A tolerogenic peptide down-regulates mature B cells in bone marrow of lupus-afflicted mice by inhibition of interleukin-7, leading to apoptosis.
Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by T and B cells. It is characterized by a variety of autoantibodies and systemic clinical manifestations. A tolerogenic peptide, designated hCDR1, ameliorated the serological and clinical manifestations of SLE in both spontaneous and induced models of lupus. In the present study, we evaluated the status of mature B cells in the bone marrow (BM) of SLE-afflicted mice, and determined the effect of treatment with the tolerogenic peptide hCDR1 on these cells. We demonstrate herein that mature B cells of the BM of SLE-afflicted (New Zealand Black x New Zealand White)F(1) mice were largely expanded, and that treatment with hCDR1 down-regulated this population. Moreover, treatment with hCDR1 inhibited the expression of the pathogenic cytokines [interferon-gamma and interleukin (IL)-10], whereas it up-regulated the expression of transforming growth factor-beta in the BM. Treatment with hCDR1 up-regulated the rates of apoptosis of mature B cells. The latter was associated with inhibited expression of the survival Bcl-xL gene and of IL-7 by BM cells. Furthermore, the addition of recombinant IL-7 abrogated the suppressive effects of hCDR1 on Bcl-xL in the BM cells and resulted in elevated levels of apoptosis. Hence, the down-regulated production of IL-7 contributes to the hCDR1-mediated apoptosis of mature B cells in the BM of SLE-afflicted mice.
Ben-David
Hava
H
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Sharabi
Amir
A
Parameswaran
Reshmi
R
Zinger
Heidy
H
Mozes
Edna
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015851:Interleukin-7 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D010446:Peptide Fragments / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology
D000911:Antibodies, Monoclonal; D015851:Interleukin-7; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; C516151:edratide; D007371:Interferon-gamma