The Regulatory Role Of AIM2 And TRIM37 In Germinal Center Formation And Antibody Production

Adaptive immune responses play an important role in the body’s defense against foreign or endogenous pathogen infections,while humoral immunity characterized by high-affinity antibody production depends on the normal formation of germinal centers.The germinal center is a short and complex dynamic microenvironment formed by multiple cells in the secondary lymphoid organs after the body receives T cell-dependent antigen stimulation.The germinal center is a place where B cells undergo rapid cell proliferation,somatic hyperthermia,and antibody affinity maturation,and each of these steps is necessary for the body to produce sufficient amounts of high-affinity antibodies.The normal formation of germinal centers depends on the synergistic effect of Naive B cells,CD4~+T cells and dendritic cells.The presentation of antigens by dendritic cells and the interaction of T and B cells are the key to the formation of germinal centers.Mature germinal centers have distinct dark zone and bright zone.The dark zone is the site where the B cells of the germinal center undergo rapid proliferation and high frequency mutation of the somatic cells;the bright zone is the site where the antibody affinity matures.The maturation of the germinal center requires the development of germinal center B cells,follicular helper T cells,and follicular dendritic cells.The interaction between germinal center B cells and follicular helper T cells plays a critical role in the differentiation of each other as well as in the antibody selection.Abnormalities in any part of the development and maturation of the germinal center can lead to the development of lymphoma,autoimmune disease or immunodeficiency disease,therefore,it is of great clinical significance to further study the mechanism of germinal center formation and antibody production.In our study,we found for the first time that AIM2 and TRIM37 play important roles in the germinal center B formation and antibody production.As a component of the classical DNA sensor and AIM2 inflammasome,AIM2 plays an important role in the pathogen infection and tumor development.With a better understanding of AIM2,the mechanism by which AIM2 plays a role in innate immunity and tumor development depending or not depending on AIM2 inflammsome has been becoming even more clearly,but the function of AIM2 in adaptive immunity has rarely been reported.In addition to high expression in macrophages and dendritic cells,AIM2also has relatively high expression in spleen and lymph nodes,suggesting that AIM2may play a role in applicative immunity.In our study,we first demonstrated the inhibitory effect of AIM2 on the differentiation and proliferation of germinal centers B cells with the classical immunological methods of inducing the germinal center formation---KLH emulsified in CFA,and we also found that AIM2 could cause severe damage to the production of high affinity antigen-specific antibody IgG2c.This is also the first discovery the important role of AIM2 in adaptive immunity.Furthermore,neither of these functions of AIM2 is dependent on AIM2 inflammasome,which further demonstrates the multiple role of AIM2.As a family of proteins with high conservation of structure and function,TRIM family proteins play a vital role in the innate immune response and tumorigenesis.With the attention of TRIM family molecules,more and more TRIM molecules activity has been identified as E3 ubiquitin ligase,but there is still unclear about the role of TRIM family molecules in adaptive immunity.TRIM37 is a newly discovered E3 ubiquitin ligase in recent years.It is clinically reported that the deletion or mutation of TRIM37could cause mulibrey nanism,and some patients are accompanied by severe infection and antibody production disorders,which suggests that TRIM37 may be important in antibody production.We immunized TRIM37-KO mice with KLH and found that TRIM37 promotes the production of germinal center B cells and further affects the production of antigen specific high-affinity antibody IgG1.This is the first time that TRIM37 has been found playing an important role in adaptive immune response.It has been found that TRIM37 plays a carcinogenic role in various tumors such as breast cancer and esophageal cancer with its E3 ubiquitin ligase activity,so that the promotion of TRIM37 to germinal center B cell differentiation may suggest a carcinogenic role of TRIM37 in germinal center B ell derived lymphoma.