Partial tolerance of autoreactive B and T cells to erythrocyte-specific self-antigens in mice.
BACKGROUND
Breakdown of humoral tolerance to RBC antigens may lead to autoimmune hemolytic anemia, a severe and sometimes fatal disease. The underlying mechanisms behind the breakdown of humoral tolerance to RBC antigens are poorly understood.


METHODS
In order to study the pathogenesis of autoimmune hemolytic anemia, we developed a murine model with RBC-specific expression of a model antigen carrying epitopes from hen egg lysozyme and ovalbumin.


RESULTS
Humoral tolerance was observed; this was not broken even by strong immunogenic stimulation (lysozyme or ovalbumin with adjuvant). Autoreactive CD4(+) T cells were detected by tetramer enrichment assays, but failed to activate or expand despite repeat stimulation, indicating a nonresponsive population rather than deletion. Adoptive transfer of autoreactive CD4(+) T cells (OT-II mice) led to autoantibody (anti-lysozyme) production by B cells in multiple anatomic compartments, including the bone marrow.


CONCLUSIONS
These data demonstrate that B cells autoreactive to RBC antigens survive in healthy mice with normal immune systems. Furthermore, autoreactive B cells are not centrally tolerized and are receptive to T-cell help. As the autoreactive T cells are present but non-responsive, these data indicate that factors that reverse T-cell non-responsiveness may be central to the pathogenesis of autoimmune hemolytic anemia.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Krystalyn E
KE
Hudson
Jeanne E
JE
Hendrickson
Chantel M
CM
Cadwell
Neal N
NN
Iwakoshi
James C
JC
Zimring
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004912:Erythrocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D001324:Autoantigens; C421864:hen egg lysozyme; D009113:Muramidase