Mannose binding protein gene mutations associated with unusual and severe infections in adults

doi:10.1016/S0140-6736(95)90009-8

The Lancet

Volume 345, Issue 8954, 8 April 1995, Pages 886-889

https://doi.org/10.1016/S0140-6736(95)90009-8 Get rights and content

Abstract

A defect in opsonisation can cause a common immunodeficiency. A mutation in mannose binding protein (MBP) caused by point mutations in the MBP gene will lead to such a defect. This type of syndrome can cause recurrent infections in infants between 6 and 18 months of age but is not generally believed to predispose to adult infections. We looked at 4 patients with severe and unusual infections in whom MBP gene mutations were the only identified cause of immunodeficiency and one patient with combined MBP and IgA deficiency. We analysed the MBPgenotypes of all the patients in whom we suspected an immunodeficiency because of their clinical history. Infections seen were recurrent skin abscesses, chronic cryptosporidial diarrhoea, meningococcal meningitis with recurrent herpes simplex, and fatal klebsiella lobar pneumonia. Both sexes were affected and ages ranged from 15 to 56 years. Two patients were homozygous for codon 54 mutations, one patient had codon 52 and codon 54 mutations and was phenotypically homozygous, and two patients were heterozygous for codon 54 mutations. Individuals homozygous for MBP mutations are unusual in the general population (approximate frequency 0·3%). The occurrence of three homozygotes for MBP mutations among these five infected patients suggests that MBP deficiency may confer a life-long risk of infection.

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Cited by (324)

