pathogens (the paradox)

The paradox, i.e., “high MBL levels increase diseases susceptibility and low MBL levels protect,” came into light when MBL was found to have predisposing effect on the infectious diseases involving leprosy and visceral leishmaniasis, both caused by the intracellular parasites [98,99]. These patients had considerably high sMBL levels in comparison to the controls. In unison, the higher prevalence of variant alleles observed in controls than in patients suggest the advantageous role of functional MBL deficiency in these controls. This unexpected frequency was explained by the fact that intracellular parasite is dependent on the phagocytosis to invade the host cells and use opsonization by complements to enter the phagocytes through complement receptors. Therefore, the presence of low MBL levels in the controls will consequently lower the probability of parasitization because of the reduction in the complement-mediated phagocytosis [98]. This could be the plausible rationale behind the few exceptions that have surplus existence of low MBL phenotypes across the globe, suggesting that these geographic areas must be prone to the intracellular parasitism. Therefore, any mechanism that diminishes C system activation would be favorable conferring the selective advantage to those individuals carrying the variant alleles and low MBL levels [71,100]. The mechanism was proposed to be similar to sickle cell anemia, where the sickle cell gene was found to provide protection against malaria that ultimately leads to the selective advantage to the carriers of sickle cell allele [101]. Overall, this suggests that low sMBL levels provide protection against intracellular pathogens.

Thus, these reports mentioned above have suggested the protective role played by MBL against diseases either through high levels or selectively by low levels. In contrast, there are reports that did not find any significant difference between the MBL levels of cases and controls [102,103]. Moreover, MBL-deficient individuals with no evidence of infections have also been reported, which argues against the defensive role played by the MBL [102,103]. However, these studies cannot be viewed as the evidence of no clinical applicability of sMBL levels. This is because different groups of scientific researchers have provided the evidence verifying the defensive role of MBL under a case–control design. In addition, the studies have also suggested that MBL paucity works in synergism with other humoral immunodeficiencies to cause diseases [104,105]. These are the discrepancies because of which no absolute level of MBL deficiency could be determined. Therefore, it is important that instead of generalizing the MBL’s role, an effort should be made in defining its versatile nature in different diseases.

8 Clinical trials and patents

The plasma-derived MBL has passed phase-I clinical trials and has successfully been used for the treatment of a 2-year-old girl with opsonic defect suffering from the devastating recurrent infections and other patients with cystic fibrosis and lung infections [106,107,108,109,110,111]. Furthermore, patents have been filed for the use of recombinant MBL for the management of melanoma cancer, lymphoma cancer, pancreatic cancer, ovarian cancer, or colorectal cancer (WO2008019322A2, US6846649B1, and WO2004026330A1). However, after some enthusiasm about MBL substitution treatment, there is a lack of well-designed large trials that could have supported the adoption of MBL supplementation. Patient numbers in the references mentioned are small, and there has been no widespread clinical use of MBL ever since. In light of this, the present literature review commands further research using larger datasets of different populations for the use of emerging MBL-supplementation as effectual treatment for different diseases in which its role has already been elucidated to authenticate the medicinal prospects of MBL.

9 Conclusion and future directions

MBL harbors a complex genetic system and several studies have shown the association of its variants with infectious diseases, suggesting its transformative role in innate immunity, exemplifying how polymorphisms were shaped by ecological pressure like infections and demographics [112]. Therefore, further research focused on elucidating MBL and the lectin pathway of complement with regard to the pathogenesis of different diseases and potential therapeutic targets within the respective pathways along with the exploration of the neglected area of “whether pathology due to MBL paucity entails one or more co-existing immune deficits or not” is needed as supported by different studies [68,104,105].

  1. Author contributions: N. K. collected the literature, designed, and wrote the manuscript. J. S. and M. K. critically checked the manuscript.

