BACKGROUND

Individuals deficient in mannose-binding lectin (MBL), an important component of the innate immune system, show increased susceptibility to infection. We investigated whether polymorphisms in the MBL2 gene and the serum level are associated with the severity and prognosis of sepsis.

METHODS

A total of 266 patients with sepsis and 398 healthy controls were enrolled. We analyzed the three single nucleotide polymorphisms (Gly54Asp, -550, and +4) in the MBL2 gene. Serum samples collected on day 1 were analyzed for the levels of MBL.

RESULTS

Patients who were heterozygous (A/B) or homozygous (B/B) at codon 54 (adjusted odds ratio (OR), 0.370; 95% confidence interval (CI), 0.207-0.661, P = 0.001) and who were heterozygous (H/L) or homozygous (L/L) at -550 (adjusted OR, 0.476; 95% CI, 0.249-0.910, P = 0.025) were less likely to have septic shock in the sepsis group. Using Cox regression analysis for 28-day mortality, an MBL level>> or = 1.3 microg/mL showed significantly lower 28-day mortality (P = 0.020; hazard ratio, 0.571; 95% CI, 0.355-0.916) in the septic shock group.

CONCLUSIONS

Homozygosity at codons 54 (A/A) and -550 (H/H) appears to be associated with the severity, but not the outcome, of sepsis, whereas a low MBL level may be an independent risk factor for mortality. These findings suggest that the genotype and serum level for MBL2 may have different clinical implications.

Rheumatic fever (RF) and its most severe sequela, chronic rheumatic heart disease (CRHD), are mediated by an abnormal immunological host response following a Streptococcus pyogenes oropharyngeal infection. Mannan-binding lectin (MBL), a collectin that activates complement, binds to N-acetylglucosamine, a molecule present on the streptococcus cell wall and on human heart valves. As high levels of MBL and MBL2 associated genotypes have previously been seen to be associated with CRHD, we investigated the association between MBL2 polymorphisms and the presence of acute carditis and arthritis in patients with a history of RF. Polymorphisms in exon 1 and in the X/Y promoter region of the MBL2 gene were determined by PCR-SSP in 149 patients with a history of RF and 147 controls. Genotypes associated with the high production of MBL (YA/YA and YA/XA) were more frequent in the patients with acute (26/35, 74%) and chronic carditis (79/107, 74%) when compared to the controls (79/147, 54%; OR 2.48, 95% CI 1.09-5.67, p=0.035 and OR 2.42, 95% CI 1.41-4.16, p=0.001, respectively). Logistic regression analysis showed that MBL levels >2,800 ng/ml increased the risk of CRHD (OR 2.91, 95% CI 1.41-6.03, p=0.003). Among the RF patients without cardiac sequela, YA/YA and YA/XA genotypes were significantly associated with acute carditis when compared to the patients without this clinical manifestation (26/28, 93% vs. 9/14, 64%, OR 7.22, 95% CI 1.18-43.98, p=0.031); on the other hand, arthritis was more frequently observed in those patients presenting MBL2 genotypes related to the low production of MBL (10/14, 71% vs. 10/28, 36%; p=0.048, OR 0.22, 95% CI 0.05-0.89). We concluded that MBL2 genotypes associated with the high production of MBL seem to be involved in the pathogenesis of rheumatic carditis and its progression to CRHD.

Mannose-binding lectin (MBL) and Toll-like receptor (TLR) polymorphisms may influence susceptibility and manifestation of Trypanosoma cruzi infection. In northern Chile, we examined 61 asymptomatic patients with chronic Chagas disease (CD), 64 patients with chronic Chagas cardiomyopathy (CCC), and 45 healthy individuals. Low-producer MBL2*B genotypes were more common in CD patients (48%) than healthy individuals (31%; adjusted odds ratio = 2.3, 95% confidence interval = 1.01-5.4, P = 0.047) but did not differ with manifestation. In contrast, the heterozygous Toll-like receptor 4 (TLR4)-deficiency genotype D299G/T399I occurred more frequently in asymptomatic (14.8%) than CCC patients (3.1%; P = 0.02). TLR1-I602S, TLR2-R753Q, TLR6-S249P, and MAL/TIRAP-S180L did not associate with CD or CCC. These findings support the complement system to be involved in defense against Trypanosoma cruzi infection and indicate that curbed TLR4 activation might be beneficial in preventing CCC.

