- Email: [email protected]
Bcg
cQ INSTITUT PASTEUR/ELSEVIER Paris 1989
Res. Immunol.
27fa FORUM IN IMMUNOLOGY
THE MACROPH:IGE
RESISTANCE GENE Lsh/1tv/Bc~
Organized by J. Blaekwell
INTRODUCTION J.M. BlackweU
London School o f Hygiene and Tropical Medicine, University o f London, Keppel Street, London WCIE 7HT
The first reports of inbred mouse
roneoas (Plant et al,~ 1982), four difI g ! _r-Ill.
segregation analysis of susceptibility and resistance to intravenously inoculated Salmonella typhimurium (Plant and Glynn, 1974, 1976) or Leishmania donovani (Bradley, 1974, 1977) appeared more than a decade ago. The genes, separately designated Ity and Lsh by the two different laboratories, were independently mapped to a position near Idh and In on mouse chromosome 1 using traditional linkage analysis in F2 and backcross mice (Plant and Glynn, 1979) and a series of 65 recombinant inbred (RI) mouse strains involving seven different progenitor strain combinations (Bradley et al., 1979). In subsequent studies, O ' B r i e n and coworkers (1980) examined some of these RI strains for S. typhimurium infection and reported discordance between Ity typings and the published Lsh typings for 3 strains. These discordant typings were later shown to be er-
la.I./KJl a.I.u[
L~-~,
lll..IW
~ l . ~ l ~71~111~
IOll
100 070 concordance between Ity, Lsh, and typings for susceptibility and resistance to intravenous, low dose inoculation with Mycobacterittm bovis or BCG (Skamene et al., 1982), which had now also been shown to come under single gene (Bcg) control (Gros et al., 1981)• Resistance and susceptibility to M. lepraemurium (Brown et ai., !.982; Skamene et al., 1984) and M. intracellulare (Goto et al., 1984) also showed full concordance with Ity/Lsh/Bcg amongst inbred and RI mouse strains, suggesting that all of these different pathogens might fall under the control of a single gene. Results of a five-point backcross analysis (Taylor and O'Brien, 1982) provided a more precise map location for the gene 9 centimorgans distal to Idh-I and 11 centimorgans proximal to in on mouse chromosome 1. Nevertheless, we cannot be certain from tradition,~ .,l,,,,ge data that Lsh/Ity/Bcg are
768
27 th F O R U M I N I M M U N O L O G Y
1984), and is abrogated by administraidentical rather than closely linked tion of silica (O'Brien et al., 1979; Gros genes. For this reason, there has been et al., 1983). Resistance is also expresgeneral consensus between laboratories sed to varying degrees in different that the gene should not be renamed unmacrophage populations isolated and til definitive evidence (e.g, a protein infected with S. typhimurium (Lissner product and/or cloning of the gene) for et al., 1983), M. boris (Stach et al., identity has been obtained. Altkough IN_O A~ ...... ,.._ ~ or L. donovani (Crocker et al., the gene appears ^'- , - h . . . . . . . 1987) in vitro. The action of this gene chromosome map (Mouse News Letter, in controlling resistance and suscepNo. 84, July 1989) as Lsh, gene designatibility to such a broad range of tion in publications usually goes accormacrophage pathogens has made it ding to the microorganism under an important target of research aimed investigation. Functional ~,tudies do at its further characterization at cellular show many common features in the and molecular (protein gene product expression of resistance and susceptia n d / o r m R N A / D N A ) levels. This bility to the three phylogenetically Forum provides an opportunity for the distinct microorganisms, L. donovani, S. typhimurium and M. boris. Expresdifferent groups currently engaged in this research to present their latest sion of resistance in vivo, for example, findings and to exchange ideas and does not require a functional T-cell hypotheses in the traditional spirit of an population (O'Brien and Metcalf, 1982; Gros et al., 1983 ; Bonventre & Nickol, Annales Forum. It is with great pleasure, too, that we invite Professors 1984) can be transferred with the donor Bradley and Glynn to review these haematopoietic system in radiation manuscripts and offer their concluding bone marrow chimaeras (Hormaeche, 1979; Gros et al., 1983; Crocker et al., remarks.
References.
