IMMUNE RESPONSE TO POLYSACCHARIDE AND CONJUGATE VACCINES

对多糖(PS)抗原的免疫反应是高度调节的 并且具有包括受限子类在内的几个区别特征， 可变区基因使用，良好的特异性和亲和力。简单PS备注 与蛋白质(如细菌Levan(BL)或奈瑟氏菌)结合 脑膜炎C组(MCPS)可引起胸腺非依赖性(TI)反应。 与蛋白质偶联的PS(例如与破伤风类毒素偶联的MCPS， (MCPS-TT))，另一方面，引起不同类型的反应， 称为胸腺依赖(TD)。最近的研究表明，单克隆 两次免疫小鼠产生的抗体(MAb) 多糖类抗原BL可表现出体细胞突变和亲和力 成熟，以前被认为只有 对TD抗原的反应。在BLmAb中，一个编码氨基酸的单一突变 CDR2中的53位氨基酸与抗体亲和力增强相关。正在进行中 研究涉及定点突变和链重组以 证明这个单一的位点可以改变抗体的亲和力 确定它是否有助于结合特异性。斑点印迹和Northern 对抗MCPS单抗的分析表明，VH基因家族用途占主导地位 VHJ558(最大的VH基因家族)。这些抗体不是从 从一个精选的生殖系基因。1705.18的VHJ558基因类似于 更接近的是，VHJ558属于抗右旋糖酐19.1.2组。 3006.18和C2/974.1与9.14.7组的抗-葡聚糖相似。这个 其他单抗可能代表第三组。其中四株单抗已测序 到目前为止属于Vk4/5系列，表示为VkOX1。这个基因家族是 用于响应半抗原2-苯基恶唑酮。的序列 1705.18单抗、1863.5单抗和2055.5单抗是密切相关的。1922.2株单抗 代表了同一家族的不同生殖系基因。很好 特异性和VH家族的使用似乎与 VH3609 mAbs例外，它专用于MCPS且仅被发现 以响应TI表格。这些抗体由VH3609.3编码 生殖系基因，几乎没有变化。一个Vk23基因已被发现 与VH3609结合，绑定MCPS。DNA序列数据表明 响应MCPS产生的几个基因也被利用 自身抗体。正在进行的序列分析将确定体细胞 突变可以解释多样性的增加和亲和力的增加 对MCPS-TT的免疫应答优于单独对MCPS的免疫应答。

The immune response to polysaccharide (PS) antigens is highly regulated and has several distinguishing features including restricted subclass, variable region gene usage, fine specificity, and avidity. Simple PS not conjugated to protein (such as bacterial levan (BL) or Neisseria meningitidis group C (MCPS)) elicit a thymus-independent (TI) response. PS conjugated to proteins (such as MCPS coupled to tetanus toxoid, (MCPS-TT)), on the other hand, elicit a different type of response, termed thymus-dependent (TD). Recent studies have shown that monoclonal antibodies (mAb) derived from mice immunized twice with a TI polysaccharide antigen, BL, can exhibit somatic mutations and affinity maturation, features previously thought to be properties only of responses to TD antigens. Among BL mAb, a single mutation encoding amino acid 53 in CDR2 correlated with increased antibody avidity. Ongoing studies involve site-directed mutagenesis and chain recombination to prove that this single site can alter the antibody avidity and to determine if it contributes to binding specificity. Dot blot and Northern analyses of anti-MCPS mAb reveal that VH gene family usage is dominated by VHJ558 (the largest VH gene family). These antibodies were not derived from a selected germ-line gene. The VHJ558 gene for 1705.18 resembles more closely the VHJ558 belonging to the anti-Dextran 19.1.2 group. 3006.18 and C2/974.1 resemble those anti-Dextran of group 9.14.7. The other mAb may represent a possible third group. Four of the mAb sequenced to date belong to the Vk4/5 family denoted VkOX1. This gene family is utilized in response to the hapten 2-phenyloxazolone. The sequences for the 1705.18, 1863.5 and 2055.5 mAbs are closely related. The 1922.2 mAb represents a different germ-line gene of the same family. Fine specificity and VH family usage do not seem to correlate with the exception of VH3609 mAbs which are specific for MCPS and are only found in response to the TI form. These antibodies are encoded by the VH3609.3 germline gene with very few changes. One Vk23 gene has been found to combine with VH3609 to bind MCPS. DNA sequence data indicated that several genes produced in response to MCPS are utilized also by auto-antibodies. Sequence analysis in progress will determine if somatic mutation can account for the increased diversity and increased avidity of the immune response to MCPS-TT over MCPS alone.