BACKGROUND

The in vivo impact of mannose-binding lectin (MBL), a molecule involved in innate immunity, on the pathogenesis of human immunodeficiency virus (HIV)-1 infection and AIDS is unknown.

METHODS

A total of 1102 HIV-positive and 2213 HIV-negative adult subjects were screened for polymorphisms in the coding and promoter regions of MBL2, the gene that encodes MBL.

RESULTS

Variations in MBL2 did not influence the risk of acquiring HIV-1. Heterozygosity for coding mutations (O allele) and homozygosity for the -221 promoter polymorphism (X allele) in MBL2 were associated with a delay in and an accelerated rate of disease progression, respectively. MBL2 variations influenced the rate of progression to AIDS-defining illnesses. In a multivariate model, the effects of MBL2 variations were independent of several parameters known to influence disease progression, including steady-state viral load, baseline CD4(+) T cell counts, and delayed-type hypersensitivity skin test responses, an in vivo marker of cell-mediated immunity. The effects of MBL2 variations were most evident in those who possessed protective genotypes of CCR5 and a high copy number of CCL3L1, the most potent HIV-suppressive CCR5 ligand.

CONCLUSIONS

MBL2 genotypes are independent determinants of HIV disease progression and heterozygosity for MBL2 coding mutations confer disease-retarding effects. MBL-dependent immune responses may play a role in the pathogenesis of HIV infection.

Mannose binding lectin (MBL) plays an important role in innate immunity. Plasma MBL levels and MBL2 gene polymorphisms were studied in HIV-1 infected patients without tuberculosis (HIV+TB-) (n=151) and with tuberculosis (HIV+TB+) (n=109), HIV negative tuberculosis patients (HIV-TB+) (n=148) and healthy controls (n=146) by ELISA and genotyping by polymerase chain reaction based methods. MBL levels were significantly increased among HIV-TB+ and HIV+TB+ patients than controls and HIV+TB- patients (P<0.05). A significantly increased frequency of OO genotype of structural polymorphism and YY genotype of -221Y/X was observed among HIV-TB+ patients than controls. In HIV+TB+ patients, a significantly increased frequency of YA/YA diplotype (associated with very high MBL levels) was observed compared to controls (P=0.03). In HIV+TB+ patients, a significantly decreased frequency of medium MBL expression diplotypes (XA/XA and YA/YO) were noticed compared to HIV+TB- and healthy controls. The results suggest that YA/YA diplotype associated with very high MBL levels may predispose HIV-infected patients to tuberculosis while O/O genotype associated with very low MBL levels may be associated with susceptibility to tuberculosis in HIV uninfected individuals. Medium MBL expression diplotypes might protect against development of TB in HIV-infected patients.

Human L-ficolin (FCN) is a serum lectin characterized by a collagen-like and a fibrinogen-like domain that can activate the lectin pathway of complement. Structural and functional similarities to mannose-binding lectin (MBL) suggest a role for L-ficolin in innate immunity. Structural polymorphisms in the MBL2 gene lead to functional deficiency of MBL. Polymorphisms in the FCN2 gene have not been studied previously. We developed 10 denaturing gradient gel electrophoresis (DGGE) assays to screen a total of 188 Dutch Caucasians for polymorphisms in FCN2. Total gene screening in this large cohort revealed 10 single nucleotide polymorphisms (SNPs). Interestingly, two conserved coding SNPs were found in exon 8, leading to amino acid substitutions within the fibrinogen-like domain. Fibrinogen-like domains are highly conserved among several proteins in many species. As this domain is responsible for binding of L-ficolin, these newly found coding polymorphisms could alter the affinity of the protein for its substrates and possibly alter the ability of L-ficolin to recognize invading microorganisms.

BACKGROUND

Polymorphisms of the mannose-binding lectin gene (MBL2) affect the concentration and functional efficiency of the protein. We recently used haplotype-specific sequencing to identify 23 MBL2 haplotypes, associated with enhanced susceptibility to several diseases.

RESULTS

In this work, we applied the same method in 288 and 470 chromosomes from Gabonese and European adults, respectively, and found three new haplotypes in the last group. We propose a phylogenetic nomenclature to standardize MBL2 studies and found two major phylogenetic branches due to six strongly linked polymorphisms associated with high MBL production. They presented high Fst values and were imbedded in regions with high nucleotide diversity and significant Tajima's D values. Compared to others using small sample sizes and unphased genotypic data, we found differences in haplotyping, frequency estimation, Fu and Li's D* and Fst results.