BoNvEm'P.E, P.F. & NICKOL,A.D. (1984), Leishmania donovani infection in athymic mice derived f-om oarental strains of the susceptible/labs) , ~ r roeietattt ~i_*~¢; tT ottrl ] ,.,ha.~,..+.,,,~ I~rtl.vb, lt,l'4.11.~t~.,. J. Leuk. Biol., 36, 651-658. BRADLEY,D.J. (1974), Genetic control of natural resistance to Leishmania donovani. Nature (Lond.), 250, 353-354. BRADLEY,D.J. (1977), Regulation of Leishmania populations within the host. -- II. Genetic control of acute susceptibility of mice to Leishmania donovani infection. Clin. exp. Immunol., 30, 130-140. BRAI)LEVD.J., TAYLOR,B.A., BLACKWELL,J.M., EVANS,E.P. & FIrEmAN, J. (1979), Regulation of Leishmania populations within the host. - - III. Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse. Clin. exp. Immunol., 37, 7-14. BROWN, I.N., GLYNN, A.A. & PLANT, J.E. (1982), Inbred mouse strain resistance to Mycobacterium lepraemurium follows the Ity/Lah pattern. Immunology, 47, 149-156. CROCKER,P.R., BLACKWELL,J.M. & BRAOLnY,D.J. (1984), Transfer of innate resistance and susceptibility to L. donovani infection in mouse radiation bone marrow chimaeras. Immunology, 52, 417-422. CROCKER,P.R., DAVIES,E.V. & BLACKWELL,J.M. (1987), Variable expression of the natural resistance gene Lsh in different macrophage populations infected in vitro with Leishmania donovani. Parasite Immunol., 9, 705-719. GOTO, Y., NAKAMURA,R.M., TAKABASm,H. & TOKtmAGA, T. (1984), Genetic control of resistance to .Mycgbacterium intracellulare infection in mice. Infect. lmmun., 46, 135-140. GRos, P., S ~ m ~ , E. & FoRo)~r, A. (1981). Genetic control of natural resistance to Mycobaeterium boris (BEG) in mice. J. ImmunoL, 127, 2417-2421. GROS,P., SicAm~r~,E. & Foxo~a', A. (1983), Cellular mechanisms of genetically controlled host resistance to Mycobacterium boris (BCG). J. Immunol., 131, 1966-1972. HORMAeCHE, C.E. (1979), The natural resistance of radiation chimaeras to Salmonella typhimurium C5. Immunology, 37, 311-318. .
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.
.
.
v t
L V t 3 t ~ t ~ t t t
MACROPHAGE
RESISTANCE
GENE Lsh/Ity/Bcg
769
LISSNER,C.R., SWANSON,R.N. & O'BRIEN,A.D. (1983), Genetic control of the innate resistance of mice to Salmonella typhimurium: expression of the Ity gene in peritoneal and splenic macrophages isolated in vitro. J. Immunol., 131, 3006-3013. O'BR|EN, A.D. & METCALF,E.S. (1982), Control of early Salmonella typhimurium growth in innately Salmonella-resistant mice does not require functional T lymphocytcs. J. Immunol., 129, 1349-1351. O'BRmN, A.D., ROSENSTR~IC,,D.L. & TAYLOR,B.A. (1980), Control of natural resistance to Salmonella typhimurium and Leishmania donovani in mice by closely linked but distinct ge.iletic loci. Nature (Lond.), 287, 440-442. O'BmEN, A.D., SC,ER, I. & FORMAL,S.B. (1979), Effect of silica on the innate resistance of inbred mice to Salmonella typhimurium infection. Infect. Immun., 25, 513-520. PLANT, J.E. & GLVr~, A.A. (1974), Natural resistance to Salmonella infection, delayed hypersensitivityand Ir genes in different strains of mice. Nature (Lond.), 248, 345-347. PLANa', J.E. & GLvr~, A.A. (1976), Genetics of resistance to infection with Salmonella typhimurium in mice. J. infect. Dis., 133, 72-78. PLANT, J.E. & GLYCOl, A.A. (1979), Locating Salmonella resistance gene on mouse chromosome 1. Clin. exp. lmmunoL, 37, 1-6. PLArcr, J.E., BLACrW~LL,J.M., O'BRmN, A.D., BP~.OLEV,D.J. & GLX,~, A.A. (1982), Are the Lsh and Ity disease resistance genes at one locus on mouse chromosome 1.9 Nature (Lond.), 297, 510-511. S ~ E r ~ , E., GRos, P., FoRcEa', A., KONGSnAW,P.A.L., ST C,~LES, C. & TAYLOR,B.A. (1982), Genetic regulation of resistance to intraceUular pathogens. Nature (Lond.), 297, 506-509. . . . . ~, Reg,,iatioa of SKAMENE,E., GROS, P., FORGET,A., PATEL, F.J. & NesuHt, M.N. :loo~, resistance to leprosy by chromosome 1 locus in the mouse. Immunogenet., 19, 117-124. STAC", J.-L., GROS, P., FORG~T, A. & Sr~M~t,~, E. (1984), Phenotypic expression of genetically-controllednatural resistance to Mycobacterium bovis 0ICG). J. Immuno!., 132, 888-892. TAYLOR,B.A. & O'BRIEN,A.D. (1982), Position on mouse chromosome 1 of a gene that controls resistance to Salmonella typhimurium. Infect. lmmun., 36, 1257-1260.
