Dysregulation of IgA responses in HIV-1-infected individuals

HIV-1 感染者 IgA 反应失调

• 批准号: 7671484
• 负责人: Zdenek Hel
• 金额: $ 47.49万
• 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/7671484
• 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

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）：在世界范围内，大多数HIV-1感染通过生殖器和肠道的粘膜表面传播。重要的是，最早和最显著的免疫学改变发生在肠粘膜中，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。因此，HIV-1感染可被视为主要是一种粘膜疾病。粘膜防御机制的中心组分是伊加，其是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应答的主要免疫球蛋白同种型。由于CD 4 + T细胞在调节伊加的类别转换、体细胞超突变和跨上皮转运中起关键作用，因此它们从粘膜组织（特别是肠粘膜）的深度消耗可能导致抗原特异性伊加产生和分泌的严重扰动。尽管在HIV-1感染患者中对各种病原体的IgG应答的缺陷已被充分记录，但伊加应答尚未被严格研究。我们和其他人最近获得的数据表明，在HIV-1感染者的抗原特异性伊加反应严重受损。理解这种缺陷的机制对于理解HIV-1的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。 我们假设：（1）HIV-1感染与伊加应答的深度抑制有关，伊加无应答水平与粘膜组织中CD 4 + T细胞的耗竭水平和IgA产生B细胞的多克隆活化水平成比例;和（2）不能建立特异性伊加应答导致粘膜屏障受损，并增加环境抗原吸收到全身区室，从而导致HIV-1感染所特有的T细胞的慢性激活。这些假设将在三个特定目的中进行检验：1）确定HIV-1感染是否失调了粘膜和全身伊加对常见微生物和食物抗原的应答; 2）确定HIV-1感染是否导致粘膜和全身免疫接种之前遇到的抗原后IgA 1和IgA 2应答受损; 3）确定HIV-1感染是否消除了伊加对新遇到的抗原的应答。此外，我们将评估免疫应答与血液和肠粘膜中CD 4 +T细胞耗竭水平、病毒载量、初始与记忆B细胞比率、T细胞的全身活化、细菌脂多糖血浆水平以及其他临床和免疫学参数之间的相关性。