CONCLUSIONS

Using extensive testing for selective neutrality, we confirmed that stochastic evolutionary factors have had a major role in shaping this polymorphic gene worldwide.

Mannose-binding lectin (MBL) is a mediator of innate immunity that influences the risk of infection in a range of clinical settings. We previously reported associations between MBL2 genotype and infection in a retrospective study of myeloablative allogeneic hematopoietic stem cell transplantation (allo-HCT). However, other studies have been inconclusive, and the role of MBL in reduced-intensity conditioning (RIC) transplantation is unknown. Here we report a prospective study examining MBL2 genotype, MBL levels, and risk of major infection following HLA-matched sibling myeloablative (n = 83) and RIC (n = 59) HCT. Baseline MBL levels were higher in recipients than donors (P < .001), and recipient MBL levels increased during the peritransplantation period (P = .001), most notably in MBL2 wild-type individuals receiving myeloablative total body irradiation (mTBI). MBL2 coding mutations were associated with major infection in recipients receiving mTBI. The cumulative incidence of major infection in recipient harboring an MBL2 mutation receiving mTBI was 70.6%, compared with 31.1% of those without mutations not receiving mTBI (P = .01). MBL status was not associated with infection in RIC transplants. These results confirm the association of MBL status with risk of infection in myeloablative, TBI-conditioned transplantation. Studies examining the role of MBL replacement therapy to prevent infection in this setting should be considered.

In this study, we describe a real-time polymerase chain reaction (PCR) for genotyping all known polymorphisms of the human mannose-binding lectin 2 (MBL2) gene. These comprised two variations in the 5' regulatory region at positions -550 (H/L) and -221 (X/Y), one in the 5' untranslated sequence at position +4 (P/Q) and three structural mutations within exon 1 at codons 52, 54, and 57, also known as the D, B and C variants, respectively. Three reactions with two different conditions were sufficient to genotype one individual unambiguously. The three mutations in exon 1 were detected in one capillary using a sensor probe covering the three mutations, whereas amplification of the variants located upstream of the coding sequence was performed in only two reactions. Single colour detection was used for detection of the (H/L) polymorphism and multiplexing by dual colour probes was used for simultaneous genotyping of (X/Y) and (P/Q). The reliability of the system was evaluated by comparison with a conventional PCR method with sequence-specific primers (PCR-SSP). For this study, 100 individuals of Danish and 30 of African descent were analysed, and the genotypes obtained were concordant in all cases. This new method is rapid and provides reliable results without ambiguities.

Common genetic variants in cancer-related genes contribute to breast cancer. The innate immune system plays a crucial role in the immune surveillance against malignancies, thus it is plausible that genetic variations in key genes of the innate immunity such as the mannose-binding lectin (MBL), MBL2, could influence the risk for breast cancer. We investigated the association of MBL2 genotypes with breast cancer and conducted a comprehensive genotype and haplotype analysis of 26 MBL2 single nucleotide polymorphisms (SNPs) in a case-control study of breast cancer [166 African-American (AA) case patients versus 180 controls and 127 Caucasian (CAU) case patients versus 137 controls]. We observed that the A allele of the 3'-UTR SNP Ex4-1067 (NCBI SNP ID: rs10824792) was significantly associated with a decreased disease risk in AA women [odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.27-0.81]. Haplotype analysis of MBL2 showed that the frequency of the corresponding 3' haplotype TATAAC (Ex4-1483, Ex4-1067, Ex4-1047, Ex4-901, Ex4-710, 3238bp 3' STP) was lower in cases than controls among AA women (0.15 versus 0.21; P = 0.02) suggesting a protective effect after adjusting for covariates (OR = 0.51, 95% CI = 0.29-0.88, P = 0.018). In conclusion, this study presents preliminary evidence that common genetic variants in the 3'-UTR of MBL2 might influence the risk for breast cancer in AA women, probably in interaction with the 5' secretor haplotypes that are associated with high concentrations of MBL.

Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation.

Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes.

Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort.

Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695.

BACKGROUND

Respiratory infections are major causes of morbidity and mortality, but determinants of susceptibility are poorly defined. We studied whether and to what extent immunologic and genetic factors are associated with increased susceptibility to respiratory infections.

