天疱疮是危重的大疱性皮肤黏膜疾病，又是自身免疫病的典型。其发病机制尚未完全清楚，但特异性自身抗体仍发挥主要的致病作用。本课题组在以往研究中发现CD4+T细胞在辅助B细胞产生抗体及抗体亚型转换中起着重要的作用。然而，自身反应性T、B细胞相互作用的分子机制，B细胞出现怎样状态的活化和分化，进而产生致病性抗体，均尚未明确。本项目将进行序贯性研究，明确患者外周血T、B细胞的活化状态及共刺激分子的作用机制；重点研究T、B细胞体外培养后诱导的CD19hiICAM-1hiB细胞的表型、功能、基因表达谱，及其对天疱疮特异性抗体产生的影响。通过本次研究，我们将提出在天疱疮的病理状态下，存在多分子参与的T-B细胞间免疫突触作用，通过诱导CD19hiICAM-1hiB细胞形成，产生致病性抗体，参与疾病发生、发展的新理论，并为天疱疮和/或其他以抗体介导为主的自身免疫病的治疗新靶点提供更为可靠的实验依据和分子基础。

Pemphigus is an organ-specific autoimmune blistering disease that is characterized by suprabasal blisters in skin and mucous membranes. Pemphigus has two major subtypes, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), which are caused primarily by pathogenic immunoglobulin G (IgG) autoantibodies against desmoglein 3 (Dsg3) and/or desmoglein (Dsg1). The binding between the antibodies and Dsg could cause the activation of protein enzymes or apoptosis of keratinocytes, which leads?to?the?loss?of?cell-cell?adhesion,?further to the clinical blisters?and?erosions. Our group has focused on the blistering diseases for many years. We found that CD4+ T cells play an important role in B cell activation and antibody production, as well as the subclass switching. However, what's the mechanism for the T-B cells interaction, including the activating status of T/B cells and the expression of co-stimulatory molecules? How are B cells activated and differentiated to antibody-secreting B cells? In this study, we try to discover the activation status of CD4+ T cells and B cells in pemphigus patients and the role of co-stimulatory molecules on B cell differentiation and antibody production. Most importantly, we attempt to identify the phenotype, the function and gene expression of CD19hiICAM-1hi B cells which induced via T/B cell incubation in vitro, compared to CD19loICAM-1lo B cells. Furthermore, we use pemphigus mouse model, which transferred with splenocytes from rDsg3 immunized Dsg3-/- mice, to confirm the function of CD19hiICAM-1hi B cells on antibody production, further to determine the role of this B cell population in the disease development. Our project will provide a novel mechanism of multiple molecules participating T-B cells interaction in pemphigus. CD19hiICAM-1hi B cells might firmly related to the antibody production, which involved in the disease induction and development. Our results might also lay the molecular foundation of studying the pathogenesis of antibody-driven autoimmune diseases as well as to screen optimized therapeutic targets in these autoimmune diseases.