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Mannose-binding lectin (MBL) in adult patients with inflammatory bowel disease
Immunobiology xxx (xxxx) xxx–xxx
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Mannose-binding lectin (MBL) in adult patients with inflammatory bowel disease Leokadia Bąk-Romaniszyna, Anna S. Świerzkob, Anna Sokołowskab, Łukasz Durkoc, Grażyna Mierzwad, Agnieszka Szala-Poździejb, Ewa Małecka-Panasc, Maciej Cedzyńskib,* Unit of Nutrition in Digestive Tract Disease, Medical University of Łódź, Rzgowska 281/289, 93-338 Łódź, Poland Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Łódź, Poland c Department of Digestive Tract Diseases, Medical University of Łódź, Kopcińskiego 22, 91-425 Łódź, Poland d Department of Vascular and Internal Diseases, Unit of Gastroenterological Nursing, L. Rydygier Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Toruń, Jagiellońska 13/15, 85-067 Bydgoszcz, Poland a
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Keywords: Crohn’s disease (CD) Inflammatory bowel disease (IBD) Mannose-binding lectin (MBL) MBL2 gene Ulcerative colitis (UC)
Inflammatory bowel disease (IBD) refers to disorders associated with progressive inflammatory processes in the gastrointestinal system. IBD consists of two major forms, Crohn’s disease (CD), and ulcerative colitis (UC). IBD became a global disease in the 21st century. Its pathogenesis is still not fully understood. Mannose-binding lectin (MBL) is a pattern-recognising molecule, involved in anti-microbial and anti-cancer immunity. It is able to opsonize microorganisms and abnormal host cells, and to initiate complement activation. The aim of this study was to investigate possible involvement of MBL in inflammatory bowel disease in adults. Forty persons diagnosed with CD and 28 with ulcerative colitis were recruited. The control group consisted of 136 healthy persons. Single nucleotide polymorphisms of the MBL2 gene (localised to both promoter and exon 1) were determined as were serum MBL concentrations. The exon 1 variant alleles and MBL deficiency-associated genotypes were more frequent among patients compared with controls, although this difference was not statistically significant. No differences of MBL levels were found between the major groups. However in MBL2 A/A homozygous IBD patients, the median was significantly higher than in corresponding healthy subjects. That was particularly evident in the case of active Crohn’s disease (1493 ng/ml vs. 800 ng/ml, p = 0.021). It may suggest that MBL and MBLdependent complement activation contributes to excessive inflammation and its adverse effects in the course of CD. It cannot also be excluded that high MBL activity constitutes in some cases part of a multifactorial network conducing to development of CD.
1. Introduction Inflammatory bowel disease (IBD) constitutes a group of disorders associated with progressive inflammatory processes in the gastrointestinal system. Its incidence in Europe is still increasing. IBD includes two major subgroups, Crohn’s disease (CD), affecting any part of the alimentary tract, and ulcerative colitis (UC), associated with the rectum and colon. IBD incidence is still increasing. In the 21st century, it became a global disease, with increasing incidence not only in Europe and North America, but also in newly industrialised Asian, African and Southern-American countries where the lifestyle was changed to “Western” (Molodecky et al., 2012; Ng et al., 2017). IBD affects individuals of all ages, including children. The highest incidence is noted between 15th and 25th years of life with the second peak within the 6th
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decade (Kaplan and Ng, 2017). Its pathogenesis is still not understood, although some impairment of the host response to enteric microorganisms is often postulated. Therefore, an interplay between individual microbiome and immune system (affected by genetic polymorphisms, regulatory mechanisms, host behaviour, environmental factors, etc.) is considered crucial (Xavier and Podolsky, 2007; Van Limbergen et al., 2014; Kelsen and Sullivan, 2017; Ramos and Papadakis, 2019; Zhao and Burisch, 2019). Normal gut microbiota is involved in such beneficial effects as protection from pathogens and nutrition. Dysbiosis influences host-microbiota interaction and host immunity, and is considered to be associated with pathogenesis of variety of diseases, including IBD (Nishida et al., 2018). It is supposed that the loss of tolerance towards intestinal microflora leads to an inflammatory response, maintained by constant exposure to
Corresponding author at: Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Łódź, Poland. E-mail address: [email protected] (M. Cedzyński).
https://doi.org/10.1016/j.imbio.2019.10.008 Received 26 September 2019; Received in revised form 16 October 2019; Accepted 16 October 2019 0171-2985/ © 2019 Elsevier GmbH. All rights reserved.
