Dysregulation of IgA responses in HIV-1-infected individuals

描述（由申请人提供）：在世界范围内，大多数HIV-1感染是通过生殖器和肠道粘膜表面传播的。重要的是，最早和最显著的免疫改变发生在肠粘膜，粘膜表面的机会性感染在未经治疗的患者中引起大量发病率。因此，HIV-1感染可能主要被视为一种粘膜疾病。IgA是粘膜防御机制的一个核心组成部分，它是一种主要的免疫球蛋白同型，负责防御粘膜病原体和调节对常见微生物群和环境抗原的免疫反应。由于CD4+ T细胞在调节IgA的类别转换、体细胞超突变和经上皮转运中起着关键作用，因此它们从粘膜组织，特别是肠粘膜中大量耗损，可能导致抗原特异性IgA的产生和分泌受到严重干扰。尽管在hiv -1感染的患者中，IgG对各种病原体的反应不足已经得到了充分的证明，但IgA反应尚未得到严格的研究。我们和其他人最近获得的数据表明，hiv -1感染个体的抗原特异性IgA反应严重受损。了解这种缺陷背后的机制对于理解HIV-1发病机制和设计针对HIV-1和其他粘膜病原体的疫苗至关重要。

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.