Btk breaks the tolerance of marginal zone macrophages to apoptotic antigens

Btk打破了边缘区巨噬细胞对凋亡抗原的耐受性

• 批准号: 8629254
• 负责人: John D Mountz
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629254
• 关键词: Activities of Daily Living; Agammaglobulinaemia tyrosine kinase; Anatomy; Antigen-Antibody Complex; Antigens; Apoptotic; Area; Arts; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biochemical; Biological Markers; Biology; Blood Circulation; Cells; Clinical; Data; Defect; Detection; Development; Dimensions; Dioxygenases; Disease; Early Diagnosis; Ensure; Event; Experimental Models; Flow Cytometry; Functional disorder; Gene Targeting; Genes; Human; Human Characteristics; Hyperactive behavior; Image; Immune; Immune System Diseases; Immunoglobulin G; Individual; Inflammatory; Interferon Type I; Interferons; Interleukin-10; Interleukin-6; Knowledge; Lead; Link; Liposomes; Lupus; Mediating; Modeling; Molecular; Mus; Onset of illness; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Positioning Attribute; Prevention; Process; Production; Recruitment Activity; Research; Resources; Role; Signal Transduction; Spleen; Staging; Structure; Systemic Lupus Erythematosus; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Tyrosine Kinase Inhibitor; Work; base; effective intervention; gene therapy; immunogenic; in vivo; indoleamine; innovation; insight; loss of function; macrophage; mouse model; nanoscience; novel; novel therapeutic intervention; pre-clinical; prevent; public health relevance; response; small hairpin RNA; success; therapeutic target; vector

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease in which autoantibodies (autoAbs) play a key role in eliciting tissue destruction. Multiple immune irregularities have been identified, including hyperactivity of T and B cells, in patients with SLE but its pathogenesis remains an enigma. This gap in knowledge is a significant impediment to timely diagnosis, early therapeutic intervention and potential prevention. We propose a highly innovative pathogenic model that links irregularities typical of patients with SLE including the presence of autoAbs several years prior to manifestation of clinical disease, the presence of large immune complexes (ICs) and autoAbs targeting apoptotic debris in the circulation, the production of higher levels of type I interferons (IFNs) and their target genes, and the hyperactivity of B and T cells. The central component of the proposed hypothetical model is that the tolerogenic capacity of marginal zone macrophages (MZMs) in the marginal zone (MZ) of the spleen plays a pivotal role in the progression of SLE. We propose that there is a gradual erosion of the normally large reserve in the tolerogenic capacity of the MZMs during the pre-clinical disease phase of SLE. When the tolerogenic capacity of the MZMs declines below a critical threshold, the individual becomes susceptible to inciting events, especially those that induce type I IFNs, that precipitate a further rapid loss of tolerogenic capacity resulting in production of high titers of pathogenic autoAbs and clinical disease. We further propose that the erosion of the tolerogenic capacity of the MZMs during the pre-clinical state is driven primarily by circulating apoptotic cell antigens (AC-Ags) and IgG ICs that enhance immunogenic signals which in combination with type I IFN pathways reduce the tolerogenic capacity of MZMs. At the molecular level, we propose that the loss of the tolerogenic capacity of the MZMs is associated with an increase in expression of Bruton tyrosine kinase (Btk) in MZMs in response to AC-Ag/ICs. As the expression of Btk is further increased, the MZMs will relocate from their anatomic position adjacent to the FO and locate to more remote areas of the MZ. Some individuals develop ICs that increase type I IFN signaling and Btk induction in MZMs to the point that a threshold is reached at which a pro-inflammatory "trigger" precipitates the onset of clinical disease. ¿ Aim 1 will determine if autoAb-ICs induction of Btk leads to MZM dysfunction and loss. ¿ Aim 2 will determine if IFN¿ and ICs work together to break MZM tolerance. ¿ Aim 3 will determine if elevation of pBtk leads to loss of MZ macrophages, development of inflammatory macrophages and elevation of type I IFN genes in SLE patients. The proposed work will use state-of-art confocal imaging and high dimension phospho-flow cytometry analyses to enable detection of the aberrant signaling events associated with loss of function and numbers of MZMs due to abnormally upregulated pBtk in both humans and mice. We will also apply B cell tetramer technology to enable tracking the development of pathogenic multireactive autoAb forming B cells associated with the decline of MZM numbers and tolerance function. Btk activity will be manipulated by systemic treatment of mice with an irreversible Btk inhibitor, PCI-32765 or liposome gene therapy to directly target Btk shRNA or PCI-32765 to MZMs. Significance: This hypothetical model, if proven true, would pinpoint a defining event in the transition from pre-clinical to clinical SLE, which would suggest a biomarker that could be used in earlier diagnosis of SLE, i.e., the numbers and Btk phenotype of the MZMs in experimental models of autoimmunity, and the Btk phenotype of PBMCs from patients. This would have major implications in terms of earlier and thus more effective intervention using currently available therapeutic strategies. In addition, the results will provide insights critical to the development of Btk as a potential therapeutic target in SLE.

系统性红斑狼疮（SLE）是一种多因素自身免疫性疾病