  2. Conflict of interest: The authors state no conflict of interest.

  3. Data availability statement: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Received: 2020-07-09
Revised: 2021-01-22
Accepted: 2021-01-29
Published Online: 2021-02-17

© 2021 Namarta Kalia et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

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  2. Identification of ZG16B as a prognostic biomarker in breast cancer
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https://doi.org/10.1515/med-2021-0239
Keywords for this article
infectious diseases; autoimmune diseases; single nucleotide polymorphisms; functional SNPs; 5′ near gene; 3′UTR; variants; phagocytosis and MBL patents
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Identification of ZG16B as a prognostic biomarker in breast cancer
  3. Behçet’s disease with latent Mycobacterium tuberculosis infection
  4. Erratum
  5. Erratum to “Suffering from Cerebral Small Vessel Disease with and without Metabolic Syndrome”
  6. Research Articles
  7. GPR37 promotes the malignancy of lung adenocarcinoma via TGF-β/Smad pathway
  8. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  9. Additional baricitinib loading dose improves clinical outcome in COVID-19
  10. The co-treatment of rosuvastatin with dapagliflozin synergistically inhibited apoptosis via activating the PI3K/AKt/mTOR signaling pathway in myocardial ischemia/reperfusion injury rats
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  13. Case Report
  14. Serratia marcescens as a cause of unfavorable outcome in the twin pregnancy
  15. Spleno-adrenal fusion mimicking an adrenal metastasis of a renal cell carcinoma: A case report and embryological background
  16. Research Articles
  17. TRIM25 contributes to the malignancy of acute myeloid leukemia and is negatively regulated by microRNA-137
  18. CircRNA circ_0004370 promotes cell proliferation, migration, and invasion and inhibits cell apoptosis of esophageal cancer via miR-1301-3p/COL1A1 axis
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  21. Rapid Communication
  22. COVID-19 vaccine: Call for employees in international transportation industries and international travelers as the first priority in global distribution
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  24. Rare squamous cell carcinoma of the kidney with concurrent xanthogranulomatous pyelonephritis: A case report and review of the literature
  25. An infertile female delivered a baby after removal of primary renal carcinoid tumor
  26. Research Articles
  27. Hypertension, BMI, and cardiovascular and cerebrovascular diseases
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  31. Correlation between kinematic sagittal parameters of the cervical lordosis or head posture and disc degeneration in patients with posterior neck pain
  32. Review Articles
  33. Hepatoid adenocarcinoma of the lung: An analysis of the Surveillance, Epidemiology, and End Results (SEER) database
  34. Research Articles
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  36. Pemetrexed-based first-line chemotherapy had particularly prominent objective response rate for advanced NSCLC: A network meta-analysis
  37. Comparison of single and double autologous stem cell transplantation in multiple myeloma patients
  38. The influence of smoking in minimally invasive spinal fusion surgery
  39. Impact of body mass index on left atrial dimension in HOCM patients
  40. Expression and clinical significance of CMTM1 in hepatocellular carcinoma
  41. miR-142-5p promotes cervical cancer progression by targeting LMX1A through Wnt/β-catenin pathway
  42. Comparison of multiple flatfoot indicators in 5–8-year-old children
  43. Early MRI imaging and follow-up study in cerebral amyloid angiopathy
  44. Intestinal fatty acid-binding protein as a biomarker for the diagnosis of strangulated intestinal obstruction: A meta-analysis
  45. miR-128-3p inhibits apoptosis and inflammation in LPS-induced sepsis by targeting TGFBR2
  46. Dynamic perfusion CT – A promising tool to diagnose pancreatic ductal adenocarcinoma
  47. Biomechanical evaluation of self-cinching stitch techniques in rotator cuff repair: The single-loop and double-loop knot stitches
  48. Review Articles
  49. The ambiguous role of mannose-binding lectin (MBL) in human immunity
  50. Case Report
  51. Membranous nephropathy with pulmonary cryptococcosis with improved 1-year follow-up results: A case report
  52. Fertility problems in males carrying an inversion of chromosome 10
  53. Acute myeloid leukemia with leukemic pleural effusion and high levels of pleural adenosine deaminase: A case report and review of literature
  54. Metastatic renal Ewing’s sarcoma in adult woman: Case report and review of the literature
  55. Burkitt-like lymphoma with 11q aberration in a patient with AIDS and a patient without AIDS: Two cases reports and literature review