Please cite this article as: Leokadia Bąk-Romaniszyn, et al., Immunobiology, https://doi.org/10.1016/j.imbio.2019.10.008
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2.4. Determination of serum concentrations of mannose-binding lectin
the stimuli (Onali et al., 2019). Another explanation (not excluding the afore-mentioned) is that inflammation becomes chronic due to failure of counter-regulatory and pro-resolving systems (Onali et al., 2019). Mannose-binding lectin (MBL) belongs to the collectin family, comprising calcium-dependent, collagen-related, multimeric lectins acting as pattern-recognising molecules, involved in anti-microbial and anti-cancer immunity. MBL forms complexes with mannose-binding lectin-associated serine proteases (MASP) which enables activation of the complement system via the lectin pathway (Cedzyński et al., 2018). It shares that property with some other collectins (CL-10, CL-11) and ficolins. MBL is also able to directly opsonize microbial and abnormal (apoptotic/necrotic/cancerous) host cells, bearing pathogen/dangerassociated molecular patterns (PAMP/DAMP). Therefore, it has a protective effect from certain infections or development of some malignancies via direct lysis of recognised cells or by enhancement of phagocytosis (Nakagawa et al., 2003). On the other hand, MBL may be involved in excessive or chronic inflammation which may be harmful to the host, leading in some cases to organ failure or carcinogenesis, respectively (Pągowska-Klimek et al., 2016; Swierzko et al., 2014). Our previous data (Bak-Romaniszyn et al., 2011) suggested an association of MBL deficiency with CD (but not UC) in children. However, the role of MBL in IBD is still controversial, and may depend on variety of other factors, including patient age. Therefore, the aim of this study was to estimate any involvement of MBL in inflammatory bowel disease in adults.
MBL concentrations were determined by ELISA, using mannan from Saccharomyces cerevisiae (Sigma-Aldrich, St. Louis, MO, USA) as coating antigen and murine anti-human MBL mAbs (HYB131-1, BioPorto Diagnostics, Copenhagen, Denmark) (Cedzynski et al., 2004). 2.5. Statistical analysis The Statistica (version 13.3, TIBCO Software) and SigmaPlot (version 12.0, Systat Software) software packages were used for data management and statistical calculations. The medians of MBL concentrations were compared using the Mann-Whitney U-test. The frequencies of genotypes were compared by two-sided Fischer’s exact test. P values < 0.05 were considered statistically significant. 3. Results Twenty-six (38.2%) patients carried one or two MBL2 gene exon 1 variant (O) alleles. Although those variants were apparently less common within the control group (39/136; 28.7%), the difference was not statistically significant [number of A/O and O/O genotypes: p = 0.2, OR = 1.54, 95% CI (0.83–2.85); frequency of D/B/C alleles: p = 0.076, OR = 1.62, 95% CI (0.06–2.72)]. Nor were significant differences observed when CD or CU groups separately were compared with healthy controls [number of A/O and O/O genotypes: p = 0.13, OR = 1.84, 95% CI (0.89–381) and p = 0.82, OR = 1.18, 95% CI (0.49–2.83), respectively]. Furthermore, numbers of MBL-deficient persons (carrying LXA/O or O/O genotypes) did not differ among the groups although MBL deficiency was twice more common within CD than within C group [(p = 0.095, OR = 2.03, 95% CI (0.87–4.72)] (Table 1). Despite the relatively high frequency of MBL2 O alleles in patients, there was a trend towards higher median MBL serum concentration in all patient groups (total IBD, 1001 ng/ml; CD, 1094 ng/ml; UC, 950 ng/ ml) compared with controls (800 ng/ml). However, when MBL levels were analysed on the genotype background, the median for IBD A/A homozygotes (1709 ng/ml) was found to be significantly higher than for corresponding healthy subjects (1325 ng/ml, p = 0.007). That difference was most marked for patients suffering from UC (median: 1942 ng/ml, p = 0.021) than from CD (median: 1667 ng/ml, p = 0.06) (Fig. 1). Furthermore, median MBL found for the 17 patients with active Crohn’s disease (1493 ng/ml) was much higher than that for the 23 patients in remission (384 ng/ml; p = 0.22) although numbers were rather small. In each subgroup mentioned, 4 patients carried MBL deficiency-associated genotypes. Within UC groups, medians for persons with active disease (1128 ng/ml, n = 18) and in remission (927 ng/ml, n = 9) appeared similar (p = 0.7).
