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Recombination and mutation shape variations in the major histocompatibility complex

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Journal of Genetics and Genomics 2022年第12期49卷 1151-1161页

作者： Yuying Sun Fang Yuan Ling Wang Dongfa Dai Zhijian Zhang Fei Liang Nan Liu Juan Long xiao Zhao yongzhi xi Department of Immunology and National Immunoassay Laboratory Fifth Medical Center of Chinese PLA General HospitalBeijing 100071China Institute of Beijing 307 Hospital Anhui Medical UniversityHefeiAnhui 230032China

The major histocompatibility complex(MHC)is closely associated with numerous diseases,but its high degree of polymorphism complicates the discovery of disease-associated variants.In principle,recombination and de novo mutations are two critical factors responsible for MHC polymorphisms.However,direct evidence for this hypothesis is lacking.Here,we report the generation of fine-scale MHC recombination and de novo mutation maps of~5 Mb by deep sequencing(>100×)of the MHC genome for 17 MHC recombination and 30 non-recombination Han Chinese families(a total of 190 individuals).Recombination hotspots and Han-specific breakpoints are located in close proximity at haplotype block boundaries.The average MHC de novo mutation rate is higher than the genome-wide de novo mutation rate,particularly in MHC recombinant individuals.Notably,mutation and recombination generated polymorphisms are located within and outside linkage disequilibrium regions of the MHC,respectively,and evolution of the MHC locus was mainly controlled by positive selection.These findings provide insights on the evolutionary causes of the MHC diversity and may facilitate the identification of disease-associated genetic variants.

关键词： Major histocompatibility complex(MHC) Recombination De novo mutation Positive selection Disease-associated genetic variants

Molecular assembly of recombinant chicken type II collagen in the yeast Pichia pastoris

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Science China(Life Sciences) 2018年第7期61卷 815-825页

作者： Caixia xi Nan Liu Fei Liang xiao Zhao Juan Long Fang Yuan Song Yun Yuying Sun yongzhi xi Department of Immunology and National Center for Biomedicine Analysis Beijing 307 Hospital Affiliated to Academy of Military Medical Sciences

Effective treatment of rheumatoid arthritis can be mediated by native chicken type II collagen(n CCII), recombinant peptide containing n CCII tolerogenic epitopes(CTEs), or a therapeutic DNA vaccine encoding the full-length CCOL2 A1 c DNA. As recombinant CCII(r CCII) might avoid potential pathogenic virus contamination during n CCII preparation or chromosomal integration and oncogene activation associated with DNA vaccines, here we evaluated the importance of propeptide and telopeptide domains on r CCII triple helix molecular assembly. We constructed p C-and p N-procollagen(without N-or Cpropeptides, respectively) as well as CTEs located in the triple helical domain lacking both propeptides and telopeptides, and expressed these in yeast Pichia pastoris host strain GS115(his4, Mut+) simultaneously with recombinant chicken prolyl-4-hydroxylase α and β subunits. Both p C-and p N-procollagen monomers accumulated inside P. pastoris cells, whereas CTE was assembled into homotrimers with stable conformation and secreted into the supernatants, suggesting that the large molecular weight p C-or p N-procollagens were retained within the endoplasmic reticulum whereas the smaller CTEs proceeded through the secretory pathway. Furthermore, resulting recombinant chicken type II collagen p Cα1(II) can induce collagen-induced arthritis(CIA) rat model, which seems to be as effective as the current standard n CCII. Notably, protease digestion assays showed that r CCII could assemble in the absence of C-and N-propeptides or telopeptides. These findings provide new insights into the minimal structural requirements for r CCII expression and folding.

关键词： pastoris 骨胶原大分子类型酵母汇编风湿性关节炎 CCII

Vaccination with a Novel Antigen-specific Tolerizing DNA Vaccine Encoding CCOL2A1 Protects Rats from Experimental Rheumatoid Arthritis

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Vaccination with a Novel Antigen-specific Tolerizing DNA Vac...

