Arginine at positions 13 or 70-71 in pocket 4 of HLA-DRB1 alleles is associated with susceptibility to tuberculoid leprosy.

Zerva, Loukia; Cizman, B.; Mehra, N. K.; Alahari, S. K.; Murali, Ramachandran; Zmijewski, Chester M.; Kamoun, Malek; Monos, Dimitri

doi:10.1084/jem.183.3.829

Cited by 97 publications

(57 citation statements)

References 42 publications

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“…Glutamic acid at position 69 corresponds to position 71 of DRβ and occurs in pocket 4. This pocket is involved in controlling antigen-specific T-cell responses (Fu et al, 1995) and is associated with susceptibility to tuberculoid leprosy (Zerva et al, 1996). A single amino acid change at position 71 of DRβ is sufficient to alter the peptide-binding characteristics and susceptibility to rheumatoid arthritis , and clearly shows the close relationship between peptide binding and disease susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Further investigation of the role of HLA-DPB1 in adult Hodgkin’s disease (HD) suggests an influence on susceptibility to different HD subtypes

et al. 1999

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Summary It has been suggested in a number of studies that susceptibility to adult Hodgkin's disease (HD) is influenced by the HLA class II region, and specifically by alleles at the HLA-DPB1 locus. Since HD is diagnostically complex, it is not clear whether different HLA-DPB1 alleles confer susceptibility to different HD subtypes. To clarify this we have extended a previous study to type DPB1 alleles in 147 adult HD patients from a single centre. We have analysed patients with nodular sclerosing (NS), mixed cellularity (MC) or lymphocyte predominant (LP) HD, and gender in relation to HLA-DPBI type, in comparison with 183 adult controls. The results confirmed previously reported associations of DPB1*0301 with HD susceptibility (relative risk (RR) = 1.42; 95% confidence interval (CI) 0.86-2.36) and DPB1*0201 with resistance to HD (RR = 0.49; CI 0.27-0.90). However, analysis by HD subtype and gender showed that *0301-associated susceptibility was confined to females with HD (RR = 2.46; CI 1.02-5.92), and *0201-associated resistance to females with NS-HD (RR = 0.28; CI 0.10-0.79). Susceptibility to NS-HD was also associated in females with *1001 (RR = 11.73; CI 1.32-104.36), and resistance with *1101 (RR = 0.08; CI 0.01-0.65). In contrast, susceptibility to LP-HD was associated in males with *2001 (RR = 32.14; CI 3.17-326.17), and to MC-HD with *3401 (RR = 16.78; CI 2.84-99.17). Comparison of DPB1-encoded polymorphic amino-acid frequencies in patients and controls showed that susceptibility to MC-HD was associated with Leucine at position 35 of DPB1 (RR = 8.85; CI 3.04-25.77), and ). In contrast, Glutamic acid 69 was significantly associated with resistance to MC-HD (RR = 0.14; CI 0.03-0.60). Certain DPB1 alleles and individual DPβ1 polymorphic amino acid residues may thus affect susceptibility and resistance to specific HD subtypes. This may be through their influence on the binding of peptides derived from an HD-associated infectious agent, and the consequent effect on immune responses to the agent.

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Section: Discussionmentioning

confidence: 99%

Further investigation of the role of HLA-DPB1 in adult Hodgkin’s disease (HD) suggests an influence on susceptibility to different HD subtypes

et al. 1999

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“…13 Numerous association studies have also been performed using various candidate genes. Significant associations have been reported between leprosy subtypes and alleles of the vitamin D receptor gene (VDR), 14 as well as different human leukocyte antigen/tumour necrosis factor alpha gene region (HLA/TNF) alleles, including class II variants, 8,[15][16][17] TNF variants, 18 and TAP variants. 19 To what extent genetic heterogeneity plays a role in the genetic control of leprosy susceptibility is presently not known.…”

Section: Introductionmentioning

confidence: 99%

Segregation of HLA/TNF region is linked to leprosy clinical spectrum in families displaying mixed leprosy subtypes

et al. 2003

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Each year an estimated 600 000 new leprosy cases are diagnosed worldwide. The spectrum of the disease varies widely from limited tuberculoid forms to extensive lepromatous forms. A measure of the risk to develop lepromatous forms of leprosy is provided by the extent of skin reactivity to lepromin (Mitsuda reaction). To address a postulated oligogenic control of leprosy pathogenesis, we investigated in the present study linkage of leprosy susceptibility, leprosy clinical subtypes, and extent of the Mitsuda reaction to six chromosomal regions carrying known or suspected leprosy susceptibility loci. The only significant result obtained was linkage of leprosy clinical subtype to the HLA/TNF region on human chromosome 6p21 (P corrected ¼ 0.00126). In addition, we established that within the same family different HLA/TNF haplotypes segregate into patients with different leprosy subtypes directly demonstrating the importance of this genome region for the control of clinical leprosy presentation.

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“…The codon 86 residue lies in binding pocket 1. In another Indian study, both 1501 and 1502 were found to be associated with tuberculoid leprosy, 46 indicating that the residue in pocket 1 may not be involved in determining the outcome of leprosy infection. Instead it appears that certain residues that contribute to the net charge in the putative peptide-specific binding pocket 4 may be more important.…”

Section: Class II Regionmentioning

confidence: 99%

Genetics of susceptibility to leprosy

2002

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The ancient disease of leprosy can cause severe disability and disfigurement and is still a major health concern in many parts of the world. Only a subset of those individuals exposed to the pathogen will go on to develop clinical disease and there is a broad clinical spectrum amongst leprosy sufferers. The outcome of infection is in part due to host genes that influence control of the initial infection and the host's immune response to that infection. Identification of the host genes that influence host susceptibility/resistance will enable a greater understanding of disease pathogenesis. In turn, this should facilitate development of more effective therapeutics and vaccines. So far at least a dozen genes have been implicated in leprosy susceptibility and a genome-wide linkage study has lead to the identification of at least one positional candidate. These findings are reviewed here.

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Arginine at positions 13 or 70-71 in pocket 4 of HLA-DRB1 alleles is associated with susceptibility to tuberculoid leprosy.

Cited by 97 publications

References 42 publications

Further investigation of the role of HLA-DPB1 in adult Hodgkin’s disease (HD) suggests an influence on susceptibility to different HD subtypes

Further investigation of the role of HLA-DPB1 in adult Hodgkin’s disease (HD) suggests an influence on susceptibility to different HD subtypes

Segregation of HLA/TNF region is linked to leprosy clinical spectrum in families displaying mixed leprosy subtypes

Genetics of susceptibility to leprosy

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