Infections in primary immunodeficiency
2022, Allergic and Immunologic Diseases: A Practical Guide to the Evaluation, Diagnosis and Management of Allergic and Immunologic Diseases
The first sign of a primary immunodeficiency is often infection. Understanding the infections that are specific to an immunodeficiency is critical to an early and often lifesaving diagnosis. In severe combined immunodeficiencies affecting both cellular and humoral immunity, onset is often in infancy and includes bacterial, viral, and fungal infections, including opportunistic infections. Slightly less severe combined immunodeficiencies (such as primary T-cell disorders, some defects of NF-κB signaling, disorders primarily affecting only CD4+ or CD8+ T cells, and disorders of B cells) may lead to later onset of symptoms or a hallmark diagnostic specific infection. Due to the syndromic features, many patients with combined immunodeficiencies with syndromic features are diagnosed by birth, and before their first infectious episode. The onset of infections is also often in infancy and early childhood and infections can be caused by viral, bacterial, and fungal pathogens and can be fatal. Other immunodeficiencies are less severe, including those that affect specific antibody responses, and some defects in innate immunity, phagocyte function, or the complement cascade. These less severe defects may present with only a subset of infectious organisms and/or may present later in life, but there are still a number of examples of significant infections. Diseases of immune dysregulation and autoimmunity are only occasionally also associated with infection, but infections can still be life-threatening. Last, a growing number of novel therapeutics act to phenocopy states of primary immunodeficiency, and many are associated with similar infections to those seen in patients with mutations in the therapeutic targets.
The role of variant alleles of the mannose-binding lectin in the inhibitor development in severe hemophilia A
2019, Thrombosis Research
Citation Excerpt :
The genotyping of MBL2 is used frequently as surrogate for MBL serum levels since SNPs in exon 1 are associated with relative or absolute serum deficiencies [22,28,29,34–37]. Low MBL concentrations have been associated with an increased susceptibility to various infectious diseases [16,17,34–36,39,40], but also with certain autoimmune diseases like Lupus erythematosus [18]. We hypothesised that the MBL2-SNPs which are linked to a functional MBL-deficiency are associated with a higher risk of inhibitor development among patients with hemophilia A due to a less efficient clearance of FVIII with exposed mannosylation sites, thereby circumventing a specific immune response.
The administration of FVIII leads to inhibitors in up to 30% of patients with hemophilia A (HA), the most severe treatment complication. FVIII-mannosylation fosters the presentation of FVIII to CD4⁺-T-lymphocytes. Mannose as primary ligand for the mannose-binding lectin (MBL) activates the lectin pathway of complement. MBL2 single nucleotide polymorphisms (SNPs) lead to low peripheral MBL concentrations that may hamper the removal of mannosylated FVIII.
Investigation of the association between the inhibitor development in hemophilia A and MBL2-SNPs.
In a case-control study the MBL2-SNPs in exon 1 at codons 52, 54 and 57 (C, B, D-Alleles respectively) were determined in 237 patients with severe hemophilia A with and without inhibitors to FVIII (119 vs 118). The association of MBL2-SNPs and the -308 G>A TNF-α-polymorphism with the presence of inhibitors were determined.
In the inhibitor group higher frequencies of the B allele (codon 54) (OR: 1.77, P < 0.05) were present. Summarising the MBL2 SNPs (alleles B, C and D) as 0, the 0/0 type occurred only in the inhibitor group (frequencies: 0.08 vs 0, P = 0.003). Based on the genetic background a functional immune response phenotype was determined. 11.8% of patients with inhibitors were of the low MBL/high TNF-α phenotype vs 0.03% of the non-inhibitor patients (OR: 3.71).
Data suggest an association of MBL2-SNPs alone or combined with the 308-TNF-α polymorphism in the inhibitor development. Investigations of components of all three complement pathways are required to comprehend their individual and overall contribution to the inhibitor development in HA.
Association of IFNG gene polymorphisms with pulmonary tuberculosis but not with spinal tuberculosis in a Chinese Han population
2017, Microbial Pathogenesis
Spinal tuberculosis (STB) is an extrapulmonary form of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), which accounts for around 2% of all TB cases and can lead to spine degeneration. It is widely accepted that host genetic factors participate in the pathogenesis of active TB, but the factors controlling which TB form will manifest after Mtb infection remain unknown. We hypothesized that a genetic difference may exist between the development of STB and pulmonary tuberculosis (PTB). Here, three single nucleotide polymorphisms (SNPs) in the IFNG gene (rs2069718), IRGM gene (rs10065172), and MBL2 gene (rs11003125) were genotyped among 183 PTB patients, 177 STB patients, and 360 healthy controls from the Chinese Han population. We found that rs2069718 genotypes were significantly associated with PTB (TT, p = 0.007; CT, p = 0.008) but not STB, and the TT genotype (p = 0.046) of rs2069718 were less common in PTB than in STB. In contrast, neither PTB nor STB were found to be associated with rs10065172 and rs11003125. Overall, we found a difference in the rs2069718 genetic distribution between the STB and PTB patients in a Chinese Han population. The rs2069718 TT genotype was associated with a protective role in PTB but not STB development during active Mtb infection.
The genetic profile of susceptibility to infectious diseases in Roman-Period populations from Central Poland
2017, Infection, Genetics and Evolution
For thousands of years human beings have resisted life-threatening pathogens. This ongoing battle is considered to be the major force shaping our gene pool as every micro-evolutionary process provokes specific shifts in the genome, both that of the host and the pathogen. Past populations were more susceptible to changes in allele frequencies not only due to selection pressure, but also as a result of genetic drift, migration and inbreeding. In the present study we have investigated the frequency of five polymorphisms within innate immune-response genes (SLC11A1 D543N, MBL2 G161A, P2RX7 A1513C, IL10 A-1082G, TLR2 –196 to –174 ins/del) related to susceptibility to infections in humans. The DNA of individuals from two early Roman-Period populations of Linowo and Rogowo was analysed. The distribution of three mutations varied significantly when compared to the modern Polish population. The TAFT analysis suggests that the decreased frequency of SLC11A1 D543N in modern Poles as compared to 2nd century Linowo samples is the result of non-stochastic mechanisms, such as purifying or balancing selection. The disparity in frequency of other mutations is most likely the result of genetic drift, an evolutionary force which is remarkably amplified in low-size groups. Together with the F_ST analysis, mtDNA haplotypes' distribution and deviation from the Hardy-Weinberg equilibrium, we suggest that the two populations were not interbreeding (despite the close proximity between them), but rather inbreeding, the results of which are particularly pronounced among Rogowo habitants.
Evaluation of Mannose-Binding Lectin is a Useful Approach to Predict the Risk of Infectious Complications Following Autologous Hematopoietic Stem Cell Transplantation
2016, Transplantation Proceedings
Hematopoietic stem cell transplantation (HSCT) associated immunocompromised state carries high risk of infectious complications. Mannose-binding lectin (MBL) is an acute phase protein involved in innate immune response. Serum MBL level is genetically determined and quite stable. According to literature, significant association was shown between low MBL concentrations and serious infections. The association between serum MBL level and frequency and severity of infections was studied in 186 patients following autologous HSCT. Double-monoclonal antibody sandwich enzyme-linked immunosorbent assay was used to determine MBL antigen level in sera. MBL levels were measured around 100 days following transplantation, in a period without active infection. Twenty-one patients (11%) were MBL deficient. The median time of first infection and number of infections during the first year post-transplantation were not significantly different between patients with MBL deficiency and those without MBL deficiency. The occurrence and number of infections after HSCT correlated with the MBL/C-reactive protein ratio. The number of severe infections was not higher among those with MBL deficiency. The occurrence of infections after the pre-engraftment period during the first year post-transplantation was significantly different in patient groups separated by MBL cut-off level. The MBL/C-reactive protein ratio might be a useful marker of infectious complications. MBL measurement may be helpful in antibiotic treatment. In case of MBL deficiency, earlier and more intensive treatment may be indicated.
MBL2 polymorphisms and the risk of asthma: A meta-analysis
2016, Annals of Allergy, Asthma and Immunology
The association between MBL2 gene polymorphisms and the risk of asthma has been evaluated in multiple studies; however, the results are inconsistent.
To perform a meta-analysis to explore whether MBL2 gene polymorphisms were associated with the risk of asthma.
We searched PubMed, Web of Science, and Cochrane Library to find relevant articles published up to March 2016. Nine studies, including 2066 cases and 2183 controls, were included in the meta-analysis. The strength of association was evaluated by odds ratio (OR) with 95% confidence interval (CI).
The results reveal that MBL2 gene polymorphisms (codon 54 A/B, –550 H/L or –221 X/Y) were not associated with the risk of asthma (codon 54 A/B: BB+AB vs AA: OR, 1.02; 95% CI, 0.85–1.23; –550 H/L: LL+HL vs HH: OR, 0.81; 95% CI, 0.63–1.03; –221 X/Y: XX+YX vs YY: OR, 0.85; 95% CI, 0.69–1.04). Subgroup analysis by ethnicity implied that the MBL2 codon 54 A/B polymorphism was not significantly associated with the risk of asthma in Asians (BB+AB vs AA: OR, 0.95; 95% CI, 0.70–1.29) or whites (BB+AB vs AA: OR, 1.07; 95% CI, 0.84–1.35).
The results indicated that MBL2 gene polymorphisms (codon 54 A/B, –550 H/L or –221 X/Y) may be not associated with the risk of asthma.

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Mannose binding protein gene mutations associated with unusual and severe infections in adults

Abstract

Lancet

Lancet

Biochem Biophys Res Commun

Lancet

Lancet

Infect Dis Clin North Am

J Allergy Clin Immunol

High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene

Hum Mol Genetics

A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein

Immunogenetics

Distinct and overlapping functions of allelic forms of human mannose binding protein

Nat Genet

Defective opsonization: a common immunity deficiency

Arch Dis Child