Antibody diversification is essential for an effective immune response,with somatic hypermutation(SHM)serving as a key molecular process in this adaptation.Activation-induced cytidine deaminase(AID)initiates SHM by in...Antibody diversification is essential for an effective immune response,with somatic hypermutation(SHM)serving as a key molecular process in this adaptation.Activation-induced cytidine deaminase(AID)initiates SHM by inducing DNA lesions,which are ultimately resolved into point mutations,as well as small insertions and deletions(indels).These mutational outcomes contribute to antibody affinity maturation.The mechanisms responsible for generating point mutations and indels involve the base excision repair(BER)and mismatch repair(MMR)pathways,which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur.In this regard,translesion synthesis(TLS)polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions.This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM.Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies(bnAbs)and autoantibodies,and has implications for vaccine design and therapeutics.展开更多
Activation-induced cytidine deaminase(AID)is required for the generation of antibody diversity through initiat-ing both somatic hypermutation(SHM)and class switch recombination.A few research groups have success-fully...Activation-induced cytidine deaminase(AID)is required for the generation of antibody diversity through initiat-ing both somatic hypermutation(SHM)and class switch recombination.A few research groups have success-fully used the feature of AID for generating mutant li-braries in directed evolution of target proteins in B cells in vitro.B cells,cultured in suspension,are not con-venient for transfection and cloning.In this study,we established an AID-based mutant accumulation and sorting system in adherent human cells.Mouse AID gene was first transfected into the human non-small cell lung carcinoma H1299 cells,and a stable cell clone(H1299-AID)was selected.Afterwards,anti-hTNF-αscFv(ATscFv)was transfected into H1299-AID cells and ATscFv was displayed on the surface of H1299-AID cells.By 4-round amplification/flow cytometric sorting for cells with the highest affinities to hTNF-alpha,two ATscFv mutant gene clones were isolated.Compared with the wild type ATscFv,the two mutants were much more efficient in neutralizing cytotoxicity of hTNF-alpha.The results indicate that directed evolution by somatic hypermutation can be carried out in adherent non-B cells,which makes directed evolution in mammalian cells easier and more efficient.展开更多
Mantle cell lymphoma (MCL) is an aggressive nonHodgkin's lymphoma, originating from naive B-cells. The blastoid MCL tumors often show complex cytogenetic aberrations. In this review, we summarized the data availabl...Mantle cell lymphoma (MCL) is an aggressive nonHodgkin's lymphoma, originating from naive B-cells. The blastoid MCL tumors often show complex cytogenetic aberrations. In this review, we summarized the data available on immunoglobulin heavy-chain (IgH) genes rearrangement for their importance in suggesting the MCL normal counterpart B-cell. Some new data suggesting an antigen selection process were also presented in this review.展开更多
SATB1(Special A-T rich Binding protein 1)is a cell type-specific factor that regulates the genetic network in developing T cells and neurons.In T cells,SATB1 is required for lineage commitment,VDJ recombination,develo...SATB1(Special A-T rich Binding protein 1)is a cell type-specific factor that regulates the genetic network in developing T cells and neurons.In T cells,SATB1 is required for lineage commitment,VDJ recombination,development and maturation.Considering that its expression varies during B-cell differentiation,the involvement of SATB1 needs to be clarified in this lineage.Using a KO mouse model in which SATB1 was deleted from the pro-B-cell stage,we examined the consequences of SATB1 deletion in naive and activated B-cell subsets.Our model indicates first,unlike its essential function in T cells,that SATB1 is dispensable for B-cell development and the establishment of a broad IgH repertoire.Second,we show that SATB1 exhibits an ambivalent function in mature B cells,acting sequentially as a positive and negative regulator of Ig gene transcription in naive and activated cells,respectively.Third,our study indicates that the negative regulatory function of SATB1 in B cells extends to the germinal center response,in which this factor limits somatic hypermutation of Ig genes.展开更多
Activation-induced deaminase (AID) initiates the secondary antibody diversification process in B lymphocytes. In mammalian B cells, this process includes somatic hypermutation (SHM) and class switch recombination ...Activation-induced deaminase (AID) initiates the secondary antibody diversification process in B lymphocytes. In mammalian B cells, this process includes somatic hypermutation (SHM) and class switch recombination (CSR), both of which require AID. AID induces U:G mismatch lesions in DNA that are subsequently converted into point mutations or DNA double stranded breaks during SHM/CSR. In a physiological context, AID targets immunogiobulin (Ig) loci to mediate SHM/CSR. However, recent studies reveal genome-wide access of AID to numerous non-Ig loci. Thus, AID poses a threat to the genome of B cells if AID-initiated DNA lesions cannot be properly repaired. In this review, we focus on the molecular mechanisms that regulate the specificity of AID targeting and the repair pathways responsible for processing AID-initiated DNA lesions.展开更多
A simple immune-based multi-objective optimizer(IBMO) is proposed, and a rigorous running time analysis of IBMO on three proposed bi-objective pseudo-Boolean functions(Bi-Trap, Bi-Plateau and Bi-Jump) is presented. Th...A simple immune-based multi-objective optimizer(IBMO) is proposed, and a rigorous running time analysis of IBMO on three proposed bi-objective pseudo-Boolean functions(Bi-Trap, Bi-Plateau and Bi-Jump) is presented. The running time of a global simple evolutionary multi-objective optimizer(GSEMO) using standard bit mutation operator with IBMO using somatic contiguous hypermutation(CHM) operator is compared with these three functions. The results show that the immune-based hypermutation can significantly beat standard bit mutation on some well-known multi-objective pseudo-Boolean functions. The proofs allow us to understand the relationship between the characteristics of the problems and the features of the algorithms more deeply. These analysis results also give us a good inspiration to analyze and design a bio-inspired search heuristics.展开更多
基金supported by the National Key Research and Development Program of China(2021YFA1301400)the National Natural Science Foundation of China(32370934)the Shanghai Jiao Tong University 2030 Initiative(2030-B23).
