Susceptibility to leprosy is associated with M-ficolin polymorphisms.

PURPOSE: Mycobacterium leprae exploits complement activation and opsonophagocytosis to infect phagocytes. M-ficolin is encoded by the FCN1 gene and initiates the lectin pathway on monocyte surfaces. We investigated FCN1 promoter polymorphisms that could be responsible for the high interindividual variability of M-ficolin levels and for modulating leprosy susceptibility. METHODS: We genotyped rs2989727 (-1981 G > A), rs28909068 (-791 G > A), rs10120023 (-542 G > A), rs17039495 (-399 G > A), rs28909976 (-271IndelT), rs10117466 (-144C > A) and rs10858293 (+33 T > G) in 400 controls and 315 leprosy patients from Southern Brazil, and in 296 Danish healthy individuals with known M-ficolin levels. RESULTS: Ten haplotypes were identified with sequence-specific PCR and/or haplotype-specific sequencing. We found evidence for a protective codominant additive effect of FCN1*-542A-144C with leprosy in Euro-Brazilians (P=0.003, PBf =0.021, OR=0.243 [CI95% =0.083-0.71]), which was independent of age, ethnic group and gender effects (P=0.029). There was a trend for a positive association of the -399A variant in Afro-Brazilians (P=0.022, PBf =0.154, OR=4.151 [CI95% =1.115-15.454], as well as for a negative association of the FCN1*3A haplotype with lepromatous leprosy, compared with less severe forms of the disease (P=0.016, PBf =0.112, OR=0.324 [CI95% =0.123-0.858]). Danish individuals with this haplotype presented M-ficolin levels higher than the population average of circa 1,000 ng/ml, and -542A-144C, which is able to modify the recognition of transcription factors in silico, occurred in individuals with levels under the 25 percentil (P=0.031). CONCLUSIONS: Our data provide the first evidence that FCN1 polymorphisms are associated with leprosy. M-ficolin may represent a novel key to understand the immunopathogenesis of M. leprae infection.

Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy.

Genetically determined differences in immune responses to environmental agents may underlie susceptibility to many autoimmune and infectious diseases. Leprosy provides an example of a polarity in the type of immune response made to an infectious agent, and there is evidence that the major histocompatibility complex is genetically linked to leprosy type. It was found that HLA-DR2 is associated with both tuberculoid and lepromatous types of leprosy; however, a variant at position -308 of the promoter of the neighboring tumor necrosis factor (TNF) gene was increased in frequency in lepromatous (odds ratio = 3.0, P = .02) but not tuberculoid leprosy. Some studies have found higher serum levels of TNF in lepromatous than tuberculoid leprosy, and high TNF levels are found in malaria and leishmaniasis, which are also associated with this TNF allele. It is speculated that this association reflects genetic variability in cytokine production, which influences the immune response to and clinical outcome of leprosy.

HLA-DQ molecules and the control of Mycobacterium leprae-specific T cell nonresponsiveness in lepromatous leprosy patients.

The major histocompatibility complex (MHC) controls of the outcome of the immune response to T cell-dependent antigens by dictating whether T cell responsiveness will result (MHC-immune response [Ir]genes) or alternatively T cell nonresponsiveness will occur, possibly through the activation of suppressor cells (MHC-immune suppression [Is] genes). In mice, I-A molecules typically restrict antigen-specific helper T cells. In contrast, H-2 I-E molecules have been reported to control nonresponsiveness to a variety of antigens through antigen-specific suppressor cells. In analogy, HLA-DR molecules are the dominant restriction elements for helper T cells in man. This forces the question whether DQ molecules may be involved in controlling nonresponsiveness in man, e.g. through suppression. In one system, T cell nonresponsiveness to Schistosoma japonicum, evidence has been presented supporting this notion. We have now used a second system, Mycobacterium leprae-specific T cell nonresponsiveness, that is typically found in lepromatous leprosy patients. We find positive but limited evidence for a role for HLA-DQ molecules in controlling T cell nonresponsiveness to M. leprae of the 22 nonresponder patients tested, 4 showed a proliferative T cell response to M. leprae after the addition of DQ- but not DR-specific mAb to the cell cultures. In one of the four BCG nonresponders, anti-DQ mAb had a similar effect.

The clinical course of dimorphous macular leprosy in the Belgian Congo

The clinical features of the development of dimorphous macular leprosy as seen in a series of 62 cases in the Belgian Congo are reviewed, together with some of the bacteriologic data of those cases. Routine examination is advocated, of material obtained by the scraped-incision method, of all cases of leprosy, especially of those showing atypical features. The epidemiologic and neurologic importance of dimorphous macular leprosy in central Africa is briefly emphasized.