2. Material and methods 2.1. Patients and controls Sixty-eight adult patients (mean age: 38 ± 16 years) suffering from inflammatory bowel disease were recruited. This (IBD) group included 40 persons (20 males, 20 females) diagnosed with Crohn’s disease (CD group) and 28 (13 males, 15 females) – with ulcerative colitis (UC group). Patients were classified based on clinical and histological examination, colonoscopy and laboratory findings, according to the Crohn's Disease Activity Index (CDAI) and Mayo Score/Disease Activity Index (DAI) for Ulcerative Colitis (Best et al., 1976; Schroeder et al., 1987). Active Crohn's disease was defined as CDAI higher than 150 while active UC was defined as DAI higher than 2 points. In the CD group, 23 patients were diagnosed with active disease and 17 with nonactive disease at the time of recruitment. Within the UC group, 18 persons had active and 10 had non-active disease. The control group consisted of 136 age and sex-matched individuals (unrelated volunteers with no history of cancer, autoimmune diseases or recurrence of infections; 66 males and 70 females). The study was approved by the Ethics Committee of the Medical University of Łódź and written informed consent from patients and controls was obtained. This work conforms to the provisions of the Declaration of Helsinki.
4. Discussion
2.2. DNA and serum samples
Numerous primary immunodeficiencies were evidenced or considered to be associated with IBD. They affect a variety of pathways,
Blood samples for DNA extraction were taken from patients into citrated tubes before chemotherapy and stored at −80 °C. DNA was extracted with the use of GeneMATRIX Quick Blood Purification Kit (EURx Ltd, Gdańsk, Poland), according to the manufacturer’s protocol. Samples for serum isolation were taken into tubes with clot activator. Sera were stored at −80 °C until testing.
Table 1 Distribution of MBL2 genotypes among Crohn’s disease (CD), ulcerative colitis (UC), inflammatory bowel disease (IBD, including both CD and UC) and controls (C). Genotype
2.3. MBL2 genotyping Single nucleotide polymorphisms of the MBL2 gene, localised to promoter (H/L, at position -550, rs11003125 and Y/X, at position -221, rs7096206) and exon 1 (A/D, codon 52, rs5030737; A/B, codon 54, rs1800450 and A/C, codon 57, rs1800451) were investigated as previously described (Bak-Romaniszyn et al., 2011).
