Deletion of the dominant autoantigen in NZB mice with autoimmune hemolytic anemia: effects on autoantibody and T-helper responses.
The mechanisms underlying apparently spontaneous autoimmune diseases, such as autoimmune hemolytic anemia (AIHA) in New Zealand Black (NZB) mice, are unknown. Here, we determine the contribution of the dominant red blood cell (RBC) autoantigen, the anion exchanger protein Band 3, to the development of NZB autoimmune responses. The approach was to prevent Band 3 expression in NZB mice by disrupting the AE1 gene. AE1(-/-) NZB mice produced RBC autoantibodies at the same levels as the wild-type strain, but they differed in recognizing antigens that correspond to glycophorins, rather than Band 3. Splenic T-helper (Th) cells from wild-type NZB mice proliferated strongly against multiple Band 3 peptides, particularly the dominant epitope within aa861-874. This helper response was severely attenuated in AE1(-/-) animals, leaving only weak proliferation to peptide aa861-874. The results demonstrate that the defect in self-tolerance in NZB AIHA is directed to the RBC type, and is not specific for, or dependent on, Band 3. However, the predisposition to RBC autoimmunity may be focused onto Band 3 by weak Th cell cross-reactivity between the helper dominant epitope and an exogenous antigen. The redundancy of the major autoantigen illustrates the requirement for specific therapy to induce dominant forms of tolerance, such as T-cell regulation.
Hall
Andrew M
AM
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK.
Ward
Frank J
FJ
Shen
Chia-Rui
CR
Rowe
Cliff
C
Bowie
Laura
L
Devine
Anne
A
Urbaniak
Stanislaw J
SJ
Elson
Christopher J
CJ
Barker
Robert N
RN
D000744:Anemia, Hemolytic, Autoimmune / Q000276:immunology*; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000172:deficiency / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens; D049109:Cell Proliferation; D003429:Cross Reactions / Q000276:immunology; D004913:Erythrocytes, Abnormal / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D017634:Self Tolerance / Q000276:immunology; D013154:Spleen / Q000166:cytology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*