Dynamic Profiles, Biodistribution and Integration Evaluation of a Novel Therapeutic DNA Vaccine Encoding Chicken Type Ⅱ Collagen for Rheumatoid Arthritis in Vaccinated Normal Rodent

第十三届全国免疫学学术大会

作者： xiao Zhao Juan Long Fei Liang Nan Liu Yuying Sun yongzhi xi Beijing 307 Hospital of PLA

Antigen-specific tolerizing DNA vaccines are one of the most promising strategies for rheumatoid arthritis(RA) treatment, and act by inducing potent immune tolerance instead of generalized immunosuppression.Recently, we developed a novel antigen-specific tolerizing DNA vaccine coding forchicken type Ⅱ collagen(pcDNA-CCOL2A1), and confirmed its potent therapeutic efficacy in an established rat model of collagen-induced arthritis(CIA).Here we report the prophylactic vaccination efficacy of a single 300 ug/kgdose of pcDNA-CCOL2A1 against CIA incidence, severity, and onset.CCOL2A1 transcripts were detected in the blood of CIA rats 14–42 days after intramuscular injection by 300 μg/kg pcDNA-CCOL2A1.The expression of CCOL2A1 transcripts increased quickly on day 21, peaked at day 28, and then gradually decreased thereafter.Importantly, a single prophylactic vaccination of pcDNA-CCOL2A1 14 days before CIA establishment significantly reduced CIA incidence and severity, and deferred its onset, and was as efficacyas the current gold-standard drug, methotrexate.The marked effects on CIA incidence and severity closely corresponded with the expression of CCOL2A1.Furthermore, prophylactic vaccination with pcDNA-CCOL2A1 markedly decreased serum contens of anti-CII IgG antibodies, induced Th1-to-Th2 and Tc1-to-Tc2 shifts, and decreased the percentages of CD4+CD29+and Th17 T cells.Prophylactic vaccination with pcDNA-CCOL2A1 also downregulated various Th1 cytokines, while upregulating both the Th2-type cytokine interleukin-10 and the Th3-type cytokine transforming growth factor β.In a word, our results indicate that thepcDNA-CCOL2A1 DNA vaccine actsas an high-efficientinducer of specific immunotolerance, and could be a promising option for RA treatment in the near future.

关键词： DNA vaccine chicken type Ⅱ collagen vaccinated efficacy immune tolerance rheumatoid arthritis

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Dynamic Profiles, Biodistribution and Integration Evaluation...

Optimization of Fermentation Conditions for an Escherichia coli Strain Engineered using the Response Surface Method to Produce a Novel Therapeutic DNA Vaccine for Rheumatoid Arthritis

第十三届全国免疫学学术大会

作者： xiao Zhao Juan Long Fei Liang Nan Liu Yuying Sun yongzhi xi Beijing 307 Hospital of PLA

Background: The persistence, biodistribution, and risk of integration into the host genome of any new therapeutic DNA vaccine must be established in preclinical studies.We previously developed the DNA vaccine pcDNA-CCOL2A1 encoding chicken type Ⅱ collagen(CCII) for the treatment of rheumatoid arthritis(RA).In the present study, we characterized its dynamic profile, biodistribution, and potential for genomic DNA integration in normal vaccinated rats.Results: A real-time quantitative PCR analysis of animals administered a single dose of pcDNA-CCOL2A1(300 μg/kg by intramuscular injection) showed that CCOL2A1 mRNA level in the blood peaked between 2–6 h post-immunization and then rapidly declined, and was undetectable between day 1 and 42.CCOL2A1 transcript was detected at the muscle injection site at 3–14 days post-immunization.Starting from day 14, the transcript was detected in the heart, liver, lungs, and kidney but not in the spleen or thymus, and was expressed only in the lungs on day 28.There was no CCOL2A1 mRNA present in the testes or ovaries at any time point.Non-invasive in vivo fluorescence imaging revealed CCII protein expression from 2 h up to 10 days and from 2 h up to 35 days after administration of pcDNA-CCOL2A1 via the intravenous and intramuscular routes, respectively;the protein had disappeared by day 42.Importantly, CCOL2A1 was not integrated into the host genome.Conclusions: These results indicate that pcDNA-CCOL2A1 vaccine is rapidly cleared within a short period of time and is therefore safe, and merits further development as a therapeutic vaccine for RA treatment.