A/A YA/O XA/O O/O
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Group CD (n = 40)
UC (n = 28)
IBD (n = 68)
C (n = 136)
23 (57.5) 9 (22.5) 5 (12.5) 3 (7.5)
19 (67.9) 5 (17.9) 2 (7.1) 2 (7.1)
42 (61.8) 14 (20.6) 7 (10.3) 5 (7.4)
97 (71.3) 26 (19.1) 10 (7.4) 3 (2.2)
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healthy subjects. It cannot also be excluded that high MBL activity constitutes in some cases a part of a multifactorial network conducing to development of CD. Zimmermann-Nielsen et al. (2005) noted higher MBL serum concentration in CD patients, compared with both healthy controls and persons diagnosed with UC. Although Coufal et al. (2019) did not confirm that finding, they reported higher MBL in patients affected with IBD associated with primary sclerosing cholangitis (PSCIBD) than in those with UC. Although the precise role of MBL in IBD remains unclear, and may be distinct in CD and UC, in the light of previously published data and our results, it may be supposed that both MBL deficiency and its overexpression are unfavourable in the context of IBD. As a patternrecognition molecule, MBL has broad specificity but, on the other hand, it is restricted to a certain sort of PAMP/DAMP. Therefore, it contributes to the elimination of certain pathogens or to excessive inflammatory response to some stimuli. Thus, its role seems to be dual, and its effect may depend on a variety of other factors including composition of microbiota and its changes, presence of defects of other innate/adaptive immunity mechanisms, patient’s age, ethnicity, diet, behaviour, disease form (CD or UC), its stage and others.
Fig. 1. Serum concentrations of mannose-binding lectin depending on MBL2 genotypes. Individual data and medians (black bars and corresponding values in ng/ml below the graph) are given. C – control group; CD – Crohn’s disease group; UC – ulcerative colitis group.
Declaration of Competing Interest including microbial sensing, signal transduction, development and controlling of inflammation, etc. (Ulhig, 2013; Ellinghaus et al., 2015; Kelsen and Sullivan, 2017). The possible involvement of MBL deficiency in pathogenesis of CD and/or UC is still unclear. Several reports suggested codon 54 variant (B) allele and correspondingly low MBL serum concentration to be associated with ulcerative colitis but not Crohn’s disease (Wang et al., 2008; Sivaram et al., 2010; Tahara et al., 2011). Earlier, Rector et al. (2001) found increased frequency of MBL2 O alleles (D, B, C corresponding to codons 52, 54, 57 polymorphisms, respectively) in UC patients compared with both unaffected individuals and those suffering from CD. However, in CD patients, compound heterozygosity seemed to be associated with anal lesions (Rector et al., 2001), although that hypothesis was based on data from a small number of patients. In children and teenagers, MBL deficiency was suggested to be a risk factor for CD (but not UC) (Bak-Romaniszyn et al., 2011) or both CD and UC (Kovacs et al., 2013) which might indicate its contribution to early onset of disease(s). Some authors found a possible link between MBL2 gene polymorphisms and/or low MBL serum concentration and presence of antiSaccharomyces cerevisiae antibodies (ASCA) in Crohn’s disease patients. That led to the suggestion that defective MBL function results in impaired clearance of mannan-rich antigens by innate immunity and increased reactivity of the adaptive immune system towards them (Seibold et al., 2004, 2007; Schoepfer et al., 2009; Choteau et al., 2016). Despite the relative high frequency of MBL2 variant alleles and LXA/O or O/O genotypes, especially within the CD group (Table 1), our data did not confirm a strong association of MBL deficiency with inflammatory bowel disease or its phenotype in adults. That is in agreement with some earlier reports (Nielsen et al., 2007; Hoffmann et al., 2010; Papp et al., 2011; Sandahl et al., 2014; Kim et al., 2014). The most important finding of this study is the significant difference in serum MBL concentrations between A/A homozygous (fully active MBL-producing genotypes) patients and controls, which was particularly evident in the case of active Crohn’s disease. That may suggest contributions of MBL and MBL-dependent complement activation to excessive inflammation and its adverse effects on disease course. Therefore, A/A homozygotes with naturally high MBL serum levels may be at higher risk of active CD or, on the other hand, MBL concentration may increase in response to inflammatory processes. Interestingly, Milanese et al. (2007) reported an upregulation of MBL2 gene expression in basal lamina cells from Crohn’s disease patients compared with
