查看“TNF超家族”的源代码

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            <strong>[[TNF超家族]]</strong>（<strong>[[TNF Superfamily]]</strong>，简称[[TNFSF]]）是一类在免疫调节、细胞生存、凋亡诱导及器官发育中发挥关键作用的[[细胞因子]]及其受体系统。该家族目前包含约19种配体（[[TNFSF]]）和29种受体（[[TNFRSF]]）。其成员如<strong>[[TNF-α]]</strong>、<strong>[[RANKL]]</strong>、<strong>[[CD40L]]</strong>和<strong>[[FasL]]</strong>，通过形成典型的[[三聚体]]结构激活下游信号通路。[[TNF超家族]]的信号转导平衡直接决定了免疫细胞的活化与程序性死亡，其异常表达与[[自身免疫性疾病]]、[[血液肿瘤]]及[[骨代谢疾病]]高度相关。作为现代生物医药的靶点富矿，针对该超家族的拮抗剂和激动剂已成为临床治疗的核心手段。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[TNF超家族]]</div>
            <div style="font-size: 0.75em; opacity: 0.85; margin-top: 4px;">[[TNFSF]] & [[TNFRSF]] · 点击展开</div>
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                    <div style="width: 140px; height: 90px; background-color: #f1f5f9; display: flex; align-items: center; justify-content: center; color: #94a3b8; font-size: 0.8em; padding: 10px; text-align: center;">[[TNF]]配体-受体复合物三聚体模型</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心结构：[[THD]]结构域</div>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 45%;">代表配体</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[TNF-α]]/[[RANKL]]/[[TRAIL]]</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">代表受体</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[TNFR1]]/[[CD40]]/[[DR5]]</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">下游信号</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[NF-κB]]/[[Caspase]]/[[MAPK]]</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">结构特征</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[II型跨膜蛋白]]</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">生物学功能</th>
                    <td style="padding: 8px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">凋亡诱导/淋巴发育</td>
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                    <th style="text-align: left; padding: 8px 12px; background-color: #f1f5f9; color: #475569;">相关药物</th>
                    <td style="padding: 12px; color: #0f172a;">[[阿达木单抗]]/[[地舒单抗]]</td>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">分子机制：信号转导的拓扑逻辑</h2>
    
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        [[TNF超家族]]的激活依赖于配体与受体间高度保守的物理交互：
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        <li style="margin-bottom: 12px;"><strong>三聚体化组装：</strong>绝大多数[[TNFSF]]配体以同源三聚体的形式存在。结合受体后，诱导受体胞内段聚集，形成信号传导支架。</li>
        <li style="margin-bottom: 12px;"><strong>双路分支决策：</strong>根据受体胞内段结构，信号分为两类：含有<strong>[[死亡结构域]]</strong>（[[DD]]）的受体（如[[Fas]]、[[TNFR1]]）直接启动[[Caspase-8]]介导的凋亡；不含[[DD]]的受体通过招募<strong>[[TRAF]]</strong>家族蛋白激活[[NF-κB]]或[[JNK]]通路，促进存活及炎症。</li>
        <li style="margin-bottom: 12px;"><strong>脱落与可溶化：</strong>膜结合型配体常被[[ADAM17]]（[[TACE]]）等蛋白酶切割成可溶形式，实现远端信号通讯或反馈调节。</li>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">核心成员分类与临床相关性矩阵</h2>

