Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Immunol Lett. 2011 Dec 30;141(1):134-9. doi: 10.1016/j.imlet.2011.09.004. Epub 2011 Sep 24.
Organ deposition of autoantibodies against the noncollagenous-1 domain of the α3 chain of type IV collagen leads to severe kidney and lung injury in anti-glomerular basement membrane disease. The origin and regulation of these highly pathogenic autoantibodies remains unknown. Anti-α3(IV) collagen B lymphocytes are predicted to mature in vivo ignorant of target antigen because α3(IV) collagen expression is highly tissue restricted and pathogenic epitopes are cryptic. However, a recent analysis of an anti-α3(IV)NC1 collagen autoantibody transgenic mouse model revealed that developing B cells are rapidly silenced by deletion and editing in the bone marrow. To dissect the role of collagen as central tolerogen in this model, we determined B cell fate in autoantibody transgenic mice genetically lacking α3(IV) collagen. We found that absence of the tissue target autoantigen has little impact on the fate of anti-α3(IV)NC1 B cells. This implies a more complex regulatory mechanism for preventing anti-glomerular basement membrane disease than has been previously considered, including the possibility that a second antigen present in bone marrow engages and tolerizes anti-α3(IV)NC1 collagen B cells.
自身抗体对Ⅳ型胶原α3 链非胶原-1 结构域的沉积导致抗肾小球基底膜病的严重肾和肺损伤。这些高致病性自身抗体的起源和调节仍不清楚。抗α3(IV)胶原 B 淋巴细胞预计在体内成熟时会忽略靶抗原，因为α3(IV)胶原的表达受到高度组织限制，且致病表位是隐蔽的。然而，最近对一种抗α3(IV)NC1 胶原自身抗体转基因小鼠模型的分析表明，在骨髓中，发育中的 B 细胞通过缺失和编辑而迅速沉默。为了解析该模型中胶原作为中枢耐受原的作用，我们在基因缺失α3(IV)胶原的自身抗体转基因小鼠中确定了 B 细胞的命运。我们发现，组织靶自身抗原的缺失对抗α3(IV)NC1 B 细胞的命运几乎没有影响。这意味着预防抗肾小球基底膜病的调控机制比以前认为的更复杂，包括在骨髓中存在第二种抗原与抗α3(IV)NC1 胶原 B 细胞结合并使其耐受的可能性。