文摘Antibody diversification is essential for an effective immune response,with somatic hypermutation(SHM)serving as a key molecular process in this adaptation.Activation-induced cytidine deaminase(AID)initiates SHM by inducing DNA lesions,which are ultimately resolved into point mutations,as well as small insertions and deletions(indels).These mutational outcomes contribute to antibody affinity maturation.The mechanisms responsible for generating point mutations and indels involve the base excision repair(BER)and mismatch repair(MMR)pathways,which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur.In this regard,translesion synthesis(TLS)polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions.This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM.Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies(bnAbs)and autoantibodies,and has implications for vaccine design and therapeutics.
基金funded by grants from the Ministry of Science and Technology of People’s Republic of China(Nos.2011CBA00906 and 2011YQ03013404).
文摘Activation-induced cytidine deaminase(AID)is required for the generation of antibody diversity through initiat-ing both somatic hypermutation(SHM)and class switch recombination.A few research groups have success-fully used the feature of AID for generating mutant li-braries in directed evolution of target proteins in B cells in vitro.B cells,cultured in suspension,are not con-venient for transfection and cloning.In this study,we established an AID-based mutant accumulation and sorting system in adherent human cells.Mouse AID gene was first transfected into the human non-small cell lung carcinoma H1299 cells,and a stable cell clone(H1299-AID)was selected.Afterwards,anti-hTNF-αscFv(ATscFv)was transfected into H1299-AID cells and ATscFv was displayed on the surface of H1299-AID cells.By 4-round amplification/flow cytometric sorting for cells with the highest affinities to hTNF-alpha,two ATscFv mutant gene clones were isolated.Compared with the wild type ATscFv,the two mutants were much more efficient in neutralizing cytotoxicity of hTNF-alpha.The results indicate that directed evolution by somatic hypermutation can be carried out in adherent non-B cells,which makes directed evolution in mammalian cells easier and more efficient.
文摘Mantle cell lymphoma (MCL) is an aggressive nonHodgkin's lymphoma, originating from naive B-cells. The blastoid MCL tumors often show complex cytogenetic aberrations. In this review, we summarized the data available on immunoglobulin heavy-chain (IgH) genes rearrangement for their importance in suggesting the MCL normal counterpart B-cell. Some new data suggesting an antigen selection process were also presented in this review.
文摘SATB1(Special A-T rich Binding protein 1)is a cell type-specific factor that regulates the genetic network in developing T cells and neurons.In T cells,SATB1 is required for lineage commitment,VDJ recombination,development and maturation.Considering that its expression varies during B-cell differentiation,the involvement of SATB1 needs to be clarified in this lineage.Using a KO mouse model in which SATB1 was deleted from the pro-B-cell stage,we examined the consequences of SATB1 deletion in naive and activated B-cell subsets.Our model indicates first,unlike its essential function in T cells,that SATB1 is dispensable for B-cell development and the establishment of a broad IgH repertoire.Second,we show that SATB1 exhibits an ambivalent function in mature B cells,acting sequentially as a positive and negative regulator of Ig gene transcription in naive and activated cells,respectively.Third,our study indicates that the negative regulatory function of SATB1 in B cells extends to the germinal center response,in which this factor limits somatic hypermutation of Ig genes.
文摘Activation-induced deaminase (AID) initiates the secondary antibody diversification process in B lymphocytes. In mammalian B cells, this process includes somatic hypermutation (SHM) and class switch recombination (CSR), both of which require AID. AID induces U:G mismatch lesions in DNA that are subsequently converted into point mutations or DNA double stranded breaks during SHM/CSR. In a physiological context, AID targets immunogiobulin (Ig) loci to mediate SHM/CSR. However, recent studies reveal genome-wide access of AID to numerous non-Ig loci. Thus, AID poses a threat to the genome of B cells if AID-initiated DNA lesions cannot be properly repaired. In this review, we focus on the molecular mechanisms that regulate the specificity of AID targeting and the repair pathways responsible for processing AID-initiated DNA lesions.
基金the National Natural Science Foundation of China(Nos.61703183,61773410,61375053)the Public Welfare Technology Research Plan of Zhejiang Province(No.LGG19F030010)
文摘A simple immune-based multi-objective optimizer(IBMO) is proposed, and a rigorous running time analysis of IBMO on three proposed bi-objective pseudo-Boolean functions(Bi-Trap, Bi-Plateau and Bi-Jump) is presented. The running time of a global simple evolutionary multi-objective optimizer(GSEMO) using standard bit mutation operator with IBMO using somatic contiguous hypermutation(CHM) operator is compared with these three functions. The results show that the immune-based hypermutation can significantly beat standard bit mutation on some well-known multi-objective pseudo-Boolean functions. The proofs allow us to understand the relationship between the characteristics of the problems and the features of the algorithms more deeply. These analysis results also give us a good inspiration to analyze and design a bio-inspired search heuristics.