Increased formation of anti-insulin B cells combines with defective central and peripheral tolerance checkpoints to contribute to type 1 diabetes liability in NOD mice (143.5)
| Autor: | Rachel Henry, Peggy Kendall, James Thomas |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 184:143.5-143.5 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.184.supp.143.5 |
| Popis: | Insulin-reactive autoantibodies precede disease development in type 1 diabetes (T1D)-prone non-obese diabetic (NOD) mice and humans, consistent with a breakdown in B cell tolerance for this key T1D autoantigen. Accelerated disease occurs in B cell receptor (BCR) transgenic NOD mice which have a small population of anti-insulin B cells. Absence of this specificity in closely related BCR transgene results in disease protection, highlighting the importance of B cell specificity for insulin in promoting disease. The genesis and maturation of anti-insulin B lymphocytes were investigated in NOD mice to identify alterations in tolerance checkpoints which underlie T1D progression. In NOD mice, polymorphic anti-insulin germline Vκ genes promote increased formation of anti-insulin B cells in the bone marrow. In contrast to non-autoimmune mice, failure to cull anti-insulin B cells in NOD mice though receptor editing or deletion in the bone marrow as well as at transitional checkpoints in the periphery permits entry of anti-insulin B cells into T1, follicular, and marginal zone B cell compartments. Entry occurs despite the presence of a large competing repertoire. These findings highlight how multiple points at which B cell tolerance is compromised in NOD mice combine to increase risk of T1D. A broad therapeutic window therefore exists during B cell development, within which successful tolerance restoration could provide effective disease intervention. |
| Databáze: | OpenAIRE |
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