A COMPARISON OF GENETIC LINKAGE MAPS SURROUNDING THE Lsh/Ity/Bcg DISEASE RESISTANCE LOCUS
B. Mock (1) and M. Seidin (2) Q) Laboratory o f Genetics, NCI, NIH, Bethesda, M D 20892 (USA), and (2) Duke University Medical Center, Department o f Medicine, Durham, N C 27710 (USA)
Introduction. Reverse genetic approaches to the isolation of disease-related loci have been successful in identif~ng genes associated with Duchenne's muscular dystrophy, chronic granulomat.ous disease, cystic fibrosis and reunoblastoma development (Monaco et al.,
1986; Koenig et al., 1987; Orkin, 1986; 1987; Rommens et al., 1989; Riordan et al., 1989; Friend et al., 1986). The basic approach has been to establish a high-resolution map of the chromosomal region harbouring the gene of interest and to identify a specific gene from the region in which mutations are correlated with the disease (Orkin, 1986).
Res. Immunol.
27fa FORUM IN IMMUNOLOGY
THE MACROPH:IGE
RESISTANCE GENE Lsh/1tv/Bc~
Organized by J. Blaekwell
INTRODUCTION J.M. BlackweU
London School o f Hygiene and Tropical Medicine, University o f London, Keppel Street, London WCIE 7HT
The first reports of inbred mouse
roneoas (Plant et al,~ 1982), four difI g ! _r-Ill.
segregation analysis of susceptibility and resistance to intravenously inoculated Salmonella typhimurium (Plant and Glynn, 1974, 1976) or Leishmania donovani (Bradley, 1974, 1977) appeared more than a decade ago. The genes, separately designated Ity and Lsh by the two different laboratories, were independently mapped to a position near Idh and In on mouse chromosome 1 using traditional linkage analysis in F2 and backcross mice (Plant and Glynn, 1979) and a series of 65 recombinant inbred (RI) mouse strains involving seven different progenitor strain combinations (Bradley et al., 1979). In subsequent studies, O ' B r i e n and coworkers (1980) examined some of these RI strains for S. typhimurium infection and reported discordance between Ity typings and the published Lsh typings for 3 strains. These discordant typings were later shown to be er-
la.I./KJl a.I.u[
L~-~,
lll..IW
~ l . ~ l ~71~111~
IOll
100 070 concordance between Ity, Lsh, and typings for susceptibility and resistance to intravenous, low dose inoculation with Mycobacterittm bovis or BCG (Skamene et al., 1982), which had now also been shown to come under single gene (Bcg) control (Gros et al., 1981)• Resistance and susceptibility to M. lepraemurium (Brown et ai., !.982; Skamene et al., 1984) and M. intracellulare (Goto et al., 1984) also showed full concordance with Ity/Lsh/Bcg amongst inbred and RI mouse strains, suggesting that all of these different pathogens might fall under the control of a single gene. Results of a five-point backcross analysis (Taylor and O'Brien, 1982) provided a more precise map location for the gene 9 centimorgans distal to Idh-I and 11 centimorgans proximal to in on mouse chromosome 1. Nevertheless, we cannot be certain from tradition,~ .,l,,,,ge data that Lsh/Ity/Bcg are
768
27 th F O R U M I N I M M U N O L O G Y