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Mannose-binding lectin (MBL) in adult patients with inflammatory bowel disease Leokadia Bąk-Romaniszyna, Anna S. Świerzkob, Anna Sokołowskab, Łukasz Durkoc, Grażyna Mierzwad, Agnieszka Szala-Poździejb, Ewa Małecka-Panasc, Maciej Cedzyńskib,* Unit of Nutrition in Digestive Tract Disease, Medical University of Łódź, Rzgowska 281/289, 93-338 Łódź, Poland Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Łódź, Poland c Department of Digestive Tract Diseases, Medical University of Łódź, Kopcińskiego 22, 91-425 Łódź, Poland d Department of Vascular and Internal Diseases, Unit of Gastroenterological Nursing, L. Rydygier Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Toruń, Jagiellońska 13/15, 85-067 Bydgoszcz, Poland a
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A R T I C LE I N FO
A B S T R A C T
Keywords: Crohn’s disease (CD) Inflammatory bowel disease (IBD) Mannose-binding lectin (MBL) MBL2 gene Ulcerative colitis (UC)
Inflammatory bowel disease (IBD) refers to disorders associated with progressive inflammatory processes in the gastrointestinal system. IBD consists of two major forms, Crohn’s disease (CD), and ulcerative colitis (UC). IBD became a global disease in the 21st century. Its pathogenesis is still not fully understood. Mannose-binding lectin (MBL) is a pattern-recognising molecule, involved in anti-microbial and anti-cancer immunity. It is able to opsonize microorganisms and abnormal host cells, and to initiate complement activation. The aim of this study was to investigate possible involvement of MBL in inflammatory bowel disease in adults. Forty persons diagnosed with CD and 28 with ulcerative colitis were recruited. The control group consisted of 136 healthy persons. Single nucleotide polymorphisms of the MBL2 gene (localised to both promoter and exon 1) were determined as were serum MBL concentrations. The exon 1 variant alleles and MBL deficiency-associated genotypes were more frequent among patients compared with controls, although this difference was not statistically significant. No differences of MBL levels were found between the major groups. However in MBL2 A/A homozygous IBD patients, the median was significantly higher than in corresponding healthy subjects. That was particularly evident in the case of active Crohn’s disease (1493 ng/ml vs. 800 ng/ml, p = 0.021). It may suggest that MBL and MBLdependent complement activation contributes to excessive inflammation and its adverse effects in the course of CD. It cannot also be excluded that high MBL activity constitutes in some cases part of a multifactorial network conducing to development of CD.
1. Introduction Inflammatory bowel disease (IBD) constitutes a group of disorders associated with progressive inflammatory processes in the gastrointestinal system. Its incidence in Europe is still increasing. IBD includes two major subgroups, Crohn’s disease (CD), affecting any part of the alimentary tract, and ulcerative colitis (UC), associated with the rectum and colon. IBD incidence is still increasing. In the 21st century, it became a global disease, with increasing incidence not only in Europe and North America, but also in newly industrialised Asian, African and Southern-American countries where the lifestyle was changed to “Western” (Molodecky et al., 2012; Ng et al., 2017). IBD affects individuals of all ages, including children. The highest incidence is noted between 15th and 25th years of life with the second peak within the 6th
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decade (Kaplan and Ng, 2017). Its pathogenesis is still not understood, although some impairment of the host response to enteric microorganisms is often postulated. Therefore, an interplay between individual microbiome and immune system (affected by genetic polymorphisms, regulatory mechanisms, host behaviour, environmental factors, etc.) is considered crucial (Xavier and Podolsky, 2007; Van Limbergen et al., 2014; Kelsen and Sullivan, 2017; Ramos and Papadakis, 2019; Zhao and Burisch, 2019). Normal gut microbiota is involved in such beneficial effects as protection from pathogens and nutrition. Dysbiosis influences host-microbiota interaction and host immunity, and is considered to be associated with pathogenesis of variety of diseases, including IBD (Nishida et al., 2018). It is supposed that the loss of tolerance towards intestinal microflora leads to an inflammatory response, maintained by constant exposure to
Corresponding author at: Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Łódź, Poland. E-mail address: [email protected] (M. Cedzyński).
https://doi.org/10.1016/j.imbio.2019.10.008 Received 26 September 2019; Received in revised form 16 October 2019; Accepted 16 October 2019 0171-2985/ © 2019 Elsevier GmbH. All rights reserved.