METHODS

We evaluated the prevalence of IgA, IgM, IgG, and IgG subclass deficiencies, impairment in the antibody response against pneumococcal polysaccharides, G2m(n) allotypes, Fc gamma RIIa polymorphisms, partial C2 and partial C4 deficiency, promoter polymorphisms in MBL2, and lymphocyte subset deficiencies in a control population and in consecutive children with recurrent respiratory infections.

RESULTS

IgA and/or IgG subclass deficiency was found in 27 of 55 patients (49%) and 6 of 43 controls (14%) (P = 0.0006). An impaired antibody response to polysaccharides was found in 7 patients (19%) and in 0 of 37 controls (P = 0.002). The Gm(n)marker was absent in 25 of 55 patients (45%) and 6 of 42 controls (14%) (P = 0.009). The MBL2 variants O/O, A/O, and A/A occurred in 9, 14, and 32 of the 55 patients, respectively, and in 1, 19, and 23 of the 43 controls, respectively (P = 0.05). There was no increase in the prevalence of partial C4 deficiency, C2 deficiency, lymphocyte subset deficiency, or Fc gamma RIIa polymorphism in the patients compared to the controls. A combination of at least 2 immune defects was found in 31 of 55 patients (56%) and in 4 of 42 controls (11.6%) (P <0.0001).

CONCLUSIONS

Specific antipolysaccharide antibody deficiency, IgA and/or IgG subclass deficiency, Gm(n) allotype, and MBL2 genotype are susceptibility factors for recurrent respiratory infections, and coexistence of several immune defects is the strongest risk factor in this study.

This study was conducted to establish the contribution of genetic host factors in the susceptibility to community acquired pneumonia (CAP) in the Russian population. Patients with CAP (n=334), volunteers without a previous history of CAP, constantly exposed to infectious agents, control A group (n=141) and a second control group B consisted of healthy persons (n=314) were included in the study. All subjects were genotyped for 13 polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, and rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), ABCB1 rs1045642); immune and inflammation response IL-6 (rs1800795), TNF-a (rs1800629), MBL2 (rs7096206), CCR5 (rs333), NOS3 (rs1799983), angiotensin-converting enzyme ACE (rs4340), and occlusive vascular disease/hyperhomocysteinemia MTHFR (rs1801133). Seven polymorphic variants in genes CYP1A1, GSTM1, ABCB1, NOS3, IL6, CCR5 and ACE were associated with CAP. For two genes CYP1A1 and GSTM1 associations remained significant after correction for multiple comparisons. Multiple analysis by the number of all risk genotypes showed a highly significant association with CAP (P=2.4×10(-7), OR=3.03, 95% CI 1.98-4.64) with the threshold for three risk genotypes. Using the ROC-analysis, the AUC value for multi-locus model was estimated as 68.38.

OBJECTIVE

Mannose-binding lectin (MBL2) is a collectin molecule able to activate the complement system and the subsequent inflammatory mechanisms. Several MBL2 genetic variants have been described, including the six variants studied in this report, which are those analyzed in most detail in the medical literature.

METHODS

The present study analyzes the prevalence of MBL2 gene variants in preterm newborns and associates individual genotypes with pulmonary outcome variables. All polymorphisms were analyzed by means of a commercially available reverse dot-blot kit.

METHODS

Tertiary neonatal intensive care unit.

METHODS

Seventy-five consecutive preterm newborns.

RESULTS

Two variants were particularly analyzed: -550G>> C and R52C. The first one is known to be associated with lower protein synthesis when included in specific haplotypes. The homozygous and heterozygous -550G>> C mutations were significantly associated with protective effects regarding different lung outcome variables, including shorter duration of mechanical ventilation, hours of continuous positive airway pressure and lower number of hemotransfusions. In contrast, the heterozygous R52C mutation was associated with unfavorable outcome, including higher bronchopulmonary dysplasia prevalence. Multivariate logistic regression analysis showed that these associations were independent of gestational age and birth weight. In addition, four groups of patients were defined on the basis of haplotype combinations. Those known to be associated with low serum MBL2 levels were linked to a better outcome in terms of factors such as hours of mechanical ventilation, continuous positive airway pressure, number of hemotransfusions and bronchopulmonary disease development.

CONCLUSIONS

The four haplotype combination groups may have a potential diagnostic use as opposite risk factors for lung disease of prematurity.

