MUCOSAL IMMUNITY IN GONOCOCCAL INFECTION

描述(改编自申请者摘要)：淋病奈瑟菌， 淋病唯一的人类病原体，是淋病的病原体 产生一种特异性地裂解人类免疫球蛋白的IgA1蛋白酶 在其铰链区的亚类1产生片段Fab和Fc。 因为密切相关的非致病性NeisSeries物种不会产生 这种酶，它可能是一种毒力因子，但它在发病机制中的作用 没有像许多其他淋球菌那样被广泛研究 毒力因素。这一提议解决了这样一个假设，即IgA1 蛋白水解酶在淋球菌感染发病机制中的作用 通过干扰特异性IgA1抗体的保护功能 粘膜表面和颠覆这些对病原体的反应 自身对宿主免疫防御的保护。一个关键的方面 对这一假说的检验是对 生殖道中的粘膜抗体对感染的反应。这个 蛋白水解酶敏感的IgA1和抗蛋白水解酶的相对比例 针对淋球菌表面的抗体的IgA2亚类 生殖器分泌物和血清中的抗原将在 自然感染淋病奈瑟氏菌的个人 他们的临床症状(无症状感染与有症状感染 男性；女性宫颈与上生殖道感染)。 答复也将根据次要问题进行评估 40%-50%的女性直肠受累，以测试 假设这种感染途径会导致另一种 粘膜免疫系统的刺激，可以增强生殖器的免疫力。 粘膜抗体反应的传播通过常见的 粘膜免疫系统将根据循环中的IgA进行评估 抗体分泌细胞与成人免疫球蛋白A抗体的形成 远程分泌物，如唾液。淋球菌IgA1与人类免疫球蛋白的关系 特定临床症状的蛋白水解酶将通过相关性进行评估 临床表现为IgA1蛋白水解酶或其典型的 生殖器分泌物中的卵裂产物，存在和水平 分泌物和分泌物中抗淋球菌IgA1蛋白酶的抑制性抗体 血清，并与淋球菌表面抗原的IgA1抗体 分泌物和血清。调查潜在的机制，通过 淋球菌IgA1蛋白酶可能作为毒力因子，其作用 淋球菌抗原IgA1抗体Fab片段的粘附性 淋球菌对培养的人上皮细胞的吞噬作用 人类中性粒细胞感染的淋球菌，将在没有或 存在相同或不同同种类型的抗体。此外， Ig A1 Fc片段对细胞代谢活化的影响 中性粒细胞将会被检测出来。如果假设淋球菌IgA1 蛋白酶对毒力的贡献是持续的，那么它可能是 被认为是潜在的疫苗成分和化疗药物 可能会设计出抑制其活性的措施。

DESCRIPTION (Adapted from applicant's abstract): Neisseria gonorrhoea, the exclusively human pathogen that is the causative agent of gonorrhea produces an IgA1 protease that specifically cleaves human immunoglobulin A subclass 1 at its hinge region to yield the fragments Fab and Fc. Because closely related non-pathogenic Neisserial species do not produce this enzyme, it may be a virulence factor, but its role in pathogenesis has not been as extensively explored as numerous other gonococcal virulence factors. This proposal addresses the hypothesis that IgA1 protease contributes to the pathogenesis of human gonococcal infection by interfering with protective function of specific IgA1 antibodies at the mucosal surface and subverting these responses for the pathogen's own protection against the host's immune defenses. A critical aspect of testing this hypothesis is an evaluation of the development of the mucosal antibodies in the genital tract in response to infection. The relative proportions of protease-susceptible IgA1 and protease-resistant IgA2 subclasses of antibodies that are directed at gonococcal surface antigens in genital secretions and serum will be evaluated in individuals who are naturally infected with N. gonorrhoea, in relation to their clinical syndrome (nonsymptomatic vs. symptomatic infection in males; cervical vs. upper genital tract infection in females). Responses will, also, be evaluated in relation to the secondary involvement of the rectum that occurs in 40-50 percent of women, to test the hypothesis that this route of infection results in an additional stimulus of the mucosal immune system that may augment genital immunity. The dissemination of mucosal antibody responses through the common mucosal immune system will be evaluated in terms of circulating IgA antibody-secreting cells and the development of IgA antibodies in a remote secretion such as saliva. The relationship of gonococcal IgA1 protease to specific clinical syndromes will be assessed by correlation of clinical syndrome with the presence of IgA1 protease or its typical cleavage products in genital secretions, with the presence and level of inhibitory antibodies to gonococcal IgA1 protease in secretions and sera, and with IgA1 antibodies to gonococcal surface antigens in secretions and sera. To investigate potential mechanisms by which gonococcal IgA1 protease might act as a virulence factor, the effect of Fab fragments of IgA1 antibodies to gonococcal antigens on adherence of gonococci to cultured human epithelial cells, and on phagocytosis of gonococci by human neutrophils, will be determined in the absence or presence of antibodies of the same or different isotype. Furthermore, the effect of Fc fragments of IgA1 on the metabolic activation of neutrophils will be determined. If the hypothesis that gonococcal IgA1 protease contributes to virulence is sustained, then it might be considered as a potential vaccine component, and chemotherapeutic measures might be devised to inhibit its activity.