Please cite this article as: Leokadia Bąk-Romaniszyn, et al., Immunobiology, https://doi.org/10.1016/j.imbio.2019.10.008
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2.4. Determination of serum concentrations of mannose-binding lectin
the stimuli (Onali et al., 2019). Another explanation (not excluding the afore-mentioned) is that inflammation becomes chronic due to failure of counter-regulatory and pro-resolving systems (Onali et al., 2019). Mannose-binding lectin (MBL) belongs to the collectin family, comprising calcium-dependent, collagen-related, multimeric lectins acting as pattern-recognising molecules, involved in anti-microbial and anti-cancer immunity. MBL forms complexes with mannose-binding lectin-associated serine proteases (MASP) which enables activation of the complement system via the lectin pathway (Cedzyński et al., 2018). It shares that property with some other collectins (CL-10, CL-11) and ficolins. MBL is also able to directly opsonize microbial and abnormal (apoptotic/necrotic/cancerous) host cells, bearing pathogen/dangerassociated molecular patterns (PAMP/DAMP). Therefore, it has a protective effect from certain infections or development of some malignancies via direct lysis of recognised cells or by enhancement of phagocytosis (Nakagawa et al., 2003). On the other hand, MBL may be involved in excessive or chronic inflammation which may be harmful to the host, leading in some cases to organ failure or carcinogenesis, respectively (Pągowska-Klimek et al., 2016; Swierzko et al., 2014). Our previous data (Bak-Romaniszyn et al., 2011) suggested an association of MBL deficiency with CD (but not UC) in children. However, the role of MBL in IBD is still controversial, and may depend on variety of other factors, including patient age. Therefore, the aim of this study was to estimate any involvement of MBL in inflammatory bowel disease in adults.
MBL concentrations were determined by ELISA, using mannan from Saccharomyces cerevisiae (Sigma-Aldrich, St. Louis, MO, USA) as coating antigen and murine anti-human MBL mAbs (HYB131-1, BioPorto Diagnostics, Copenhagen, Denmark) (Cedzynski et al., 2004). 2.5. Statistical analysis The Statistica (version 13.3, TIBCO Software) and SigmaPlot (version 12.0, Systat Software) software packages were used for data management and statistical calculations. The medians of MBL concentrations were compared using the Mann-Whitney U-test. The frequencies of genotypes were compared by two-sided Fischer’s exact test. P values < 0.05 were considered statistically significant. 3. Results Twenty-six (38.2%) patients carried one or two MBL2 gene exon 1 variant (O) alleles. Although those variants were apparently less common within the control group (39/136; 28.7%), the difference was not statistically significant [number of A/O and O/O genotypes: p = 0.2, OR = 1.54, 95% CI (0.83–2.85); frequency of D/B/C alleles: p = 0.076, OR = 1.62, 95% CI (0.06–2.72)]. Nor were significant differences observed when CD or CU groups separately were compared with healthy controls [number of A/O and O/O genotypes: p = 0.13, OR = 1.84, 95% CI (0.89–381) and p = 0.82, OR = 1.18, 95% CI (0.49–2.83), respectively]. Furthermore, numbers of MBL-deficient persons (carrying LXA/O or O/O genotypes) did not differ among the groups although MBL deficiency was twice more common within CD than within C group [(p = 0.095, OR = 2.03, 95% CI (0.87–4.72)] (Table 1). Despite the relatively high frequency of MBL2 O alleles in patients, there was a trend towards higher median MBL serum concentration in all patient groups (total IBD, 1001 ng/ml; CD, 1094 ng/ml; UC, 950 ng/ ml) compared with controls (800 ng/ml). However, when MBL levels were analysed on the genotype background, the median for IBD A/A homozygotes (1709 ng/ml) was found to be significantly higher than for corresponding healthy subjects (1325 ng/ml, p = 0.007). That difference was most marked for patients suffering from UC (median: 1942 ng/ml, p = 0.021) than from CD (median: 1667 ng/ml, p = 0.06) (Fig. 1). Furthermore, median MBL found for the 17 patients with active Crohn’s disease (1493 ng/ml) was much higher than that for the 23 patients in remission (384 ng/ml; p = 0.22) although numbers were rather small. In each subgroup mentioned, 4 patients carried MBL deficiency-associated genotypes. Within UC groups, medians for persons with active disease (1128 ng/ml, n = 18) and in remission (927 ng/ml, n = 9) appeared similar (p = 0.7).
