Post genomic structural and functional aspects of antibody in heath and disease

对于宿主防御、疾病预防和治疗，了解免疫系统及其在健康和疾病中的调节是至关重要的。为了实现这一目标，我们的研究集中在抗体遗传学和自身免疫方面。我们在牛身上首次发现了独特的功能性IgM抗体，这是已知在一个物种中存在的最大的抗体。这为开发新的抗体工程策略来预防那些传统疗法无效的疾病提供了机会，例如癌症、自身免疫性疾病和病毒感染。我提出的研究旨在确定这些新型抗体的‘结构-功能’关系，并开发一种针对牛白血病病毒的疫苗。这些研究还涉及了解新生儿免疫系统的发展，目的是加强新生儿对感染的宿主防御。其他研究的重点是自身抗体的来源，这些抗体会导致系统性自身免疫性疾病，如狼疮和关节炎。我们观察到致病性自身抗体起源于新生儿期抗体库发育受损。B细胞选择在全身性自身免疫性疾病发生中的作用还不是很清楚。拟议的研究旨在确定产生致病性自身抗体的白细胞(B细胞)的解剖位置，特别是IgM型抗体，以便对患有自身免疫性疾病的患者进行治疗干预，以消除这些抗体。之所以研究IgM自身抗体类型，是因为它们最先出现并引发自身免疫性疾病。

For host defence, disease prevention and therapy, knowledge of the immune system and its regulation in health and disease is of fundamental importance. Towards this goal, our research is focused on 'antibody genetics and autoimmunity'. We made an original discovery of unique functional IgM antibodies in cattle, the largest known to exist in a species. This offers opportunity to develop novel antibody engineering strategies for prevention of those diseases where conventional therapies fail, e.g., cancer, autoimmune diseases and viral infections. My proposed research aims at defining 'structure-function' relationships of these novel types of antibodies and, also to develop a vaccine against bovine leukemia virus. These studies also involve understanding the development of the neonatal immune system aimed at strengthening the host defence of newborns against infections. Other studies are focused on the origin of autoantibodies that cause systemic autoimmune disease, such as Lupus and arthritis. We have observed that pathogenic autoantibodies originate from the impaired development of the antibody repertoire at newborn stage. The role of B-cell selection in generating systemic autoimmune disease is not well understood. The proposed studies are aimed at identifying the anatomical location where white blood cells (B-cells) producing pathogenic autoantibodies, especially of the IgM type, originate so that these could be targeted for elimination by therapeutic intervention in patients afflicted with autoimmune disease. The IgM autoantibody type is studied since these appear first and initiate autoimmune disease.