Leukocyte Signalling Laboratory, Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia.
Front Immunol. 2022 May 12;13:875359. doi: 10.3389/fimmu.2022.875359. eCollection 2022.
Systemic lupus erythematosus (SLE) is a complex, heterogeneous autoimmune disease. A common manifestation, lupus nephritis, arises from immune complex deposition in the kidney microvasculature promoting leukocyte activation and infiltration, which triggers glomerular damage and renal dysfunction. CD11b is a leukocyte integrin mainly expressed on myeloid cells, and aside from its well-ascribed roles in leukocyte trafficking and phagocytosis, it can also suppress cytokine production and autoreactivity. Genome-wide association studies have identified loss-of-function polymorphisms in the CD11b-encoding gene that are strongly associated with SLE and lupus nephritis; however, it is not known whether these polymorphisms act alone to induce disease or in concert with other risk alleles. Herein we show using mice that loss of CD11b led to mild inflammatory traits, which were insufficient to trigger autoimmunity or glomerulonephritis. However, deficiency of CD11b in autoimmune-prone Lyn-deficient mice ( ) accelerated lupus-like disease, driving early-onset immune cell dysregulation, autoantibody production and glomerulonephritis, impacting survival. Migration of leukocytes to the kidney in mice was unhindered by lack of CD11b. Indeed, kidney inflammatory macrophages were further enriched, neutrophil retention in glomerular capillaries was increased and kidney inflammatory cytokine responses were enhanced in mice. These findings indicate that is a non-monogenic autoimmune susceptibility gene, with loss of functional CD11b exacerbating disease without impeding glomerular leukocyte trafficking when in conjunction with other pre-disposing genetic mutations. This highlights a primarily protective role for CD11b in restraining inflammation and autoimmune disease and provides a potential therapeutic avenue for lupus treatment.
系统性红斑狼疮（SLE）是一种复杂的、异质性的自身免疫性疾病。狼疮肾炎是一种常见的表现，它源于免疫复合物在肾脏微血管中的沉积，促进白细胞的激活和浸润，从而引发肾小球损伤和肾功能障碍。CD11b 是一种主要表达于髓样细胞的白细胞整合素，除了在白细胞迁移和吞噬作用中具有良好的作用外，它还可以抑制细胞因子的产生和自身反应性。全基因组关联研究已经确定了编码 CD11b 的基因中的功能丧失多态性，这些多态性与 SLE 和狼疮肾炎强烈相关；然而，目前尚不清楚这些多态性是否单独作用于诱导疾病，还是与其他风险等位基因协同作用。本文中，我们使用 小鼠模型表明，CD11b 的缺失导致了轻微的炎症特征，这些特征不足以引发自身免疫或肾小球肾炎。然而，在自身免疫倾向的 Lyn 缺陷型小鼠（ ）中缺乏 CD11b 会加速狼疮样疾病的发展，导致早期免疫细胞失调、自身抗体产生和肾小球肾炎，并影响生存。缺乏 CD11b 的 小鼠的白细胞向肾脏的迁移不受阻碍。事实上，在 小鼠中，肾脏炎症性巨噬细胞进一步富集，肾小球毛细血管中中性粒细胞的滞留增加，肾脏炎症性细胞因子反应增强。这些发现表明， 是一种非单基因自身免疫易感性基因，缺失功能性 CD11b 会在与其他易感性基因突变结合时加重疾病，但不会阻碍肾小球白细胞的迁移。这突出表明 CD11b 主要通过抑制炎症和自身免疫性疾病发挥保护作用，并为狼疮治疗提供了一个潜在的治疗途径。