2. Material and methods 2.1. Patients and controls Sixty-eight adult patients (mean age: 38 ± 16 years) suffering from inflammatory bowel disease were recruited. This (IBD) group included 40 persons (20 males, 20 females) diagnosed with Crohn’s disease (CD group) and 28 (13 males, 15 females) – with ulcerative colitis (UC group). Patients were classified based on clinical and histological examination, colonoscopy and laboratory findings, according to the Crohn's Disease Activity Index (CDAI) and Mayo Score/Disease Activity Index (DAI) for Ulcerative Colitis (Best et al., 1976; Schroeder et al., 1987). Active Crohn's disease was defined as CDAI higher than 150 while active UC was defined as DAI higher than 2 points. In the CD group, 23 patients were diagnosed with active disease and 17 with nonactive disease at the time of recruitment. Within the UC group, 18 persons had active and 10 had non-active disease. The control group consisted of 136 age and sex-matched individuals (unrelated volunteers with no history of cancer, autoimmune diseases or recurrence of infections; 66 males and 70 females). The study was approved by the Ethics Committee of the Medical University of Łódź and written informed consent from patients and controls was obtained. This work conforms to the provisions of the Declaration of Helsinki.
4. Discussion
2.2. DNA and serum samples
Numerous primary immunodeficiencies were evidenced or considered to be associated with IBD. They affect a variety of pathways,
Blood samples for DNA extraction were taken from patients into citrated tubes before chemotherapy and stored at −80 °C. DNA was extracted with the use of GeneMATRIX Quick Blood Purification Kit (EURx Ltd, Gdańsk, Poland), according to the manufacturer’s protocol. Samples for serum isolation were taken into tubes with clot activator. Sera were stored at −80 °C until testing.
Table 1 Distribution of MBL2 genotypes among Crohn’s disease (CD), ulcerative colitis (UC), inflammatory bowel disease (IBD, including both CD and UC) and controls (C). Genotype
2.3. MBL2 genotyping Single nucleotide polymorphisms of the MBL2 gene, localised to promoter (H/L, at position -550, rs11003125 and Y/X, at position -221, rs7096206) and exon 1 (A/D, codon 52, rs5030737; A/B, codon 54, rs1800450 and A/C, codon 57, rs1800451) were investigated as previously described (Bak-Romaniszyn et al., 2011).
