The Role of Natural Human Anergic B cells in Systemic Lupus Erythematosus Patholo

我们首次鉴定了具有无能表型的成熟人类B细胞，提供了一种 与二十年来对小鼠的研究有着重要的联系。这些低IgM的幼稚B细胞主要是自身反应的 而且它们转运钙、磷酸化酪氨酸的能力降低，或者在刺激后存活。激烈的 刺激导致这些细胞被激活，这与长期以来的观点一致，即无能B细胞可能 是系统性红斑狼疮等疾病的病理性自身抗体的来源。从长远来看 这里提出的实验的目标是将我们对中央机制的新的基本理解 将人类免疫耐受性的无能转化为一种新的思维，将导致狼疮的切实治疗。我们 怀疑在各种狼疮患者中可能存在典型的无能B细胞缺陷，每种缺陷都可能 极大地改变了我们对这种疾病的理解和治疗策略。我们假设无能是 不诱导或维持SLE患者的自身反应性B细胞，使这些细胞完全 功能齐全。无能B细胞可能是产生病理性自身免疫的自身反应性B细胞池 回应。为了在特定的目标1中检验这些假设，我们将使用流式细胞术和分子变量基因 狼疮患者年龄和年龄与无能B细胞频率和表型的比较分析 性别与未受影响的对照组相匹配。在特定的目标2中，我们将确定狼疮患者的无能B细胞是否 改变功能和涉及的分子，导致完全的免疫反应，尽管是自体反应。在……里面 具体目标3我们将比较一组重组人单抗的特异性和亲和力 狼疮患者无能B细胞抗体与健康对照抗体的关系通过这一分析，我们将 识别可能逃脱耐受性并导致SLE患者病理的天然自身抗原。

For the first time, we have characterized mature human B cells that have an anergic phenotype, providing a critical link to twenty years of research in mice. These IgM-Low naive B cells are predominantly autoreactive and they have a reduced capacity to flux calcium, phosphorylate tyrosines or survive after stimulation. Intense stimulation causes these cells to be activated, consistent with the long-standing view that anergic B cells may be a source of pathological autoantibodies in diseases such as systemic lupus erythematosus. The long term goal of the experiments proposed herein is to translate our new basic understanding of a central mechanism of immune tolerance in humans, anergy, into a new thinking that will lead to tangible treatments of lupus. We suspect there are defects in anergic B cells that may be typical in various lupus patients, each of which could substantially alter our understanding and treatment strategies of this disease. We hypothesize that anergy is not induced or maintained for autoreactive B cells in SLE patients, allowing these cells to become fully functional. Anergic B cells may be a pool of autoreactive B cells that produce pathological autoimmune responses. To test these hypotheses in Specific aim 1, we will use flow cytometry and molecular variable gene analysis to compare the frequency and phenotype of anergic B cells in a cohort of lupus patients with age and sex matched unaffected controls. In specific aim 2 we will determine if anergic B cells in lupus patients have altered function and the molecules involved, leading to full immune reactivity despite being autoreactive. In specific Aim 3 we will compare the specificities and affinities of a panel of recombinant human monoclonal antibodies from anergic B cells of lupus patients to antibodies from healthy controls. With this analysis we will identify natural autoantigens that may escape tolerance and cause pathology in SLE patients.