Consequences of MALT1 mutation for B cell tolerance

在中国约10%的人患有自身免疫性疾病，其中大多数不知道病因或没有治愈的方法。自身免疫性疾病最核心的问题是我们的免疫系统无法通过免疫细胞上的受体来区分自我和非我。许多患者往往携带影响其免疫受体信号传导的基因突变。同样的突变也经常出现在淋巴瘤患者身上。因此我们假设是否存在一个常见的基因突变，能通过破坏B细胞受体信号传导，导致淋巴瘤和自身免疫病的共同发生。在对574例B细胞淋巴瘤患者的活检样本进行测序后，我们发现MALT1中一个反复出现的突变。它可能破坏B细胞受体信号传导，并激活这些细胞中的NFkB通路。MALT1是B细胞受体信号传递的转导蛋白，是CARD11/BCL10/MALT1复合物的关键组成部分。通过逆转录病毒感染技术，本项目拟研究MALT1突变对B细胞活化、增殖和对自身抗原耐受的影响。本项目的完成将进一步加深我们对淋巴瘤和自身免疫性疾病分子机制的理解，从而为这些疾的治疗提供更好方案。

Autoimmune diseases affect approximately 10% of the Chinese population, most with no known cause or cure. Center to autoimmune diseases is our immune system’s inability to distinguish, through the receptors on immune cells, between what’s foreign and what’s parts of own body. Patients who suffer from autoimmune disease often have genetic mutations that affect how their immune receptors signal. The same mutations are often found in people with lymphoma, a type of white blood cell derived cancer. Thus, we hypothesize that a common gene mutation that disrupt B cell receptor signaling can cause both lymphoma and autoimmunity. We sequenced 574 primary biopsies from diffuse large B cell lymphoma patients. We found a recurring mutation in MALT1 that potently disrupts B cell receptor signaling and activates the NFkappaB pathways in these cells. MALT1 is an adaptor protein in B cell receptor signaling and a key component of the CARD11/BCL10/MALT1 complex. By using retroviral gene transfer, we propose to investigate the consequences of MALT1 mutation for B cell activation, proliferation and tolerance to self-antigen. Our proposed project will further enhance our understanding on the molecular mechanism of lymphoma and autoimmune diseases, thus providing better treatment options for these conditions.