Dysregulation of IgA responses in HIV-1-infected individuals

HIV-1 感染者 IgA 反应失调

• 批准号: 7911850
• 负责人: Zdenek Hel
• 金额: $ 47.02万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911850
• 关键词: Address; Antibodies; Antigens; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; Cell Count; Characteristics; Chronic; Clinical; Data; Defense Mechanisms; Disease; Extravasation; Food; Frequencies; Genital system; HIV-1; Immune response; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulin-Secreting Cells; Immunologics; Impairment; Individual; Infection; Intestinal Mucosa; Intestines; Keyhole Limpet Hemocyanin; Lipopolysaccharides; Memory B-Lymphocyte; Morbidity - disease rate; Mucous Membrane; Opportunistic Infections; Oral; Pathogenesis; Patients; Plasma; Play; Polysaccharides; Production; Regulation; Research Personnel; Role; Saliva; Serum; Surface; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Vaccination; Vaccine Design; Vagina; Viral Load result; absorption; influenzavirus; microbial; pathogen; programs; rectal; response; Address; Antibodies; Antigens; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; Cell Count; Characteristics; Chronic; Clinical; Data; Defense Mechanisms; Disease; Extravasation; Food; Frequencies; Genital system; HIV-1; Immune response; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulin-Secreting Cells; Immunologics; Impairment; Individual; Infection; Intestinal Mucosa; Intestines; Keyhole Limpet Hemocyanin; Lipopolysaccharides; Memory B-Lymphocyte; Morbidity - disease rate; Mucous Membrane; Opportunistic Infections; Oral; Pathogenesis; Patients; Plasma; Play; Polysaccharides; Production; Regulation; Research Personnel; Role; Saliva; Serum; Surface; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Vaccination; Vaccine Design; Vagina; Viral Load result; absorption; influenzavirus; microbial; pathogen; programs; rectal; response

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.

描述（由申请人提供）：在全球范围内，大多数HIV-1感染均在生殖器和肠道的粘膜表面传播。重要的是，最早，最显着的免疫学改变发生在肠粘膜和粘膜表面的机会性感染中，导致未治疗的患者的大量发病率。因此，HIV-1感染可能主要是粘膜疾病。粘膜防御机制的一个核心组成部分是IgA，这是负责防御粘膜病原体的主要免疫球蛋白同种型，并调节对常见菌群和环境抗原的免疫反应。由于CD4+ T细胞在调节类别的转换，体细胞超突变和IgA的跨旋转转运中起着至关重要的作用，因此它们对粘膜组织（尤其是肠道粘膜）的严重消耗可能会导致抗原特异性IGA产生和分泌物的严重扰动。尽管在HIV-1感染的患者中已经充分证明了IgG对各种病原体的反应缺陷，但尚未对IgA反应进行严格研究。我们和其他人最近获得的数据表明，HIV-1感染的个体严重损害了抗原特异性IgA反应。了解这种缺陷的基础机制对于对HIV-1发病机理的理解以及针对HIV-1和其他粘膜病原体的设计至关重要。 我们假设：（1）HIV-1感染与IgA反应的深刻抑制作用有关，IgA无反应性水平与CD4+ T细胞在粘膜组织和产生IgA产生B细胞的多克隆激活下的耗竭水平成正比； （2）无法安装特定的IgA反应会导致粘膜屏障的损害，并增加环境抗原对全身室的吸收，这有助于HIV-1感染的T细胞的长期激活。这些假设将以三个特定目的进行检验：1）确定HIV-1感染是否会失调粘膜和全身IgA对常见微生物和食物抗原的反应； 2）确定在粘膜和全身免疫后，HIV-1感染是否会导致LGA1和LGA2反应损害，而先前遇到的抗原； 3）确定HIV-1感染是否消除了IgA对新遇到的抗原的反应。此外，我们将评估血液和肠粘膜中CD4+T细胞耗竭水平之间的相关性，病毒负荷，天真记忆B细胞的比率，T细胞的全身性激活，细菌脂肪酸的血浆水平，以及其他临床和免疫学参数。