A/A YA/O XA/O O/O
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Group CD (n = 40)
UC (n = 28)
IBD (n = 68)
C (n = 136)
23 (57.5) 9 (22.5) 5 (12.5) 3 (7.5)
19 (67.9) 5 (17.9) 2 (7.1) 2 (7.1)
42 (61.8) 14 (20.6) 7 (10.3) 5 (7.4)
97 (71.3) 26 (19.1) 10 (7.4) 3 (2.2)
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healthy subjects. It cannot also be excluded that high MBL activity constitutes in some cases a part of a multifactorial network conducing to development of CD. Zimmermann-Nielsen et al. (2005) noted higher MBL serum concentration in CD patients, compared with both healthy controls and persons diagnosed with UC. Although Coufal et al. (2019) did not confirm that finding, they reported higher MBL in patients affected with IBD associated with primary sclerosing cholangitis (PSCIBD) than in those with UC. Although the precise role of MBL in IBD remains unclear, and may be distinct in CD and UC, in the light of previously published data and our results, it may be supposed that both MBL deficiency and its overexpression are unfavourable in the context of IBD. As a patternrecognition molecule, MBL has broad specificity but, on the other hand, it is restricted to a certain sort of PAMP/DAMP. Therefore, it contributes to the elimination of certain pathogens or to excessive inflammatory response to some stimuli. Thus, its role seems to be dual, and its effect may depend on a variety of other factors including composition of microbiota and its changes, presence of defects of other innate/adaptive immunity mechanisms, patient’s age, ethnicity, diet, behaviour, disease form (CD or UC), its stage and others.
Fig. 1. Serum concentrations of mannose-binding lectin depending on MBL2 genotypes. Individual data and medians (black bars and corresponding values in ng/ml below the graph) are given. C – control group; CD – Crohn’s disease group; UC – ulcerative colitis group.
Declaration of Competing Interest including microbial sensing, signal transduction, development and controlling of inflammation, etc. (Ulhig, 2013; Ellinghaus et al., 2015; Kelsen and Sullivan, 2017). The possible involvement of MBL deficiency in pathogenesis of CD and/or UC is still unclear. Several reports suggested codon 54 variant (B) allele and correspondingly low MBL serum concentration to be associated with ulcerative colitis but not Crohn’s disease (Wang et al., 2008; Sivaram et al., 2010; Tahara et al., 2011). Earlier, Rector et al. (2001) found increased frequency of MBL2 O alleles (D, B, C corresponding to codons 52, 54, 57 polymorphisms, respectively) in UC patients compared with both unaffected individuals and those suffering from CD. However, in CD patients, compound heterozygosity seemed to be associated with anal lesions (Rector et al., 2001), although that hypothesis was based on data from a small number of patients. In children and teenagers, MBL deficiency was suggested to be a risk factor for CD (but not UC) (Bak-Romaniszyn et al., 2011) or both CD and UC (Kovacs et al., 2013) which might indicate its contribution to early onset of disease(s). Some authors found a possible link between MBL2 gene polymorphisms and/or low MBL serum concentration and presence of antiSaccharomyces cerevisiae antibodies (ASCA) in Crohn’s disease patients. That led to the suggestion that defective MBL function results in impaired clearance of mannan-rich antigens by innate immunity and increased reactivity of the adaptive immune system towards them (Seibold et al., 2004, 2007; Schoepfer et al., 2009; Choteau et al., 2016). Despite the relative high frequency of MBL2 variant alleles and LXA/O or O/O genotypes, especially within the CD group (Table 1), our data did not confirm a strong association of MBL deficiency with inflammatory bowel disease or its phenotype in adults. That is in agreement with some earlier reports (Nielsen et al., 2007; Hoffmann et al., 2010; Papp et al., 2011; Sandahl et al., 2014; Kim et al., 2014). The most important finding of this study is the significant difference in serum MBL concentrations between A/A homozygous (fully active MBL-producing genotypes) patients and controls, which was particularly evident in the case of active Crohn’s disease. That may suggest contributions of MBL and MBL-dependent complement activation to excessive inflammation and its adverse effects on disease course. Therefore, A/A homozygotes with naturally high MBL serum levels may be at higher risk of active CD or, on the other hand, MBL concentration may increase in response to inflammatory processes. Interestingly, Milanese et al. (2007) reported an upregulation of MBL2 gene expression in basal lamina cells from Crohn’s disease patients compared with
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