Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is prevalent in India, where about half of the world's estimated 800,000 cases occur. A role for the genetics of the host in variable susceptibility to leprosy has been indicated by familial clustering, twin studies, complex segregation analyses and human leukocyte antigen (HLA) association studies. We report here a genetic linkage scan of the genomes of 224 families from South India, containing 245 independent affected sibpairs with leprosy, mainly of the paucibacillary type. In a two-stage genome screen using 396 microsatellite markers, we found significant linkage (maximum lod score (MLS) = 4.09, P < 2x10-5) on chromosome 10p13 for a series of neighboring microsatellite markers, providing evidence for a major locus for this prevalent infectious disease. Thus, despite the polygenic nature of infectious disease susceptibility, some major, non-HLA-linked loci exist that may be mapped through obtainable numbers of affected sibling pairs.

Lsr2 protein of Mycobacterium leprae was shown earlier to elicit B and T cell responses in leprosy patients (20, 28). Lymphoproliferation to M. leprae and Lsr2 antigens was observed in >70% of tuberculoid (T) patients and in 16 and 34% of lepromatous (L) patients, respectively. We focused on the M. leprae nonresponders in the lepromatous group using 22 synthetic Lsr2 peptides (end-to-end peptides A to F and overlapping peptides p1 to p16) in in vitro T cell responses. A total of 125 leprosy and 13 tuberculosis patients and 19 healthy controls from the area of endemicity (here, healthy controls, or HC) were investigated. The highest responses were observed (67 to 100%) in HC for all peptides except p1 to p3, and the lowest was observed in tuberculosis patients. Significant differences in lymphoproliferation were observed in T, L, and HC groups (analysis of variance [ANOVA], P ‫؍‬ 0.000 to 0.015) for all end-to-end peptides except B and for p5 and p7 to p10. Hierarchical recognition between lepromatous and tuberculoid leprosy was noted for p8 (P < 0.05) and between the HC and L groups for p7 to p10, p15, and p16 (P < 0.005 to P < 0.02). Significant lymphoproliferation was observed to peptides A to F and p1 to p9, p11, p12, p15, p16 (P ‫؍‬ 0.000 to 0.001) with 40% responding to peptides C and p16 in L patients. Lepromatous patients also showed significantly higher levels of a gamma interferon (IFN-␥) response to peptide C than to other peptides (P < 0.05). Major histocompatibility complex (MHC) class II bias for peptide recognition was not observed. These studies indicate that Lsr2 has multiple T cell epitopes that induce in vitro T cell responses in the highly infective lepromatous leprosy patients. Though the prevalence of leprosy has been reduced due to multidrug therapy regimens, the incidence continues to be a public health worry in some countries (40). Leprosy is caused by the noncultivable Mycobacterium leprae and is defined by distinct clinical-pathological types in humans (29), with the paucibacillary localized tuberculoid forms (borderline tuberculoid/tuberculoid [BT/TT]) having good in vitro and in vivo T cell functions and low levels of antibodies. In contrast, the multibacillary generalized lepromatous leprosy patients (borderline leprosy/lepromatous leprosy [BL/LL]) show abundant antibody responses and T cell unresponsiveness unique to the leprosy bacillus and not to other antigenically related mycobacteria such as Mycobacterium tuberculosis. Moreover, 10 to 15% of stable leprosy patients undergo inflammatory episodes of types 1 (reversal reactions [RR]) and 2 (erythema nodosum leprosum [ENL]) which are localized to the lesion or produce systemic signs of fever, joint pains, and skin nodules. The inverse relationship between cellular and humoral immunity as well as the dichotomy in the leprosy types has been intensely investigated (21,30). The mechanisms underlying the antigen-specific anergy are not completely understood as it is long-lasting and not reversed by conventional therapy. Attempts to impr...

Infect. Immun. 62:86-90, 1994) that polyclonal antibodies directed against selective sequences in the Mycobacterium leprae recombinant protein designated LSR were present in lepromatous leprosy patients undergoing erythema nodosum leprosum (ENL) reactions (type 2 reactions). In this study using peptides with

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