1984), and is abrogated by administraidentical rather than closely linked tion of silica (O'Brien et al., 1979; Gros genes. For this reason, there has been et al., 1983). Resistance is also expresgeneral consensus between laboratories sed to varying degrees in different that the gene should not be renamed unmacrophage populations isolated and til definitive evidence (e.g, a protein infected with S. typhimurium (Lissner product and/or cloning of the gene) for et al., 1983), M. boris (Stach et al., identity has been obtained. Altkough IN_O A~ ...... ,.._ ~ or L. donovani (Crocker et al., the gene appears ^'- , - h . . . . . . . 1987) in vitro. The action of this gene chromosome map (Mouse News Letter, in controlling resistance and suscepNo. 84, July 1989) as Lsh, gene designatibility to such a broad range of tion in publications usually goes accormacrophage pathogens has made it ding to the microorganism under an important target of research aimed investigation. Functional ~,tudies do at its further characterization at cellular show many common features in the and molecular (protein gene product expression of resistance and susceptia n d / o r m R N A / D N A ) levels. This bility to the three phylogenetically Forum provides an opportunity for the distinct microorganisms, L. donovani, S. typhimurium and M. boris. Expresdifferent groups currently engaged in this research to present their latest sion of resistance in vivo, for example, findings and to exchange ideas and does not require a functional T-cell hypotheses in the traditional spirit of an population (O'Brien and Metcalf, 1982; Gros et al., 1983 ; Bonventre & Nickol, Annales Forum. It is with great pleasure, too, that we invite Professors 1984) can be transferred with the donor Bradley and Glynn to review these haematopoietic system in radiation manuscripts and offer their concluding bone marrow chimaeras (Hormaeche, 1979; Gros et al., 1983; Crocker et al., remarks.
References.
BoNvEm'P.E, P.F. & NICKOL,A.D. (1984), Leishmania donovani infection in athymic mice derived f-om oarental strains of the susceptible/labs) , ~ r roeietattt ~i_*~¢; tT ottrl ] ,.,ha.~,..+.,,,~ I~rtl.vb, lt,l'4.11.~t~.,. J. Leuk. Biol., 36, 651-658. BRADLEY,D.J. (1974), Genetic control of natural resistance to Leishmania donovani. Nature (Lond.), 250, 353-354. BRADLEY,D.J. (1977), Regulation of Leishmania populations within the host. -- II. Genetic control of acute susceptibility of mice to Leishmania donovani infection. Clin. exp. Immunol., 30, 130-140. BRAI)LEVD.J., TAYLOR,B.A., BLACKWELL,J.M., EVANS,E.P. & FIrEmAN, J. (1979), Regulation of Leishmania populations within the host. - - III. Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse. Clin. exp. Immunol., 37, 7-14. BROWN, I.N., GLYNN, A.A. & PLANT, J.E. (1982), Inbred mouse strain resistance to Mycobacterium lepraemurium follows the Ity/Lah pattern. Immunology, 47, 149-156. CROCKER,P.R., BLACKWELL,J.M. & BRAOLnY,D.J. (1984), Transfer of innate resistance and susceptibility to L. donovani infection in mouse radiation bone marrow chimaeras. Immunology, 52, 417-422. CROCKER,P.R., DAVIES,E.V. & BLACKWELL,J.M. (1987), Variable expression of the natural resistance gene Lsh in different macrophage populations infected in vitro with Leishmania donovani. Parasite Immunol., 9, 705-719. GOTO, Y., NAKAMURA,R.M., TAKABASm,H. & TOKtmAGA, T. (1984), Genetic control of resistance to .Mycgbacterium intracellulare infection in mice. Infect. lmmun., 46, 135-140. GRos, P., S ~ m ~ , E. & FoRo)~r, A. (1981). Genetic control of natural resistance to Mycobaeterium boris (BEG) in mice. J. ImmunoL, 127, 2417-2421. GROS,P., SicAm~r~,E. & Foxo~a', A. (1983), Cellular mechanisms of genetically controlled host resistance to Mycobacterium boris (BCG). J. Immunol., 131, 1966-1972. HORMAeCHE, C.E. (1979), The natural resistance of radiation chimaeras to Salmonella typhimurium C5. Immunology, 37, 311-318. .
