Evolution of Adaptive Immunity

鲨鱼是最古老的脊椎动物类别的代表，具有以免疫球蛋白(Ig)、T细胞受体(TCR)和主要组织相容性复合体(MHC)为基础的适应性免疫系统，并具有VDJ基因重排和体细胞突变机制。与人鼠免疫系统相比，鲨鱼免疫系统的属性揭示了抵御病原体不可或缺的共同特征。我们将研究所有免疫学家普遍感兴趣的鲨鱼免疫系统的特征，特别是在次级淋巴组织中的次级体液免疫反应(在没有生发中心的情况下)的阐明，以及个体发育早期“先天”Ig受体的表达。为了做到这一点，我们将研究我们在护士鲨中发现的3个分子：1)NAR(护士鲨或新抗原受体)，其基因在非常高的水平发生突变，并被认为是次级反应的主要参与者；2)IGW，它以两种主要形式表达，被认为是为了迎合特定的免疫挑战；以及3)IgM(1GJ)，它在发育早期表达，并由不经历重排的V基因编码。这3种受体(连同常规的IgM)被认为提供鲨鱼VDJ为基础的体液免疫系统的所有先天和适应性功能。具体目的是：1)揭示护鲨免疫系统的基本组织结构。我们将确定初级和次级淋巴组织的结构，并检查抗原受体在每个器官中的表达和共表达；2)检查分泌的抗原受体的功能，特别是在次级反应中。将跟踪每个抗原受体的血清反应，并通过噬菌体展示研究与次级淋巴组织中淋巴细胞的体细胞突变和发育相关的亲和力成熟；3)研究胚系与VDJ基因的个体发育和功能，假设它们在发育早期起重要的防御或内稳态作用。

Sharks are representatives of the oldest vertebrate class having an adaptive immune system grounded on immunoglobulins (Ig), T cell receptors (TCR) and the major histocompatibility complex (MHC), and with VDJ gene rearrangement and somatic mutation mechanisms. Attributes of the shark immune system, in comparison with that of mouse/man, reveal common features indispensable for defense against pathogens. We will study characteristics of the shark immune system that are of general interest to all immunologists, specifically the elucidation of secondary humoral immune responses in secondary lymphoid tissues (in the absence of germinal centers) and the expression of "innate" Ig receptors early in ontogeny. To accomplish this, we will study 3 molecules that we discovered in the nurse shark: 1) NAR (nurse shark or new antigen receptor), the genes of which mutate at very high levels and that is proposed to be a major player in secondary responses; 2) IgW, which is expressed in 2 major forms and is proposed to cater to specific immune challenges; and 3) IgM(1gj), which is expressed early in development and is encoded by a V gene that does not undergo rearrangement. These 3 receptors (along with conventional IgM) are proposed to provide all of the innate and adaptive functions of the shark VDJ-based humoral immune system. The Specific Aims are: 1) Reveal the basic organization of the nurse shark immune system. We will define structures of primary and secondary lymphoid tissues and examine expression and co-expression of antigen receptors in each organ; 2) Examine the function of the secreted antigen receptors, especially in secondary responses. Serum responses of each antigen receptor will be followed and affinity maturation, correlated with somatic mutation and development of lymphocytes in secondary lymphoid tissues, will be studied by phage display; 3) Study the ontogeny and function of germline joined VDJ genes, with the hypothesis that they serve an important role in defense or homeostasis early in development.