Single nucleotide polymorphisms in the mannose-binding lectin (MBL2) gene, as well as the serum MBL2 level, have been associated with various autoimmune diseases. We investigated whether such polymorphisms and/or the serum MBL2 level were associated with rheumatoid arthritis (RA) in an Indian population. The frequency of the B variant (codon 54) of the MBL2 gene was quite frequent in the healthy Indian population and was significantly (P=6.35x10(-6)) lower in RA patients. We replicated this association (P=1.78x10(-5)) in an independent cohort of control individuals. Promoter polymorphism at -550 nt showed a significant overrepresentation (P=0.003) of the minor allele G in severe RA patients compared with the less severe group. Haplotype LYA frequency was significantly (P=0.03) high in the less severe group, while the frequency of the HYA haplotype was significantly (P=0.04) increased in the severe RA patients. No statistically significant difference in serum MBL2 was observed as a whole, but the individuals homozygous for the LYA haplotype had significantly lower (P=0.017) serum MBL2 levels compared with individuals homozygous for the HYA haplotype. Therefore, the B variant of the MBL2 gene may be associated with protection from RA in our study population, and the promoter polymorphism (-550 nt) seems to have some role in disease progression.

BACKGROUND

The literature on the involvement of mannose-binding lectin (MBL) in human immunodeficiency virus (HIV) transmission and acquired immunodeficiency syndrome (AIDS) is conflicting. Polymorphisms in the MBL2 gene reduce the level of protein and alter its structure. Thus, we investigated whether MBL2 alleles and plasma concentrations of MBL are associated with perinatal HIV transmission and disease progression.

METHODS

Frequencies of MBL2 allelic variants (B, C, D, and X) were estimated among 345 HIV-exposed children and 147 blood donors. AIDS-free time was evaluated for different MBL2 genotypes and MBL plasma levels. The median duration of follow-up was 96.5 months.

RESULTS

In the Argentinean population, gene frequencies of MBL2 variants were 18%, 15%, and 3% for the X, B, and D alleles, respectively, with no identified C allele. The haplotype XA/XA was associated with an 8-fold risk of acquiring HIV-1 (P= .054; odds ratio [OR], 8.11 [95% confidence interval {CI}, 0.96-67.86]) and almost a 3-fold risk of progression to pediatric AIDS (P= .026; OR, 2.81 [95% CI, 1.14-7.47]). We also found an independent positive correlation between the rate of AIDS progression and MBL plasma concentration (P= .008; OR, 1.28 [95% CI, 1.07-1.55]).

CONCLUSIONS

Our results demonstrate that homozygosity for the MBL2 promoter genotype XA/XA is an important genetic determinant of HIV-1 acquisition through vertical transmission and the pathogenesis of pediatric HIV/AIDS, via a mechanism that remains to be established.

OBJECTIVE

Mannose-binding lectin (MBL) is an important component of the innate immunity, present at the mucosal level in vagina: a common pathogen's entry point.

METHODS

We used a rapid genotyping method based on melting temperature assay to search for three single nucleotide polymorphisms (SNPs) located in the first exon of the MBL2 gene and we also measured MBL serum levels in patients with recurrent bacterial vaginosis (rBV) and recurrent vulvovaginal candidiasis (rVVC).

RESULTS

Detected frequencies of MBL2 SNPs were comparable to the ones already reported for the Italian population and no significant differences were found between rVVC, rBV and controls. MBL serum levels did not show significant differences between the studied groups.

CONCLUSIONS

No correlation for the screened mutations has been found neither in protecting nor in favoring the infection in rVVC and rBV patients. Our data demonstrate a lack of association between functional polymorphisms in the first exon of MBL2 gene, MBL deficiency, VVC and rBV.