_
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
v t
L V t 3 t ~ t ~ t t t
MACROPHAGE
RESISTANCE
GENE Lsh/Ity/Bcg
769
LISSNER,C.R., SWANSON,R.N. & O'BRIEN,A.D. (1983), Genetic control of the innate resistance of mice to Salmonella typhimurium: expression of the Ity gene in peritoneal and splenic macrophages isolated in vitro. J. Immunol., 131, 3006-3013. O'BR|EN, A.D. & METCALF,E.S. (1982), Control of early Salmonella typhimurium growth in innately Salmonella-resistant mice does not require functional T lymphocytcs. J. Immunol., 129, 1349-1351. O'BRmN, A.D., ROSENSTR~IC,,D.L. & TAYLOR,B.A. (1980), Control of natural resistance to Salmonella typhimurium and Leishmania donovani in mice by closely linked but distinct ge.iletic loci. Nature (Lond.), 287, 440-442. O'BmEN, A.D., SC,ER, I. & FORMAL,S.B. (1979), Effect of silica on the innate resistance of inbred mice to Salmonella typhimurium infection. Infect. Immun., 25, 513-520. PLANT, J.E. & GLVr~, A.A. (1974), Natural resistance to Salmonella infection, delayed hypersensitivityand Ir genes in different strains of mice. Nature (Lond.), 248, 345-347. PLANa', J.E. & GLvr~, A.A. (1976), Genetics of resistance to infection with Salmonella typhimurium in mice. J. infect. Dis., 133, 72-78. PLANT, J.E. & GLYCOl, A.A. (1979), Locating Salmonella resistance gene on mouse chromosome 1. Clin. exp. lmmunoL, 37, 1-6. PLArcr, J.E., BLACrW~LL,J.M., O'BRmN, A.D., BP~.OLEV,D.J. & GLX,~, A.A. (1982), Are the Lsh and Ity disease resistance genes at one locus on mouse chromosome 1.9 Nature (Lond.), 297, 510-511. S ~ E r ~ , E., GRos, P., FoRcEa', A., KONGSnAW,P.A.L., ST C,~LES, C. & TAYLOR,B.A. (1982), Genetic regulation of resistance to intraceUular pathogens. Nature (Lond.), 297, 506-509. . . . . ~, Reg,,iatioa of SKAMENE,E., GROS, P., FORGET,A., PATEL, F.J. & NesuHt, M.N. :loo~, resistance to leprosy by chromosome 1 locus in the mouse. Immunogenet., 19, 117-124. STAC", J.-L., GROS, P., FORG~T, A. & Sr~M~t,~, E. (1984), Phenotypic expression of genetically-controllednatural resistance to Mycobacterium bovis 0ICG). J. Immuno!., 132, 888-892. TAYLOR,B.A. & O'BRIEN,A.D. (1982), Position on mouse chromosome 1 of a gene that controls resistance to Salmonella typhimurium. Infect. lmmun., 36, 1257-1260.
A COMPARISON OF GENETIC LINKAGE MAPS SURROUNDING THE Lsh/Ity/Bcg DISEASE RESISTANCE LOCUS
B. Mock (1) and M. Seidin (2) Q) Laboratory o f Genetics, NCI, NIH, Bethesda, M D 20892 (USA), and (2) Duke University Medical Center, Department o f Medicine, Durham, N C 27710 (USA)
Introduction. Reverse genetic approaches to the isolation of disease-related loci have been successful in identif~ng genes associated with Duchenne's muscular dystrophy, chronic granulomat.ous disease, cystic fibrosis and reunoblastoma development (Monaco et al.,
1986; Koenig et al., 1987; Orkin, 1986; 1987; Rommens et al., 1989; Riordan et al., 1989; Friend et al., 1986). The basic approach has been to establish a high-resolution map of the chromosomal region harbouring the gene of interest and to identify a specific gene from the region in which mutations are correlated with the disease (Orkin, 1986).