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Human Mannose-binding Lectin in Immunity: Friend, Foe, or Both?

Casanova JL, Abel L - J. Exp. Med. (2004)

Bottom Line: Human mannose-binding lectin (MBL) recognizes a wide range of microorganisms and triggers the most ancient pathway of complement activation.However, approximately 5% of individuals lack functional serum MBL and have not been found to be prone to severe infections in prospective studies.These data suggest that human MBL is largely redundant for protective immunity and may even have been subject to counter selection because of a deleterious impact.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Hematology-Immunology Unit, Necker Enfants-Malades Hospital, Paris, France. casanova@necker.fr

ABSTRACT
Human mannose-binding lectin (MBL) recognizes a wide range of microorganisms and triggers the most ancient pathway of complement activation. However, approximately 5% of individuals lack functional serum MBL and have not been found to be prone to severe infections in prospective studies. These data suggest that human MBL is largely redundant for protective immunity and may even have been subject to counter selection because of a deleterious impact.

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Distribution of the seven MBL haplotypes in different indigenous populations from Africa (Kenya and Mozambique; references 10 and 11), Europe (Denmark; references 11 and 38), Asia (Japan; reference 39), Australia (reference 40), Greenland (references 10 and 11), and South America (Argentina; reference 11). Only haplotypes with a frequency >5% are shown (with the actual frequency in brackets). Those carrying a coding sequence mutation (B, C, or D) are indicated in color, and the functionally deficient haplotype (LXPA) is indicated in italics. Of the three haplotypes encoding missense mutations, LYQC is typically found in sub-Saharan Africans, HYPD mainly in Caucasians, and LYPB has spread from Europeans to native Americans via Asian populations following historical migrations, whereas all three of these haplotypes are lacking in indigenous Australian populations (reference 40). Overall, haplotypes associated with missense (HYPD, LYQC, and LYPB) or regulatory (LXPA) deleterious mutations are very common, with frequencies exceeding 30% in many areas worldwide.
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fig1: Distribution of the seven MBL haplotypes in different indigenous populations from Africa (Kenya and Mozambique; references 10 and 11), Europe (Denmark; references 11 and 38), Asia (Japan; reference 39), Australia (reference 40), Greenland (references 10 and 11), and South America (Argentina; reference 11). Only haplotypes with a frequency >5% are shown (with the actual frequency in brackets). Those carrying a coding sequence mutation (B, C, or D) are indicated in color, and the functionally deficient haplotype (LXPA) is indicated in italics. Of the three haplotypes encoding missense mutations, LYQC is typically found in sub-Saharan Africans, HYPD mainly in Caucasians, and LYPB has spread from Europeans to native Americans via Asian populations following historical migrations, whereas all three of these haplotypes are lacking in indigenous Australian populations (reference 40). Overall, haplotypes associated with missense (HYPD, LYQC, and LYPB) or regulatory (LXPA) deleterious mutations are very common, with frequencies exceeding 30% in many areas worldwide.

Mentions: The first clue to the physiological function of MBL was obtained in 1989 (6). Super et al. (6) found that a syndrome characterized by impaired yeast opsonization and multiple infections, first reported in 1968 (7), resulted from a lack of functional serum MBL. The first pathogenic mutation in MBL2, the gene encoding MBL (MBL1 is a pseudogene) was found in 1991 (8). Three common missense mutations, affecting codons 52, 54, and 57 in the first MBL2 exon encoding the NH2-terminal part of the collagen helix, have since been found, and the corresponding alleles were designated D, B, and C, respectively (A is the wild-type allele for all three positions). The pathogenic effects of these three coding sequence mutations involve the impairment of MBL multimerization, decreasing ligand binding, and resulting in a lack of complement activation (9). Three common regulatory mutations were also identified in the MBL2 promoter and 5′ untranslated regions: H/L at position −550, X/Y at position −221, and P/Q at position +4 (10). The regulatory and coding variants are in strong linkage disequilibrium, with only seven haplotypes defined in human populations (HYPA, LYQA, LYPA, LXPA, HYPD, LYQC, and LYPB), and therefore most likely result from founder mutational events (11). Among haplotypes carrying the wild-type A allele, HYPA results in the production of high amounts of MBL, whereas LXPA is associated with the most severe defect in MBL secretion. The frequencies of the seven haplotypes vary considerably between populations (Fig. 1), reflecting the respective ages of the founder mutations, the history of human migrations, and selective environmental pressures acting on the human genome.