  56. Skull hemophilia pseudotumor: A case report
  57. Judicious use of low-dosage corticosteroids for non-severe COVID-19: A case report
  58. Adult-onset citrullinaemia type II with liver cirrhosis: A rare cause of hyperammonaemia
  59. Clinicopathologic features of Good’s syndrome: Two cases and literature review
  60. Fatal immune-related hepatitis with intrahepatic cholestasis and pneumonia associated with camrelizumab: A case report and literature review
  61. Research Articles
  62. Effects of hydroxyethyl starch and gelatin on the risk of acute kidney injury following orthotopic liver transplantation: A multicenter retrospective comparative clinical study
  63. Significance of nucleic acid positive anal swab in COVID-19 patients
  64. circAPLP2 promotes colorectal cancer progression by upregulating HELLS by targeting miR-335-5p
  65. Ratios between circulating myeloid cells and lymphocytes are associated with mortality in severe COVID-19 patients
  66. Risk factors of left atrial appendage thrombus in patients with non-valvular atrial fibrillation
  67. Clinical features of hypertensive patients with COVID-19 compared with a normotensive group: Single-center experience in China
  68. Surgical myocardial revascularization outcomes in Kawasaki disease: systematic review and meta-analysis
  69. Decreased chromobox homologue 7 expression is associated with epithelial–mesenchymal transition and poor prognosis in cervical cancer
  70. FGF16 regulated by miR-520b enhances the cell proliferation of lung cancer
  71. Platelet-rich fibrin: Basics of biological actions and protocol modifications
  72. Accurate diagnosis of prostate cancer using logistic regression
  73. miR-377 inhibition enhances the survival of trophoblast cells via upregulation of FNDC5 in gestational diabetes mellitus
  74. Prognostic significance of TRIM28 expression in patients with breast carcinoma
  75. Integrative bioinformatics analysis of KPNA2 in six major human cancers
  76. Exosomal-mediated transfer of OIP5-AS1 enhanced cell chemoresistance to trastuzumab in breast cancer via up-regulating HMGB3 by sponging miR-381-3p
  77. A four-lncRNA signature for predicting prognosis of recurrence patients with gastric cancer
  78. Knockdown of circ_0003204 alleviates oxidative low-density lipoprotein-induced human umbilical vein endothelial cells injury: Circulating RNAs could explain atherosclerosis disease progression
  79. Propofol postpones colorectal cancer development through circ_0026344/miR-645/Akt/mTOR signal pathway
  80. Knockdown of lncRNA TapSAKI alleviates LPS-induced injury in HK-2 cells through the miR-205/IRF3 pathway
  81. COVID-19 severity in relation to sociodemographics and vitamin D use
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  83. Cis-regulatory elements in conserved non-coding sequences of nuclear receptor genes indicate for crosstalk between endocrine systems
  84. Four long noncoding RNAs act as biomarkers in lung adenocarcinoma
  85. Real-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens
  86. Relation between IL-8 level and obstructive sleep apnea syndrome
  87. circAGFG1 sponges miR-28-5p to promote non-small-cell lung cancer progression through modulating HIF-1α level
  88. Nomogram prediction model for renal anaemia in IgA nephropathy patients
  89. Effect of antibiotic use on the efficacy of nivolumab in the treatment of advanced/metastatic non-small cell lung cancer: A meta-analysis
  90. NDRG2 inhibition facilitates angiogenesis of hepatocellular carcinoma
  91. A nomogram for predicting metabolic steatohepatitis: The combination of NAMPT, RALGDS, GADD45B, FOSL2, RTP3, and RASD1
  92. Clinical and prognostic features of MMP-2 and VEGF in AEG patients
  93. The value of miR-510 in the prognosis and development of colon cancer
  94. Functional implications of PABPC1 in the development of ovarian cancer
  95. Prognostic value of preoperative inflammation-based predictors in patients with bladder carcinoma after radical cystectomy
  96. Sublingual immunotherapy increases Treg/Th17 ratio in allergic rhinitis
  97. Prediction of improvement after anterior cruciate ligament reconstruction
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  99. circ_0038467 promotes PM2.5-induced bronchial epithelial cell dysfunction
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  103. Characteristics of BCR–ABL gene variants in patients of chronic myeloid leukemia
  104. Knee alterations in rheumatoid arthritis: Comparison of US and MRI
  105. Long non-coding RNA TUG1 aggravates cerebral ischemia and reperfusion injury by sponging miR-493-3p/miR-410-3p
  106. lncRNA MALAT1 regulated ATAD2 to facilitate retinoblastoma progression via miR-655-3p
  107. Development and validation of a nomogram for predicting severity in patients with hemorrhagic fever with renal syndrome: A retrospective study
