IMMUNE RESPONSE TO POLYSACCHARIDE AND CONJUGATE VACCINES

对多糖（PS）抗原的免疫应答是高度调节的 并且具有几个区别特征，包括受限子类， 可变区基因的使用、良好的特异性和亲合力。 简单PS注释 与蛋白质（例如细菌莱万（BL）或奈瑟氏球菌）缀合 C组脑膜炎（MCPS））引起胸腺非依赖性（TI）应答。 与蛋白质偶联的PS（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， 称为胸腺依赖性（TD）。最近的研究表明，单克隆 来源于用TI免疫两次的小鼠的抗体（mAb） 多糖抗原BL可以表现出体细胞突变和亲和力， 成熟，以前被认为是属性的功能，只有 对TD抗原的反应。 在BL mAb中，编码氨基酸的单个突变 CDR 2中的酸53与抗体亲和力的增加相关。正在进行 研究涉及定点诱变和链重组， 证明这个单一位点可以改变抗体的亲合力， 确定其是否有助于结合特异性。斑点杂交和北方 抗MCPS单克隆抗体的分析显示VH基因家族的使用占主导地位 VHJ 558（最大的VH基因家族）。这些抗体不是来自 从一个选定的生殖系基因。1705.18的VHJ 558基因类似于 更接近地，VHJ 558属于抗葡聚糖19.1.2组。 3006.18和C2/974.1与第9.14.7组的抗葡聚糖类似。的 其它mAb可能代表第三组。对其中四种mAb进行测序 迄今为止属于Vk 4/5家族，表示为VkOX 1。这个基因家族在 用于响应半抗原2-苯基恶唑酮。序列为 1705.18、1863.5和2055.5 mAb密切相关。1922.2 mAb 代表同一家族的不同种系基因。罚款 特异性和VH家族的使用似乎与 VH 3609 mAb除外，其对MCPS具有特异性，仅在 在TI表格中。这些抗体由VH3609.3编码。 几乎没有变化的生殖系基因。已经发现一个Vk 23基因 联合收割机与VH 3609结合MCPS。 DNA序列数据表明， 还利用了响应于MCPS产生的几种基因， 自身抗体正在进行的序列分析将确定 突变可以解释增加的多样性和增加的亲合力 对MCPS-TT的免疫应答超过单独的MCPS。

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.