Enhanced responsiveness to T-cell help causes loss of B-lymphocyte tolerance to a β-cell neo-self-antigen in type 1 diabetes prone NOD mice.
Self-reactive B lymphocytes contribute to type 1 diabetes pathogenesis as APC and auto-Ab producers in NOD mice and humans. To shed light on the mechanisms responsible for the breakdown in B-lymphocyte self-tolerance to β-cell Ag, we utilised a model whereby hen-egg lysozyme (HEL)-specific Ig Tg (IgHEL-Tg)-Tg B lymphocytes were allowed to develop in or were transferred into mice expressing the HEL Tg under an insulin promoter (insHEL-Tg). IgHEL-Tg B lymphocytes enhanced type 1 diabetes susceptibility of insHEL-Tg NOD mice. A comparison of the tolerogenic activity of IgHEL-Tg B lymphocytes with NOD and non-autoimmune-prone C57BL/6 genetic backgrounds showed that both were rendered anergic in the presence of insHEL when competing with polyclonal B lymphocytes. Nevertheless, NOD IgHEL-Tg B lymphocytes transferred into insHEL-Tg mice were more readily susceptible to rescue from anergy than their C57BL/6 counterparts, following provision of in vivo T-cell help. The different tolerogenic outcomes were an intrinsic property of B lymphocytes rather than being related to the quality of T-cell help, with the defective response being at least partially controlled by genes mapping to insulin-dependent diabetes (Idd) susceptibility loci on Chromosome 1 (Idd5) and 4 (Idd9/11).
Immunology Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Selwyn Lewis
SL
Cox
Jessica
J
Stolp
Nicole L
NL
Hallahan
Jacqueline
J
Counotte
Wenyu
W
Zhang
David V
DV
Serreze
Antony
A
Basten
Pablo A
PA
Silveira
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017634:Self Tolerance / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019076:Transgenes / Q000235:genetics; D018183:Transplantation Chimera
D001324:Autoantigens; D016207:Cytokines; D007136:Immunoglobulins; D007328:Insulin; C421864:hen egg lysozyme; D009113:Muramidase