Human Mannose-binding Lectin in Immunity: Friend, Foe, or Both?

Casanova JL, Abel L - J. Exp. Med. (2004)

Distribution of the seven MBL haplotypes in different indigenous populations from Africa (Kenya and Mozambique; references 10 and 11), Europe (Denmark; references 11 and 38), Asia (Japan; reference 39), Australia (reference 40), Greenland (references 10 and 11), and South America (Argentina; reference 11). Only haplotypes with a frequency >5% are shown (with the actual frequency in brackets). Those carrying a coding sequence mutation (B, C, or D) are indicated in color, and the functionally deficient haplotype (LXPA) is indicated in italics. Of the three haplotypes encoding missense mutations, LYQC is typically found in sub-Saharan Africans, HYPD mainly in Caucasians, and LYPB has spread from Europeans to native Americans via Asian populations following historical migrations, whereas all three of these haplotypes are lacking in indigenous Australian populations (reference 40). Overall, haplotypes associated with missense (HYPD, LYQC, and LYPB) or regulatory (LXPA) deleterious mutations are very common, with frequencies exceeding 30% in many areas worldwide.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211810&req=5

fig1: Distribution of the seven MBL haplotypes in different indigenous populations from Africa (Kenya and Mozambique; references 10 and 11), Europe (Denmark; references 11 and 38), Asia (Japan; reference 39), Australia (reference 40), Greenland (references 10 and 11), and South America (Argentina; reference 11). Only haplotypes with a frequency >5% are shown (with the actual frequency in brackets). Those carrying a coding sequence mutation (B, C, or D) are indicated in color, and the functionally deficient haplotype (LXPA) is indicated in italics. Of the three haplotypes encoding missense mutations, LYQC is typically found in sub-Saharan Africans, HYPD mainly in Caucasians, and LYPB has spread from Europeans to native Americans via Asian populations following historical migrations, whereas all three of these haplotypes are lacking in indigenous Australian populations (reference 40). Overall, haplotypes associated with missense (HYPD, LYQC, and LYPB) or regulatory (LXPA) deleterious mutations are very common, with frequencies exceeding 30% in many areas worldwide.
Mentions: The first clue to the physiological function of MBL was obtained in 1989 (6). Super et al. (6) found that a syndrome characterized by impaired yeast opsonization and multiple infections, first reported in 1968 (7), resulted from a lack of functional serum MBL. The first pathogenic mutation in MBL2, the gene encoding MBL (MBL1 is a pseudogene) was found in 1991 (8). Three common missense mutations, affecting codons 52, 54, and 57 in the first MBL2 exon encoding the NH2-terminal part of the collagen helix, have since been found, and the corresponding alleles were designated D, B, and C, respectively (A is the wild-type allele for all three positions). The pathogenic effects of these three coding sequence mutations involve the impairment of MBL multimerization, decreasing ligand binding, and resulting in a lack of complement activation (9). Three common regulatory mutations were also identified in the MBL2 promoter and 5′ untranslated regions: H/L at position −550, X/Y at position −221, and P/Q at position +4 (10). The regulatory and coding variants are in strong linkage disequilibrium, with only seven haplotypes defined in human populations (HYPA, LYQA, LYPA, LXPA, HYPD, LYQC, and LYPB), and therefore most likely result from founder mutational events (11). Among haplotypes carrying the wild-type A allele, HYPA results in the production of high amounts of MBL, whereas LXPA is associated with the most severe defect in MBL secretion. The frequencies of the seven haplotypes vary considerably between populations (Fig. 1), reflecting the respective ages of the founder mutations, the history of human migrations, and selective environmental pressures acting on the human genome.

Bottom Line: Human mannose-binding lectin (MBL) recognizes a wide range of microorganisms and triggers the most ancient pathway of complement activation.However, approximately 5% of individuals lack functional serum MBL and have not been found to be prone to severe infections in prospective studies.These data suggest that human MBL is largely redundant for protective immunity and may even have been subject to counter selection because of a deleterious impact.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Hematology-Immunology Unit, Necker Enfants-Malades Hospital, Paris, France. casanova@necker.fr

ABSTRACT
Human mannose-binding lectin (MBL) recognizes a wide range of microorganisms and triggers the most ancient pathway of complement activation. However, approximately 5% of individuals lack functional serum MBL and have not been found to be prone to severe infections in prospective studies. These data suggest that human MBL is largely redundant for protective immunity and may even have been subject to counter selection because of a deleterious impact.

Show MeSH
Related in: MedlinePlus