Insulin resistance is a feature of gestational diabetes mellitus (GDM). Inverse correlations between indexes of insulin sensitivity and serum markers of inflammation have been observed and, particularly, TNF-alpha has been shown to be associated with the appearance of insulin resistance in pregnancy. Mannose-binding lectin (MBL) is a protein member of the collectin family. Its deficiency is genetically determined and predisposes to recurrent infections and chronic inflammatory diseases. To test the hypothesis that a genetic predisposition to a proinflammatory state could favor the appearance of GDM during pregnancy, we studied R52C and G54D polymorphisms of MBL2 gene and plasma MBL levels from 105 consecutive GDM women and 173 healthy pregnant women. An association was found between G54D and GDM [odds ratio, 2.03 (1.18-3.49); P < 0.01], and this association remained significant when the presence of both mutated alleles was considered [odds ratio, 1.76 (1.04-2.96); P < 0.05] but not for the R52C. GDM patients who carried the G54D mutation required insulin therapy more frequently (56.4 vs. 30.4%, chi(2) =5.83; P = 0.027) and had heavier infants (3326.4 +/- 546.9 vs. 3087.5 +/- 395.5 g; P < 0.05) than GDM women homozygous for the wild-type allele. An inverse correlation in GDM patients between neonatal weight and plasma MBL levels (r = -0.320; P = 0.002) was found, remaining significant after adjustment for confounding variables. In conclusion, pregnant women bearing the G54D MBL allele have a greater risk for developing GDM and having heavier infants.

Celiac disease is a multifactorial disorder caused, in genetically susceptible patients, by the ingestion of dietary gluten. Very little is known about the genetic factors, but there is a strong association of two HLA haplotypes (DQ2 or alpha1*05, beta1*02 and DQ8 or alpha1*0301, beta1*0302) with the disease. We investigated the relationship between polymorphisms in the first exon of the MBL2 gene, which encodes for mannose binding lectin (MBL) and celiac disease. Moreover we studied the MBL role by immunohistochemistry and TUNEL. Results were confirmed by clinical findings. We enrolled 149 Italian celiac patients; 116 were characterized by the presence of DQ2 or DQ8. The HLA haplotype was established by allelic specific PCR while the MBL2 genotype was resolved by melting temperature assay. Immunohistochemistry and TUNEL assays were performed on serial sections of biopsy specimens from celiac patients and healthy controls. MBL2 allele and genotype frequencies varied significantly between celiac patients and healthy controls. The frequencies of the 0 allele were 28% in DQ2 or DQ8 celiac patients, 36% in HLA atypical celiac patients, and 22% in healthy controls. Interestingly, the MBL2 0/0 genotype was present in 7 of 33 HLA atypical celiac patients (21%) and in 13 of 116 HLA typical celiac patients (13%) but in only 7 of 147 healthy controls (5%). Furthermore, we found that MBL2 genotype is strongly associated with the occurrence of secondary autoimmune diseases. Immunohistochemistry and TUNEL findings support a role of MBL2 in the clearance of apoptotic cells. In conclusion, MBL2 variants, responsible for lower MBL levels, are associated with celiac disease and higher risk of developing autoimmune diseases. Here we propose a role for MBL in the disease which could be easily applied to other autoimmune disorders.

Mannose-binding protein (MBP) is a member of a family of collagenous lectins (collectins), which are believed to play an important role in first-line host defense. In this study, the two genes encoding MBP in mice--Mbl1 and Mbl2--have been isolated and their exon-intron structure studied to understand their evolutionary relationship to the single human (MBL) and the two rat MBP genes. Mouse Mbl1 and Mbl2 have five and six exons, respectively. The structure of the mouse Mbl genes is similar to that of the rat and human MBP genes and shows homology to the other collectin genes, with the entire carbohydrate recognition domain being encoded in a single exon and all introns being in phase 1. The MBP encoded by mouse Mbl1 with three cysteines in the first coding exon, like the rat Mbl1 and human MBL, is capable of a higher degree of multimerization and has apparent ability to fix complement in the absence of antibody or C1q. However, the structural features of other exons, that is, the larger size of collagen domain region in the first coding exon (64 bp in Mbl2 vs 46 bp in Mbl1) and the smaller size of the exon encoding the trimerization domain (69 bp in Mbl2 vs 75 bp in Mbl1) reveal that the single human MBL gene is closely related to rodent Mbl2 rather than rodent Mbl1. The findings in this study suggest that in contrast to the evolution of another collectin gene--bovine surfactant protein-D--which duplicated in bovidae after divergence from humans, MBP gene most likely duplicated prior to human-rodent divergence, and that the human homolog to Mbl1 was perhaps lost during evolution.

