Cognate T cell help is sufficient to trigger anti-nuclear autoantibodies in naive mice.
The mechanisms involved in the initiation of anti-nuclear autoantibodies are unknown. In this study, we show that one factor allowing anti-nuclear autoantibodies to develop is the incomplete nature of immune tolerance to many of these proteins. Immune responses in mice toward the ubiquitous nuclear autoantigen La/SS-B are much weaker than responses to the xenoantigen, human La (hLa; 74% identical). However, in transgenic (Tg) mice expressing hLa, the Ab response to this neo-autoantigen was reduced to a level resembling the weak autoimmune response to mouse LA: Partial tolerance to endogenous La autoantigen was restricted to the T compartment because transfer of CD4(+) T cells specific for one or more hLa determinants into mice bearing the hLa transgene was sufficient to elicit production of anti-hLa autoantibodies. Notably, only hLa- specific T cells from non-Tg mice, and not T cells from hLa Tg mice, induced autoantibody production in hLa Tg mice. These findings confirm partial Th tolerance to endogenous La and indicate the existence in normal animals of autoreactive B cells continuously presenting La nuclear AG: Therefore, the B cell compartment is constitutively set to respond to particular nuclear autoantigens, implicating limiting Th responses as a critical checkpoint in the development of anti-nuclear autoantibodies in normal individuals.
Keech
C L
CL
Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia.
Farris
A D
AD
Beroukas
D
D
Gordon
T P
TP
McCluskey
J
J
D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis / Q000096:biosynthesis*; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020014:K562 Cells; D008211:Lymphocyte Cooperation / Q000235:genetics; D051379:Mice; D008805:Mice, Inbred A; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology; D012261:Ribonucleoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000637:transplantation; D000097585:SS-B Antigen
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D011994:Recombinant Proteins; D012261:Ribonucleoproteins; D000097585:SS-B Antigen