Unité d'immuno-hématologie pédiatrique, Hôpital Necker-Enfant Malades, Assistance Publique des Hôpitaux de Paris, Paris, France; Développement normal et pathologique du système immunitaire, Unité INSERM U768, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France;
Cytokines, hématopoïèse et réponses immunes, CNRS-UMR 8147, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France; Service d'anatomopathologie, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
Blood. 2014 Sep 4;124(10):1597-609. doi: 10.1182/blood-2014-02-553834. Epub 2014 Jun 26.
Autoimmune lymphoproliferative syndrome (ALPS) caused by impaired FAS-mediated apoptosis of lymphocytes is characterized by lymphoproliferation, autoimmunity, but also an increased risk of invasive bacterial infection, notably following splenectomy. We surveyed a cohort of 100 ALPS patients (including 33 splenectomized) and found that 12 (10 splenectomized) had experienced 23 invasive bacterial infections mainly caused by Streptococcus pneumoniae. This vulnerability was associated with evidence of defective B-cell function characterized by low serum immunoglobulin (Ig) M, low IgM antibody production in response to S pneumoniae following nonconjugated immunization, and low blood memory B-cells counts (including marginal zone [MZ] B-cell counts). This immunodeficiency strongly correlated with intensity of lymphoproliferation. Spleen sections from 9 ALPS patients revealed double-negative T-cell (DN-T) infiltration of the MZ, which was depleted of B cells. MZ in ALPS patients contained an abnormally thick layer of MAdCAM-1((+)) stromal cells and an excess of DN-Ts. DN-Ts were shown to express MAdCAM-1 ligand, the α4β7 integrin. These observations suggest that accumulating DN-Ts are trapped within stromal cell meshwork and interfere with correct localization of MZ B cells. Similar observations were made in spleens of fas-deficient mice. Our data revealed an unexpected mechanism by which ALPS results in anti-polysaccharide IgM antibody production-specific defect. Splenectomy should be avoided.
自身免疫性淋巴细胞增生综合征（ALPS）是由淋巴细胞 Fas 介导的凋亡受损引起的，其特征是淋巴细胞增生、自身免疫，但也增加了侵袭性细菌感染的风险，尤其是在脾切除术后。我们调查了 100 名 ALPS 患者（包括 33 名脾切除患者）的队列，发现有 12 名（10 名脾切除患者）经历了 23 次侵袭性细菌感染，主要由肺炎链球菌引起。这种易感性与 B 细胞功能缺陷有关，表现为血清免疫球蛋白（Ig）M 水平低、非结合免疫接种后对肺炎链球菌的 IgM 抗体产生减少以及血记忆 B 细胞计数（包括边缘区[MZ]B 细胞计数）低。这种免疫缺陷与淋巴细胞增生的强度密切相关。9 名 ALPS 患者的脾切片显示 MZ 中有双阴性 T 细胞（DN-T）浸润，B 细胞耗竭。ALPS 患者的 MZ 中含有异常厚的 MAdCAM-1（+）基质细胞层和过多的 DN-T。DN-T 表达 MAdCAM-1 配体，即α4β7 整合素。这些观察结果表明，积聚的 DN-T 被困在基质细胞网中，干扰了 MZ B 细胞的正确定位。在 fas 缺陷小鼠的脾脏中也观察到了类似的观察结果。我们的数据揭示了一种意想不到的机制，即 ALPS 导致针对多糖 IgM 抗体产生的特异性缺陷。应避免脾切除术。
