Issekutz Andrew C, Nakazato Satoru, Issekutz Thomas B
Departments of Pediatrics, Pathology and Microbiology-Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Immunol Cell Biol. 2003 Oct;81(5):397-408. doi: 10.1046/j.1440-1711.2003.01187.x.
The role of the integrins VLA-4 and LFA-1 and of the selectin adhesion molecules in autoimmune arthritis was investigated. Adjuvant arthritis was induced in Lewis rats by active immunization (s.c.) with Mycobacterium butyricum or by adoptive transfer of immune T cells. With active adjuvant arthritis, Lewis rats develop maximal polyarticular joint inflammation and migration of radiolabelled (111In and 51Cr) blood neutrophils and monocytes to the joints 14 days post Mycobacterium butyricum immunization. Using blocking monoclonal antibodies we osbserved that at this stage monocyte recruitment was dependent (85%) on P-selectin plus VLA-4 (alpha4B1) and neutrophil recruitment depended (> 80%) on P-selectin plus LFA-1 (CD11a/CD18). E-selectin played a minimal role in inflammatory cell recruitment to the already inflamed joint. In contrast, during the development of active adjuvant arthritis, blockade of P-selectin beginning at day 5 post-immunization had no effect on subsequent arthritis. However, E-selectin blockade at this stage reduced arthritic scores by 70% (P < 0.01) and combined E-selectin plus VLA-4 blockade prevented development of arthritis. Either treatment nearly abolished neutrophil and monocyte recruitment to joints at day 14 and prevented cartilage damage. VLA-4 blockade alone was less effective. Adoptive T-cell transfer of adjuvant arthritis to naive rats employed spleen/lymph node lymphocytes from Mycobacterium butyricum immunized rats stimulated with Concanavalin A in vitro (48 h). E-selectin +/- P-selectin blockade had no effect on the development of adoptive arthritis. However, VLA-4 integrin blockade inhibited adoptive arthritis severity by 55% (P < 0.01). LFA-1 blockade had no effect. In adoptive adjuvant arthritis, inhibition of arthritis clinically and by histology was essentially complete (> 90%) when E- and P-selectin blockade was combined with VLA-4 blockade. Thus, in the development of actively induced arthritis E-selectin plays an important role, likely mediating early antigen reactive T-cell recruitment to joints. In contrast, VLA-4 and multiple selectin mechanisms are involved in arthritis induction by ex vivo restimulated arthritogenic T cells. Furthermore, in actively induced adjuvant arthritis, P- and E-selectin and VLA-4 are differently important in the initiation of arthritis, and at the time of fully developed joint inflammation.
研究了整合素VLA - 4和LFA - 1以及选择素粘附分子在自身免疫性关节炎中的作用。通过用丁酸分枝杆菌进行主动免疫（皮下注射）或通过免疫T细胞的过继转移在Lewis大鼠中诱导佐剂性关节炎。在主动佐剂性关节炎中，Lewis大鼠在接种丁酸分枝杆菌14天后出现最大程度的多关节炎症，以及放射性标记（111In和51Cr）的血液中性粒细胞和单核细胞向关节的迁移。使用阻断单克隆抗体，我们观察到在这个阶段单核细胞募集（85%）依赖于P - 选择素加VLA - 4（α4β1），中性粒细胞募集（>80%）依赖于P - 选择素加LFA - 1（CD11a/CD18）。E - 选择素在炎症细胞募集到已经发炎的关节中起的作用最小。相比之下，在主动佐剂性关节炎的发展过程中，在免疫后第5天开始阻断P - 选择素对随后的关节炎没有影响。然而，在这个阶段阻断E - 选择素使关节炎评分降低了70%（P < 0.01），并且联合阻断E - 选择素和VLA - 4可预防关节炎的发展。两种治疗方法在第14天时几乎都消除了中性粒细胞和单核细胞向关节的募集，并预防了软骨损伤。单独阻断VLA - 4效果较差。将佐剂性关节炎过继转移给未免疫的大鼠，采用来自体外（48小时）用伴刀豆球蛋白A刺激的接种丁酸分枝杆菌的大鼠的脾/淋巴结淋巴细胞。阻断E - 选择素+/- P - 选择素对过继性关节炎的发展没有影响。然而，阻断VLA - 4整合素使过继性关节炎的严重程度降低了55%（P < 0.01）。阻断LFA - 1没有效果。在过继性佐剂性关节炎中，当联合阻断E - 选择素和P - 选择素与VLA - 4时，从临床和组织学上对关节炎的抑制基本完全（>90%）。因此，在主动诱导的关节炎发展过程中，E - 选择素起重要作用，可能介导早期抗原反应性T细胞向关节的募集。相比之下，VLA - 4和多种选择素机制参与了体外再刺激的致关节炎T细胞诱导的关节炎。此外，在主动诱导的佐剂性关节炎中，P - 选择素、E - 选择素和VLA - 4在关节炎的起始阶段以及在关节炎症充分发展时的重要性各不相同。
