Abstract：
BACKGROUND: Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists.
METHODS: Two patients with inborn errors of immunity, X- linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T cell (NST) response, B cell reconstitution, and norovirus-specific antibody production. Samples were obtained in the peri-hematopoietic stem cell transplant setting (HSCT) before and after CNI clearance. The norovirus strain causing CNI was followed longitudinally for norovirus stool viral loads and sequencing.
RESULTS: The noroviruses were identified as GII.4 Sydney[P4 New Orleans] in one patient and GII.17[P17] in the other. An exacerbation of diarrhea post-HSCT in the patient with X-SCID was consistent with norovirus infection but not with graft-vs-host-disease on pathologic samples. Both patients recovered polyfunctional NSTs in the CD4 and CD8 T cell compartments which recognized multiple norovirus structural and non-structural viral antigens. T cell responses were minimal during active CNI but detectable after resolution. Mapping of norovirus-specific T cell responses between the patient with DOCK8 and his matched sibling donor were nearly identical. B cell reconstitution or new endogenous antibody production for IgA or IgG were not observed.
CONCLUSIONS: This report is the first to demonstrate reconstitution of norovirus-specific T cell immunity after HSCT closely temporally aligned with clearance of CNI suggesting that cellular immunity is sufficient for norovirus clearance.
METHODS: Two patients with inborn errors of immunity, X- linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T cell (NST) response, B cell reconstitution, and norovirus-specific antibody production. Samples were obtained in the peri-hematopoietic stem cell transplant setting (HSCT) before and after CNI clearance. The norovirus strain causing CNI was followed longitudinally for norovirus stool viral loads and sequencing.
RESULTS: The noroviruses were identified as GII.4 Sydney[P4 New Orleans] in one patient and GII.17[P17] in the other. An exacerbation of diarrhea post-HSCT in the patient with X-SCID was consistent with norovirus infection but not with graft-vs-host-disease on pathologic samples. Both patients recovered polyfunctional NSTs in the CD4 and CD8 T cell compartments which recognized multiple norovirus structural and non-structural viral antigens. T cell responses were minimal during active CNI but detectable after resolution. Mapping of norovirus-specific T cell responses between the patient with DOCK8 and his matched sibling donor were nearly identical. B cell reconstitution or new endogenous antibody production for IgA or IgG were not observed.
CONCLUSIONS: This report is the first to demonstrate reconstitution of norovirus-specific T cell immunity after HSCT closely temporally aligned with clearance of CNI suggesting that cellular immunity is sufficient for norovirus clearance.
摘要：
背景：慢性诺如病毒感染（CNI）在免疫受损患者中引起显著的发病率。目前尚无有效的预防或治疗方法。
方法：两名先天性免疫错误患者，X-连锁严重联合免疫缺陷（X-SCID）和DOCK8缺陷，纵向随访临床过程，免疫重建，诺如病毒特异性T细胞（NST）反应，B细胞重建,和诺如病毒特异性抗体的生产。在CNI清除之前和之后,在周围造血干细胞移植设置(HSCT)中获得样品。纵向跟踪引起CNI的诺如病毒株的诺如病毒粪便病毒载量和测序。
结果：诺如病毒在一名患者中被鉴定为GII.4悉尼[P4新奥尔良]，在另一名患者中被鉴定为GII.17[P17]。X-SCID患者HSCT后腹泻加重与诺如病毒感染一致，但与病理样本上的移植物抗宿主病无关。两名患者在CD4和CD8T细胞区室中恢复了识别多种诺如病毒结构和非结构病毒抗原的多功能NST。T细胞应答在活性CNI期间最小,但在解析后可检测到。患有DOCK8的患者与其匹配的同胞供体之间的诺如病毒特异性T细胞反应的图谱几乎相同。未观察到B细胞重建或IgA或IgG的新内源性抗体产生。
结论：本报告首次证明HSCT后诺如病毒特异性T细胞免疫的重建与CNI清除时间上密切相关，表明细胞免疫足以清除诺如病毒。
方法：两名先天性免疫错误患者，X-连锁严重联合免疫缺陷（X-SCID）和DOCK8缺陷，纵向随访临床过程，免疫重建，诺如病毒特异性T细胞（NST）反应，B细胞重建,和诺如病毒特异性抗体的生产。在CNI清除之前和之后,在周围造血干细胞移植设置(HSCT)中获得样品。纵向跟踪引起CNI的诺如病毒株的诺如病毒粪便病毒载量和测序。
结果：诺如病毒在一名患者中被鉴定为GII.4悉尼[P4新奥尔良]，在另一名患者中被鉴定为GII.17[P17]。X-SCID患者HSCT后腹泻加重与诺如病毒感染一致，但与病理样本上的移植物抗宿主病无关。两名患者在CD4和CD8T细胞区室中恢复了识别多种诺如病毒结构和非结构病毒抗原的多功能NST。T细胞应答在活性CNI期间最小,但在解析后可检测到。患有DOCK8的患者与其匹配的同胞供体之间的诺如病毒特异性T细胞反应的图谱几乎相同。未观察到B细胞重建或IgA或IgG的新内源性抗体产生。
结论：本报告首次证明HSCT后诺如病毒特异性T细胞免疫的重建与CNI清除时间上密切相关，表明细胞免疫足以清除诺如病毒。
