Circulating and intrahepatic antiviral B cells are defective in hepatitis B.
Circulating and intrahepatic antiviral B cells are defective in hepatitis B.
复制标题
DOI：
10.1172/jci121960
复制
发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Maini MK
中科院分区：
文献类型：
--
作者：
Burton AR;Pallett LJ;McCoy LE;Suveizdyte K;Amin OE;Swadling L;Alberts E;Davidson BR;Kennedy PT;Gill US;Mauri C;Blair PA;Pelletier N;Maini MK
B细胞越来越多地被认为在持续控制B型肝炎病毒（HBV）中发挥重要作用。抗病毒表面抗原（HBV表面抗原[HBVAgs]）抗体的开发构成了急性感染消退的标志，也是慢性HBV（CHB）功能性治愈的治疗目标。我们的特点是B细胞直接离体从血液和肝脏的CH B患者调查其抗病毒潜力的限制。出乎意料的是，我们发现，在许多慢性乙型肝炎B患者的血液和肝脏中，抗病毒抗原特异性B细胞持续存在，并且富含T-bet，这是B细胞中抗病毒潜力的标志。然而，从CH B患者中纯化的、分化的HBsAg特异性B细胞具有缺陷的抗体产生，与体内检测不到的抗-HBs抗体一致。HBsAg特异性和全局B细胞具有高表达抑制性受体（包括PD-1）的CD 21-CD 27-非典型记忆B细胞（atMBC）蓄积。这些atMBC表现出改变的信号传导、归巢、分化为抗体产生细胞、存活和抗病毒/促炎细胞因子产生，这些可以通过PD-1阻断部分挽救。对健康和HBV感染肝脏内B细胞的分析表明，这种致耐受性小生境和HBV感染的组合驱动PD-1 hiatMBC并损害B细胞免疫。
B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface antigen [HBsAgs]) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21–CD27– atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1hiatMBC and impairing B cell immunity.