Genetic dissection of systemic lupus erythematosus pathogenesis: evidence for functional expression of Sle3/5 by non-T cells.
On the non-autoimmune C57BL/6 (B6) background, the chromosome 7-derived lupus susceptibility loci Sle3 and Sle5 have been shown to mediate an elevated CD4:CD8 ratio with an increase in activated CD4(+) T cells, decreased susceptibility to apoptosis, and a break in humoral tolerance. Development of subcongenic strains has subsequently shown that the elevated CD4:CD8 ratio is due to Sle3 but that both loci contribute to the development of autoantibodies. To elucidate the functional expression patterns of these loci, adoptive transfer experiments were conducted. All possible combinations of bone marrow reconstitution, including syngenic, were conducted between the congenic B6 and B6.Sle3/5 strains. It was found that the Sle3/5 locus was functionally expressed by bone marrow-derived cells, but not by host cells, and that the elevated CD4:CD8 phenotype could be reconstituted in radiation chimeras. Using Ly5-marked congenic strains and B6 host mice, additional experiments surprisingly demonstrated that the elevated CD4:CD8 ratio was neither an intrinsic property of the T cells nor of single positive thymocytes. Allotype-marked chimeras indicated that autoantibody production by B cells was also an extrinsic property, as shown by the fact that B cells without the Sle3/5 interval contributed to autoantibody production. These experiments strongly suggest that a gene within the B6.Sle3/5 interval was expressed by a bone marrow-derived, nonlymphocyte population in the thymus and periphery and was affecting T cell selection and/or survival.
Sobel
Eric S
ES
Department of Medicine and Division of Rheumatology and Clinical Immunology, College of Medicine, University of Florida, Gainesville, FL 32610, USA. sobeles@medicine.ufl.edu
Morel
Laurence
L
Baert
Raquel
R
Mohan
Chandra
C
Schiffenbauer
Joel
J
Wakeland
Edward K
EK
D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D000950:Antigens, Ly / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000473:pathology; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002843:Chromatin / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D007126:Immunoglobulin Allotypes / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D037181:Lectins, C-Type; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D011828:Radiation Chimera / Q000276:immunology; D013045:Species Specificity; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D018800:Thy-1 Antigens / Q000032:analysis; D000099192:CD69 Antigens
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000950:Antigens, Ly; D002843:Chromatin; D005819:Genetic Markers; D007126:Immunoglobulin Allotypes; D007143:Immunoglobulin Heavy Chains; D037181:Lectins, C-Type; D018800:Thy-1 Antigens; D000099192:CD69 Antigens