Damgaard C, Reinholdt J, Palarasah Y, Enevold C, Nielsen C, Brimnes M K, Holmstrup P, Nielsen C H
Section for Periodontology, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
J Periodontal Res. 2017 Jun;52(3):485-496. doi: 10.1111/jre.12414. Epub 2016 Sep 24.
The periodontal pathogen Aggregatibacter actinomycetemcomitans has been proposed as pro-atherogenic, and complement-mediated adherence to red blood cells (RBCs) may facilitate its systemic spread. We investigated the ability of four strains of A. actinomycetemcomitans with differential expression of leukotoxin A (LtxA) and fimbriae to activate complement, adhere to RBCs and elicit cytokine responses by mononuclear cells (MNCs).
Aggregatibacter actinomycetemcomitans serotype b strains HK 921, HK 1651, HK 2092 and HK 2108 were fluorescence-labeled, incubated with human whole blood cells in the presence of autologous serum, and assessed for RBC adherence by flow cytometry and for capacity to induce cytokine production by cytometric bead array analysis. The levels of IgG to A. actinomycetemcomitans serotype b were quantified by ELISA, as was consumption of complement.
The JP2 clone variants HK 1651 and, to a lesser extent, HK 2092, consumed complement efficiently, while HK 2108 (= strain Y4) consumed complement poorly. Nonetheless, the four tested strains adhered equally well to RBCs in the presence of autologous serum, without causing RBC lysis. The JP2 clone variant HK 2092, selectively lacking LtxA production, induced higher production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10 by MNCs than did the other three strains, while the four strains induced similar production of IL-12p70. RBCs facilitated the HK 2092-induced production of TNF-α and IL-1β, and IL-6 was enhanced by RBCs, and this facilitation could be counteracted by blockade of complement receptor 3 (CD11b/CD18).
Our data suggest that the JP2 clone of A. actinomycetemcomitans, most closely resembled by the variant HK 1651, activates complement well, while strain Y4, represented by HK 2108, activates complement poorly. However, all strains of A. actinomycetemcomitans adhere to RBCs and, when capable of producing LtxA, prevent production of inflammatory cytokines by MNCs. This "immunologically silent" immune adherence may facilitate systemic spread and atherogenesis.
牙周病原体伴放线聚集杆菌被认为具有促动脉粥样硬化作用，补体介导的对红细胞（RBC）的黏附可能促进其在体内的传播。我们研究了四株伴放线聚集杆菌，它们的白细胞毒素A（LtxA）和菌毛表达存在差异，检测其激活补体、黏附红细胞以及引发单核细胞（MNC）细胞因子反应的能力。
将伴放线聚集杆菌b血清型菌株HK 921、HK 1651、HK 2092和HK 2108进行荧光标记，在自体血清存在的情况下与人全血细胞共同孵育，通过流式细胞术评估红细胞黏附情况，并通过细胞计数珠阵列分析评估诱导细胞因子产生的能力。采用酶联免疫吸附测定（ELISA）法定量检测抗伴放线聚集杆菌b血清型的IgG水平以及补体消耗情况。
JP2克隆变体HK 1651以及程度稍轻的HK 2092能有效消耗补体，而HK 2108（= Y4菌株）消耗补体的能力较差。尽管如此，在自体血清存在的情况下，四株受试菌株对红细胞的黏附能力相同，且不会导致红细胞裂解。选择性缺乏LtxA产生的JP2克隆变体HK 2092，相较于其他三株菌株，能诱导MNC产生更高水平的肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、IL-6和IL-10，而四株菌株诱导产生的IL-12p70水平相似。红细胞促进了HK 2092诱导的TNF-α和IL-1β的产生，且红细胞增强了IL-6的产生，这种促进作用可通过阻断补体受体3（CD11b/CD18）来抵消。
我们的数据表明，最接近HK 1651变体的伴放线聚集杆菌JP2克隆能很好地激活补体，而以HK 2108为代表的Y4菌株激活补体的能力较差。然而，所有伴放线聚集杆菌菌株均能黏附红细胞，并且当能够产生LtxA时，可阻止MNC产生炎性细胞因子。这种“免疫沉默”的免疫黏附可能促进其在体内的传播以及动脉粥样硬化的发生。
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