ABSTRACT
The chromosomal region 10p13 has been linked to paucibacillary leprosy in two independent studies. The MRC1 gene, encoding the human mannose receptor (MR), is located in the 10p13 region and non-synonymous SNPs in exon 7 of the gene have been suggested as leprosy susceptibility factors. We determined that G396S is the only non-synonymous exon 7-encoded polymorphism in 396 unrelated Vietnamese subjects. This SNP was genotyped in 490 simplex and 90 multiplex leprosy families comprising 704 patients (47% paucibacillary; 53% multibacillary). We observed significant under-transmission of the serine allele of the G396S polymorphism with leprosy per se (P = 0.036) and multibacillary leprosy (P = 0.034). In a sample of 384 Brazilian leprosy cases (51% paucibacillary; 49% multibacillary) and 399 healthy controls, we observed significant association of the glycine allele of the G396S polymorphism with leprosy per se (P = 0.016) and multibacillary leprosy (P = 0.023). In addition, we observed a significant association of exon 7 encoded amino acid haplotypes with leprosy per se (P = 0.012) and multibacillary leprosy (P = 0.004). Next, we tested HEK293 cells over-expressing MR constructs (293-MR) with three exon 7 haplotypes of MRC1 for their ability to bind and internalize ovalbumin and zymosan, two classical MR ligands. No difference in uptake was measured between the variants. In addition, 293-MR failed to bind and internalize viable Mycobacterium leprae and BCG. We propose that the MR-M. leprae interaction is modulated by an accessory host molecule of unknown identity.
Subject(s)
Exons , Lectins, C-Type/genetics , Leprosy/genetics , Mannose-Binding Lectins/genetics , Polymorphism, Single Nucleotide , Receptors, Cell Surface/genetics , Case-Control Studies , Cells, Cultured , Cloning, Molecular , Genetic Predisposition to Disease , Humans , Lectins, C-Type/metabolism , Lectins, C-Type/physiology , Linkage Disequilibrium , Mannose Receptor , Mannose-Binding Lectins/metabolism , Mannose-Binding Lectins/physiology , Mutant Proteins/genetics , Mycobacterium bovis/metabolism , Mycobacterium leprae/metabolism , Polymorphism, Single Nucleotide/physiology , Protein Binding , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/physiology , TransfectionABSTRACT
Langerhans cells (LCs) represent a unique DC subset populating the outermost body surface, i.e., the epidermis. Although CD1a and langerin (CD207) are used as specific markers to distinguish LCs from other DC subsets, their immunological functions have remained mostly unknown. A new paper (see the related article beginning on page 701) demonstrates that LCs utilize these markers to induce cellular immune responses to Mycobacterium leprae: CD1a mediates the presentation of nonpeptide antigens to T cells, while langerin facilitates uptake of microbial fragments and perhaps their delivery to a specialized subcellular compartment.
Subject(s)
Antigens, CD1/physiology , Antigens, Surface/physiology , Islets of Langerhans/cytology , Lectins, C-Type/physiology , Mannose-Binding Lectins/physiology , Animals , Antigen Presentation , Antigens/chemistry , Antigens, CD , Biological Transport , Humans , Lectins/chemistry , Lipids/chemistry , Models, Biological , Mycobacterium leprae/pathogenicityABSTRACT
Langerhans cells (LCs) constitute a subset of DCs that initiate immune responses in skin. Using leprosy as a model, we investigated whether expression of CD1a and langerin, an LC-specific C-type lectin, imparts a specific functional role to LCs. LC-like DCs and freshly isolated epidermal LCs presented nonpeptide antigens of Mycobacterium leprae to T cell clones derived from a leprosy patient in a CD1a-restricted and langerin-dependent manner. LC-like DCs were more efficient at CD1a-restricted antigen presentation than monocyte-derived DCs. LCs in leprosy lesions coexpress CD1a and langerin, placing LCs in position to efficiently present a subset of antigens to T cells as part of the host response to human infectious disease.