Dysregulation of IgA responses in HIV-1-infected individuals

描述(申请人提供)：在世界范围内，大多数HIV-1感染是通过生殖器和肠道的粘膜表面传播的。重要的是，最早和最戏剧性的免疫学改变发生在肠粘膜，黏膜表面的机会性感染在未经治疗的患者中会导致相当大的发病率。因此，HIV-1感染可能主要被视为一种粘膜疾病。黏膜防御机制的核心成分是IgA，它是一种主要的免疫球蛋白亚型，负责防御粘膜病原体，并调节对常见微生物区系和环境抗原的免疫反应。由于CD4+T细胞在调节免疫球蛋白A的类别转换、体细胞超突变和跨上皮运输中起着关键作用，它们从粘膜组织，特别是肠粘膜中的大量消耗，可能会导致抗原特异性的免疫球蛋白A的产生和分泌受到严重干扰。虽然HIV-1感染者对各种病原体的免疫球蛋白反应的缺陷已经被很好地记录下来，但对免疫球蛋白A的反应还没有得到严格的调查。我们和其他人最近获得的数据表明，HIV-1感染者的抗原特异性IgA反应严重受损。了解这一缺陷的机制对于了解HIV-1的发病机制以及设计针对HIV-1和其他粘膜病原体的疫苗至关重要。 我们假设：(1)HIV-1感染与IgA反应的严重抑制有关，而IgA无应答的水平与粘膜组织中CD4+T细胞的耗竭水平和产生IgA的B细胞的多克隆激活水平成正比；以及(2)无法安装特定的IgA反应导致粘膜屏障受损，环境抗原对全身隔室的吸收增加，从而导致HIV-1感染特有的T细胞的慢性激活。这些假说将在三个特定目的进行检验：1)确定HIV-1感染是否扰乱了黏膜和系统对常见微生物和食物抗原的IgA反应；2)确定HIV-1感染是否导致用以前遇到的抗原进行粘膜和系统免疫后lgA1和lgA2反应的损害；以及3)确定HIV-1感染是否取消了对新遇到的抗原的IgA反应。此外，我们还将评估免疫应答与血液和肠粘膜中CD4+T细胞耗竭水平、病毒载量、初始B细胞与记忆B细胞比率、T细胞系统激活、血浆细菌脂多糖水平以及其他临床和免疫学指标的相关性。

DESCRIPTION (provided by applicant): Worldwide, the majority of HIV-1 infections is transmitted across the mucosal surfaces of the genital and intestinal tracts. Importantly, the earliest and most dramatic immunologic alterations occur in the intestinal mucosa and opportunistic infections of mucosal surfaces cause substantial morbidity in untreated patients. Thus, HIV-1 infection may be viewed as primarily a mucosal disease. A central component of mucosal defense mechanisms is IgA, the major immunoglobulin isotype responsible for the defense against mucosal pathogens and regulation of immune responses to common microbiota and environmental antigens. Since CD4+ T cells play a critical role in the regulation of class switching, somatic hypermutation, and transepithelial transport of IgA, their profound depletion from mucosal tissues, particularly intestinal mucosa, is likely to result in severe perturbations in antigen-specific IgA production and secretion. Although deficiencies in IgG responses to various pathogens have been well documented in HIV-1-infected patients, IgA responses have not been critically investigated. We and others have recently obtained data suggesting a severe impairment of antigen-specific IgA responses in HIV-1-infected individuals. Understanding the mechanisms underlying this deficiency is paramount to the understanding of HIV-1 pathogenesis and the design of vaccines against HIV-1 and other mucosal pathogens. We hypothesize that: (1) HIV-1 infection is associated with a profound suppression of IgA responses and the level of IgA unresponsiveness is proportional to the level of depletion of CD4+ T cells at mucosal tissues and polyclonal activation of IgA-producing B cells; and (2) Inability to mount specific IgA responses results in an impairment of the mucosal barrier and increased absorption of environmental antigens to the systemic compartment contributing to the chronic activation of T cells characteristic for HIV-1 infection. These hypotheses will be tested in three Specific Aims: 1) Determine whether HIV-1 infection dysregulates mucosal and systemic IgA responses to common microbial and food antigens; 2) Determine whether HIV-1 infection causes an impairment of lgA1 and lgA2 responses following mucosal and systemic immunization with previously encountered antigens; and 3) Determine whether HIV-1 infection abrogates IgA response to newly encountered antigens. In addition, we will evaluate the correlations between the responsiveness to immunization and the levels of CD4+T cell depletion in blood and intestinal mucosa, viral load, ratio of naive versus memory B cells, systemic activation of T cells, plasma levels of bacterial lipopolysaccharide, and other clinical and immunological parameters.