免疫重建不良和 T 细胞库紊乱可能与复发内脏利什曼病合并艾滋病患者的胸腺输出受损有关。
Impaired Thymic Output Can Be Related to the Low Immune Reconstitution and T Cell Repertoire Disturbances in Relapsing Visceral Leishmaniasis Associated HIV/AIDS Patients.
机构信息
Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.
Núcleo de Ciências Biomédicas Aplicadas, Instituto Federal de Educação, Ciência e Tecnologia Do Rio de Janeiro (IFRJ), Rio de Janeiro, Brazil.
出版信息
Front Immunol. 2020 May 20;11:953. doi: 10.3389/fimmu.2020.00953. eCollection 2020.
Visceral leishmaniasis/HIV-co-infected patients (VL/HIV) accounts for around 8% of VL reported cases in Brazil. Relapses of infection after anti-leishmanial treatment constitute a great challenge in the clinical practice because of the disease severity and drug resistance. We have shown that non-relapsing-VL/HIV (NR-) evolved with increase of CD4 T-cell counts and reduction of activated CD4 and CD8 T cells after anti-leishmanial treatment. This immune profile was not observed in relapsing-VL/HIV patients (R-), indicating a more severe immunological compromising degree. Elevated activation status may be related to a deficient immune reconstitution and could help to explain the frequent relapses in VL/HIV co-infection. Our aim was to evaluate if this gain of T cells was related to changes in the peripheral TCRVβ repertoire and inflammatory status, as well as the possible thymus involvement in the replenishment of these newly formed T lymphocytes. VL/HIV patients, grouped into non-relapsing (NR- = 6) and relapsing (R- = 12) were evaluated from the active phase up to 12 months post-treatment (mpt). HIV-infected patients (non-VL) and healthy subjects (HS) were included. The TCRVβ repertoire was evaluated by flow cytometry, whereas the plasmatic cytokine levels were assessed by Luminex assay. To evaluate the thymic output, DNA was extracted from PBMCs for TCR rearrangement excision circles (TREC) quantification by qPCR. VL/HIV cases presented an altered mobilization profile (expansions or retractions) of the TCRVβ families when compared to HS independent of the follow-up phase ( < 0.05). TCRVβ repertoire on CD4 T-cells was more homogeneous in the NR-VL/HIV cases, but heterogeneous on CD8 T-cells, since different Vβ-families were mobilized. NR-VL/HIV had the inflammatory pattern reduced after 6 mpt. Importantly, VL/HIV patients showed number of TREC copies lower than controls during all follow-up. An increase of recent thymic emigrants was observed in NR-VL/HIV individuals at 10 mpt compared to R- patients ( < 0.01), who maintained lower TREC contents than the HIV controls. VL/HIV patients that maintain the thymic function, thus generating new T-cells, seem able to replenish the T lymphocyte compartment with effector cells, then enabling parasite control.
内脏利什曼病/艾滋病毒合并感染患者(VL/HIV)约占巴西报告的利什曼病病例的 8%。抗利什曼病治疗后感染复发是临床实践中的一大挑战,因为疾病的严重程度和耐药性。我们已经表明,非复发内脏利什曼病/艾滋病毒(NR-)患者在抗利什曼病治疗后,随着 CD4 T 细胞计数的增加和激活的 CD4 和 CD8 T 细胞的减少而演变。这种免疫特征在复发内脏利什曼病/艾滋病毒患者(R-)中没有观察到,表明免疫受损程度更严重。激活状态的升高可能与免疫重建不足有关,并有助于解释 VL/HIV 合并感染中经常复发的原因。我们的目的是评估这种 T 细胞的增加是否与外周 TCRVβ 库的变化和炎症状态有关,以及胸腺是否可能参与这些新形成的 T 淋巴细胞的补充。 将 VL/HIV 患者分为非复发(NR-=6)和复发(R-=12)两组,从活动期评估至治疗后 12 个月(mpt)。包括 HIV 感染患者(非 VL)和健康受试者(HS)。通过流式细胞术评估 TCRVβ 库,通过 Luminex 测定法评估血浆细胞因子水平。为了评估胸腺输出,从 PBMC 中提取 DNA,通过 qPCR 定量 TCR 重排切除环(TREC)。 与 HS 相比,VL/HIV 病例在随访阶段(<0.05)中,TCRVβ 家族的动员模式(扩张或收缩)发生改变。NR-VL/HIV 患者的 CD4 T 细胞 TCRVβ 库更均匀,但 CD8 T 细胞不均匀,因为动员了不同的 Vβ 家族。NR-VL/HIV 在 6 mpt 后炎症模式减少。重要的是,VL/HIV 患者在整个随访期间的 TREC 拷贝数均低于对照组。NR-VL/HIV 患者在 10 mpt 时观察到新的胸腺迁出细胞增加,与 R-患者相比(<0.01),后者的 TREC 含量低于 HIV 对照组。 维持胸腺功能的 VL/HIV 患者,因此生成新的 T 细胞,似乎能够用效应细胞补充 T 淋巴细胞池,从而控制寄生虫。