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                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 20%;">配体([[TNFSF]])</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">受体([[TNFRSF]])</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">生理/病理功能</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a;">代表性治疗药物</th>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[TNF-α]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[TNFR1]] / [[TNFR2]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">全身炎症应答、关节炎致病核心。</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[阿达木单抗]] / [[英夫利昔单抗]]</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[RANKL]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[RANK]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">破骨细胞分化、骨吸收调节。</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[地舒单抗]] (Denosumab)</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[CD40L]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[CD40]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">B细胞活化、生发中心形成、免疫协同。</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[CD40拮抗单抗]] (研发中)</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[BAFF]] / [[APRIL]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[TACI]] / [[BCMA]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">B细胞稳态、[[系统性红斑狼疮]]。</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[贝利尤单抗]] / [[泰它西普]]</td>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">诊疗策略：靶向抑制与协同活化</h2>
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        基于[[TNF超家族]]的干预策略涵盖了从免疫抑制到肿瘤免疫激活的广泛谱系：
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        <li style="margin-bottom: 12px;"><strong>拮抗策略：</strong>针对[[TNF-α]]、[[IL-17]](平行通路)或[[RANKL]]的单克隆抗体，是目前治疗[[类风湿关节炎]]和[[骨质疏松]]的金标准。</li>
        <li style="margin-bottom: 12px;"><strong>激动剂策略：</strong>利用[[OX40L]]、[[4-1BBL]]等共刺激分子开发激动型单抗（[[Agonistic mAb]]），旨在增强[[效应T细胞]]的抗肿瘤活性。</li>
        <li style="margin-bottom: 12px;"><strong>双特异性抗体演进：</strong>通过[[BsAb]]同时靶向[[TNF]]家族成员与其他检查点（如[[PD-L1]]），以期克服单一抑制的反馈性耐药。</li>
        <li style="margin-bottom: 12px;"><strong>安全性监测：</strong>长期抑制[[TNF]]信号需严密监测[[潜伏结核再激活]]及[[继发感染]]风险。</li>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">关键相关概念</h2>
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            <li style="margin-bottom: 8px;"><strong>[[死亡受体]] (Death Receptor)：</strong>[[TNF]]受体家族中含有[[死亡结构域]]的子集，主导细胞凋亡。</li>
            <li style="margin-bottom: 8px;"><strong>[[TRAF]]：</strong>TNF受体相关因子，是连接受体与胞内激酶网络的关键适配蛋白。</li>
            <li style="margin-bottom: 8px;"><strong>[[THD结构域]]：</strong>TNF同源结构域，决定了配体三聚化及其与受体结合的特异性。</li>
            <li style="margin-bottom: 8px;"><strong>[[免疫关卡协同]]：</strong>[[TNF]]超家族成员常作为[[B细胞]]和[[T细胞]]活化的第二信号。</li>
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        <span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献与权威点评</span>
        
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            [1] <strong>Aggarwal BB. (2003).</strong> <em>Signalling pathways of the TNF superfamily: a double-edged sword.</em> <strong>[[Nature Reviews Immunology]]</strong>. 3(9):745-56.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：该研究奠定了理解TNF家族在炎症与死亡平衡间调节的基础框架。</span>
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            [2] <strong>Locksley RM, et al. (2001).</strong> <em>The TNF and TNF receptor superfamilies: integrating mammalian biology.</em> <strong>[[Cell]]</strong>. 104(4):487-501.<br>
            <span style="color: #475569;">[核心价值]：系统性归纳了TNF家族在哺乳动物发育及免疫系统整合中的宏观角色。</span>
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            [[TNF超家族]] 生物网络 · 知识图谱
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">关联因子</td>
                <td style="padding: 10px 15px; color: #334155;">[[NF-κB]]•[[Caspase-3]]•[[TRAF2/6]]•[[ADAM17]]•[[MAPK]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">临床药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[阿达木单抗]]•[[地舒单抗]]•[[依那西普]]•[[贝利尤单抗]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">研究前沿</td>
                <td style="padding: 10px 15px; color: #334155;">[[TNFR2激动剂增强Treg功能]]•[[4-1BB/PD-L1双抗]]•[[BCMA靶向CAR-T]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">病理相关</td>
                <td style="padding: 10px 15px; color: #334155;">[[类风湿关节炎]]•[[多发性骨髓瘤]]•[[骨质疏松]]•[[克罗恩病]]</td>
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