Mannose-binding lectin (MBL) is a serum protein which initiates innate immune responses to microbial pathogens by binding to non-self surface oligosaccharides. MBL deficiency is the most common congenital immunodeficiency of human and has been shown to predispose to infections, particularly in children and immune compromised. In a matched case-control study among 870 Ghanaian children, we examined the influence of six polymorphisms of the MBL2 gene on Plasmodium falciparum infection and severe malaria. A missense mutation resulting in low MBL activity (MBL2*C) was found in 35% of healthy controls, but in 42% of asymptomatically infected children (P=0.01), and in 46% of patients with severe malaria (P=0.007). Heterozygosity for MBL2*C was associated with increased odds of infection (odds ratio (OR), 1.6; 95% confidence interval (CI), 1.1-2.1), severe malaria (OR, 1.7; 95% CI, 1.2-2.4), and of severe anemia in particular (OR, 2.3; 95% CI, 1.4-3.8). The population attributable fraction of severe malaria cases attributable to MBL2*C heterozygosity was 17%. Our results suggest that the MBL pathway of the complement system is a critical determinant of both, susceptibility to P. falciparum infection and manifestation of severe malaria, particularly in young children in whom specific immune responses are weak or absent.

Mannose-binding protein (MBL) is a critical component of innate immunity and provides first-line protection against pathogens. Both circulating MBL serum levels and functional activity have been correlated with common genetic variants in the MBL2 gene. Associations between MBL deficiency and severe infections have been reported in immuno-incompetent patients and for autoimmune disorders; however, measured MBL serum levels do not fully correlate with the 'secretor haplotypes'. Previously, the MBL2 locus was resequenced and determined that a recombination hotspot divides MBL2 into two haplotype blocks. It was sought to investigate whether additional variants, in either block structure could associate with MBL serum levels. Therefore, 31 common variants were analysed across the locus in 212 DNA samples of healthy Caucasian individuals with known MBL serum concentrations. The additional 5' variants were in strong linkage to the elements of the 'secretor haplotypes'; functional alleles B, C and D also lie on restricted haplotypes. Four variants in the 3' block (Ex4-1483T>C, Ex4-1067G>A, Ex4-901G>A and Ex4-710G>A) are components of a distinct haplotype block. The results of this study suggest that additional 5' variants as well as markers of distinct 3' haplotype blocks in MBL2 may contribute to circulating protein levels, but further studies are required to confirm these observations. Last, there could be a selective advantage for diversification of the 3' region of the gene.

Genes of innate immunity may be involved in early onset of chronic Pa (Pseudomonas aeruginosa) colonization (cPaC) in cystic fibrosis (CF) patients. We studied 19 single nucleotide polymorphisms (SNPs) in 5 genes coding for proteins of the lectin complement pathway: MBL2 (Mannose binding lectin 2), MASP 1, 2, 3 (MBL-associated serine Protease) and FCN 1, 2 (Ficolin) gene in 96 CF patients. Association survival analysis using different genetic models was performed looking for an association between SNPs and age at onset of cPaC. CF patients who are MBL deficient are earlier chronic Pa colonized compared to MBL sufficient patients. Also patients with MBL2 genotype YO/YO, YO/XA, XA/XA, YA/YO and YA/XA are earlier chronic Pa colonized. CF patients heterozygous or homozygous for mutant alleles of two linked SNPs in the FCN1 gene (rs2989727 and rs1071583) are earlier colonized with Pa. Similarly, earlier onset of Pa colonization is seen in CF patients heterozygous for linked SNPs of FCN2 gene (rs7865453 and rs7851696) and MASP3 gene (rs7851696). Variants in MBL2, FCN1, FCN2 and MASP3 genes are significantly associated with earlier onset of chronic P. aeruginosa colonization.

The serum concentration of mannose-binding lectin (MBL) is genetically determined by a series of allelic polymorphisms in the <em>MBL2</em> gene. Since several polymorphisms of the <em>MBL2</em> gene have been suggested to be risk locus for systemic lupus erythematosus (SLE), we investigated <em>MBL2</em> polymorphisms in 315 SLE patients from Hungary and 182 geographically matched healthy controls. Within the group of patients, we found that homozygotes for an <em>MBL2</em> down-regulating promoter polymorphism at position -221 (YA to XA) (rs7096206) were significantly (p=0.017) younger at diagnosis than the other patients. The frequency of juvenile-onset SLE (<or=20 years) was particularly high among XA/XA homozygotes (17.4%) as compared to the rest of the patients (5.6%) (p=0.004). XA/XA carriers did have significantly higher risk of development of cutaneous manifestations (p=0.003) and pleuritis/pericarditis (p=0.013) as compared with the rest of the patients. These data indicate that MBL may act as a disease modifier in SLE patients through a mechanism to be identified.