Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), Technical University Munich, Munich, Germany.
Institute of Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.
Parasitol Res. 2019 Oct;118(10):2957-2968. doi: 10.1007/s00436-019-06451-2. Epub 2019 Sep 4.
A striking feature of lymphatic filariasis (LF) is the clinical heterogeneity among exposed individuals. While endemic normals (EN) remain free of infection despite constant exposure to the infective larvae, a small group of patients, generally microfilaria free (Mf-) develops severe pathology (CP) such as lymphedema or hydrocele. Another group of infected individuals remains asymptomatic while expressing large amounts of microfilariae (Mf+). This Mf+ group is characterized by an immune-suppressed profile with high levels of anti-inflammatory cytokines and elevated IgG4. This particular immunoglobulin is unable to activate the complement. The complement system plays a critical role in both innate and adaptive immunity. However, its importance and regulation during LF is not fully understood. Using affinity chromatography and solid-phase-enzyme-immunoassays, we investigated the ability of antibody isotypes from LF clinical groups to bind C1q, the first element of the complement's classical pathway. The results indicate that while C1q is similarly expressed in all LF clinical groups, IgG1-2 in the plasma from Mf+ individuals presented significantly lower affinity to C1q compared to EN, Mf-, and CP. In addition, selective depletion of IgG4 significantly enhanced the affinity of IgG1-2 to C1q in Mf+ individuals. Strikingly, no effect was seen on the ability of IgG3 to bind C1q in the same conditions. More interestingly, papain-generated IgG4-Fc-portions interacted with Fc portions of IgG1-2 as revealed by far-western blot analysis. These data suggest that while being unable to bind C1q, IgG4 inhibits the first steps of the complement classical pathway by IgG1 or IgG2 via Fc-Fc interactions.
淋巴丝虫病（LF）的一个显著特征是暴露个体之间的临床异质性。尽管地方性正常人（EN）持续接触感染性幼虫，但仍未感染，而一小部分患者通常无微丝蚴（Mf-）发展为严重病理（CP），如淋巴水肿或鞘膜积液。另一组受感染的个体无症状，但表达大量微丝蚴（Mf+）。该 Mf+组的特征是免疫抑制状态，具有高水平的抗炎细胞因子和升高的 IgG4。这种特殊的免疫球蛋白无法激活补体。补体系统在先天和适应性免疫中都起着关键作用。然而，其在 LF 中的重要性和调节作用尚不完全清楚。我们使用亲和层析和固相酶免疫测定法，研究了 LF 临床组的抗体同种型结合 C1q 的能力，C1q 是补体经典途径的第一个成分。结果表明，尽管所有 LF 临床组中 C1q 的表达相似，但 Mf+个体血浆中的 IgG1-2 与 EN、Mf-和 CP 相比，与 C1q 的亲和力显著降低。此外，选择性耗尽 IgG4 可显著增强 Mf+个体中 IgG1-2 与 C1q 的亲和力。引人注目的是，在相同条件下，IgG3 结合 C1q 的能力没有受到影响。更有趣的是，木瓜蛋白酶生成的 IgG4-Fc 部分与 IgG1-2 的 Fc 部分相互作用，如远西方印迹分析所示。这些数据表明，虽然无法结合 C1q，但 IgG4 通过 Fc-Fc 相互作用抑制了 IgG1 或 IgG2 的补体经典途径的最初步骤。