  108. Analysis of COVID-19 outbreak origin in China in 2019 using differentiation method for unusual epidemiological events
  109. Laparoscopic versus open major liver resection for hepatocellular carcinoma: A case-matched analysis of short- and long-term outcomes
  110. Travelers’ vaccines and their adverse events in Nara, Japan
  111. Association between Tfh and PGA in children with Henoch–Schönlein purpura
  112. Can exchange transfusion be replaced by double-LED phototherapy?
  113. circ_0005962 functions as an oncogene to aggravate NSCLC progression
  114. Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells
  115. Serum intact fibroblast growth factor 23 in healthy paediatric population
  116. Algorithm of rational approach to reconstruction in Fournier’s disease
  117. A meta-analysis of exosome in the treatment of spinal cord injury
  118. Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma
  119. Dexmedetomidine may decrease the bupivacaine toxicity to heart
  120. Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression
  121. Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p
  122. External fixation via the anterior inferior iliac spine for proximal femoral fractures in young patients
  123. miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12
  124. HAGLR promotes neuron differentiation through the miR-130a-3p-MeCP2 axis
  125. Phosphoglycerate mutase 2 is elevated in serum of patients with heart failure and correlates with the disease severity and patient’s prognosis
  126. Cell population data in identifying active tuberculosis and community-acquired pneumonia
  127. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression
  128. Mean platelet volume and red blood cell distribution width is associated with prognosis in premature neonates with sepsis
  129. 3D-printed porous scaffold promotes osteogenic differentiation of hADMSCs
  130. Association of gene polymorphisms with women urinary incontinence
  131. Influence of COVID-19 pandemic on stress levels of urologic patients
  132. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer
  133. miR-519d downregulates LEP expression to inhibit preeclampsia development
  134. Comparison of single- and triple-port VATS for lung cancer: A meta-analysis
  135. Fluorescent light energy modulates healing in skin grafted mouse model
  136. Silencing CDK6-AS1 inhibits LPS-induced inflammatory damage in HK-2 cells
  137. Predictive effect of DCE-MRI and DWI in brain metastases from NSCLC
  138. Severe postoperative hyperbilirubinemia in congenital heart disease
  139. Baicalin improves podocyte injury in rats with diabetic nephropathy by inhibiting PI3K/Akt/mTOR signaling pathway
  140. Clinical factors predicting ureteral stent failure in patients with external ureteral compression
  141. Novel H2S donor proglumide-ADT-OH protects HUVECs from ox-LDL-induced injury through NF-κB and JAK/SATA pathway
  142. Triple-Endobutton and clavicular hook: A propensity score matching analysis
  143. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis
  144. Serum exosomal miR-122-5p, GAS, and PGR in the non-invasive diagnosis of CAG
  145. miR-513b-5p inhibits the proliferation and promotes apoptosis of retinoblastoma cells by targeting TRIB1
  146. Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p
  147. The diagnostic and prognostic value of miR-92a in gastric cancer: A systematic review and meta-analysis
  148. Prognostic value of α2δ1 in hypopharyngeal carcinoma: A retrospective study
  149. No significant benefit of moderate-dose vitamin C on severe COVID-19 cases
  150. circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p
  151. Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions
  152. Educational program for orthopedic surgeons’ influences for osteoporosis
  153. Expression and function analysis of CRABP2 and FABP5, and their ratio in esophageal squamous cell carcinoma
  154. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells
  155. lncRNA-ZFAS1 promotes the progression of endometrial carcinoma by targeting miR-34b to regulate VEGFA expression
  156. Anticoagulation is the answer in treating noncritical COVID-19 patients
  157. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT
  158. Comparison of Dako HercepTest and Ventana PATHWAY anti-HER2 (4B5) tests and their correlation with silver in situ hybridization in lung adenocarcinoma
  159. VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway
  160. Comparison of vaginal birth outcomes in midwifery-led versus physician-led setting: A propensity score-matched analysis
  161. Treatment of osteoporosis with teriparatide: The Slovenian experience
  162. New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB
  163. Superenhancer–transcription factor regulatory network in malignant tumors
  164. β-Cell function is associated with osteosarcopenia in middle-aged and older nonobese patients with type 2 diabetes: A cross-sectional study
  165. Clinical features of atypical tuberculosis mimicking bacterial pneumonia
  166. Proteoglycan-depleted regions of annular injury promote nerve ingrowth in a rabbit disc degeneration model
  167. Effect of electromagnetic field on abortion: A systematic review and meta-analysis
  168. miR-150-5p affects AS plaque with ASMC proliferation and migration by STAT1
  169. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p
  170. Effects of remifentanil and propofol on distant organ lung injury in an ischemia–reperfusion model
  171. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway
  172. Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer
  173. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy
  174. Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
  175. circATP2A2 promotes osteosarcoma progression by upregulating MYH9
  176. Prognostic role of oxytocin receptor in colon adenocarcinoma
  177. Review Articles
  178. The function of non-coding RNAs in idiopathic pulmonary fibrosis
  179. Efficacy and safety of therapeutic plasma exchange in stiff person syndrome
  180. Role of cesarean section in the development of neonatal gut microbiota: A systematic review
  181. Small cell lung cancer transformation during antitumor therapies: A systematic review
  182. Research progress of gut microbiota and frailty syndrome
  183. Recommendations for outpatient activity in COVID-19 pandemic
  184. Rapid Communication
  185. Disparity in clinical characteristics between 2019 novel coronavirus pneumonia and leptospirosis
  186. Use of microspheres in embolization for unruptured renal angiomyolipomas
  187. COVID-19 cases with delayed absorption of lung lesion
  188. A triple combination of treatments on moderate COVID-19
  189. Social networks and eating disorders during the Covid-19 pandemic
  190. Letter
  191. COVID-19, WHO guidelines, pedagogy, and respite
  192. Inflammatory factors in alveolar lavage fluid from severe COVID-19 pneumonia: PCT and IL-6 in epithelial lining fluid
  193. COVID-19: Lessons from Norway tragedy must be considered in vaccine rollout planning in least developed/developing countries
  194. What is the role of plasma cell in the lamina propria of terminal ileum in Good’s syndrome patient?
  195. Case Report
  196. Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature
  197. CTU findings of duplex kidney in kidney: A rare duplicated renal malformation
  198. Synchronous primary malignancy of colon cancer and mantle cell lymphoma: A case report
  199. Sonazoid-enhanced ultrasonography and pathologic characters of CD68 positive cell in primary hepatic perivascular epithelioid cell tumors: A case report and literature review
  200. Persistent SARS-CoV-2-positive over 4 months in a COVID-19 patient with CHB
  201. Pulmonary parenchymal involvement caused by Tropheryma whipplei
  202. Mediastinal mixed germ cell tumor: A case report and literature review
  203. Ovarian female adnexal tumor of probable Wolffian origin – Case report
  204. Rare paratesticular aggressive angiomyxoma mimicking an epididymal tumor in an 82-year-old man: Case report
  205. Perimenopausal giant hydatidiform mole complicated with preeclampsia and hyperthyroidism: A case report and literature review
  206. Primary orbital ganglioneuroblastoma: A case report
  207. Primary aortic intimal sarcoma masquerading as intramural hematoma
  208. Sustained false-positive results for hepatitis A virus immunoglobulin M: A case report and literature review
  209. Peritoneal loose body presenting as a hepatic mass: A case report and review of the literature
  210. Chondroblastoma of mandibular condyle: Case report and literature review
  211. Trauma-induced complete pacemaker lead fracture 8 months prior to hospitalization: A case report
  212. Primary intradural extramedullary extraosseous Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (PIEES/PNET) of the thoracolumbar spine: A case report and literature review
  213. Computer-assisted preoperative planning of reduction of and osteosynthesis of scapular fracture: A case report
  214. High quality of 58-month life in lung cancer patient with brain metastases sequentially treated with gefitinib and osimertinib
  215. Rapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report
  216. Retrieval of intrarenal coiled and ruptured guidewire by retrograde intrarenal surgery: A case report and literature review
  217. Usage of intermingled skin allografts and autografts in a senior patient with major burn injury
  218. Retraction
  219. Retraction on “Dihydromyricetin attenuates inflammation through TLR4/NF-kappa B pathway”
  220. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part I
  221. An artificial immune system with bootstrap sampling for the diagnosis of recurrent endometrial cancers
  222. Breast cancer recurrence prediction with ensemble methods and cost-sensitive learning
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