关键词： therapeutic DNA vaccine dynamic profiles biodistribution genomic integration rheumatoid arthriti

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Optimization of Fermentation Conditions for an Escherichia c...

电转人IL－6受体基因在大鼠急性髓细胞白血病模型中的表达

第十三届全国免疫学学术大会

作者： Juan Long xiao Zhao Fei Liang Nan Liu Yuying Sun yongzhi xi Beijing 307 Hospital of PLA

Background: Fermentation condition optimization and nutrients screening are of equal importance for efficient production of plasmid DNA vaccines.This directly affects the downstream purification and final quality and yield of plasmid DNA vaccines.The present study aimed to optimize the fermentation conditions for high-throughput production of therapeutic DNA vaccine pcDNA-CCOL2A1 by engineered Escherichia coli DH5α, using the response surface method(RSM).Results: We hypothesized that optimized fermentation conditions significantly increase the yield of pcDNA-CCOL2A1 therapeutic DNA vaccine, a novel DNA vaccine for treating rheumatoid arthritis(RA).Single-factor analysis was performed to evaluate the optimal basal culture medium from LB, 2×YT, TB, M9(Glycerol) and M9(Glucose), respectively.Thereafter, the Plackett-Burman design(PBD) was used to ascertain the three most significant factors affecting the vaccine yields, followed by the paths of steepest ascent to move to the nearest region of maximum response.Initial screening through the PBD revealed that the most key factors were peptone, mannitol, and inoculum concentration.Subsequent use of RSM was further optimized for the production of therapeutic DNA vaccine pcDNA-CCOL2A1 throughBox-Behnken design(BBD).The final optimized fermentation conditions were as follows: peptone, 25.86 g/L;mannitol, 8.08 g/L;inoculum concentration, OD=0.36.Using this statistical experimental design, the yield of therapeutic DNA vaccine pcDNA-CCOL2A1 markedly increased from 223.37 mg/L to 339.32 mg/L under optimal conditions, and a 51.9%increase was observed compared with the original medium.Conclusions: The present results provide a basis for further production of high-quality and high-yield therapeutic DNA vaccine pcDNA-CCOL2A1 in pilot-scale and even industrial-scale.

关键词： Therapeutic DNA vaccine Chicken type Ⅱ procollagen Engineered Escherichia coli Optimizing fermentation conditions Rheumatoid arthritis

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中华血液学杂志 1994年第3期15卷 139-141页

作者：奚永志唐佩弦北京军事医学科学院基础医学研究所

应用平方波脉冲电转法将编码人ＩＬ－６受体的ｃＤＮＡ转入不表达ＩＬ－６Ｒ的ＢＮＭＬ大鼠急性早幼粒细胞白血病ＬＴ１２细胞中，转染细胞经含６００μｇ／ｍｌ的Ｇ４１８半固体。液体二步法培养，筛出Ｇ４１８抗性细胞；ＦＡＣＳ检测... 详细信息

应用平方波脉冲电转法将编码人ＩＬ－６受体的ｃＤＮＡ转入不表达ＩＬ－６Ｒ的ＢＮＭＬ大鼠急性早幼粒细胞白血病ＬＴ１２细胞中，转染细胞经含６００μｇ／ｍｌ的Ｇ４１８半固体。液体二步法培养，筛出Ｇ４１８抗性细胞；ＦＡＣＳ检测显示该细胞与ＦＩＴＣ标记的抗ＩＬ－６Ｒ单抗呈显著的荧光强度；￣（１２５）Ｉ－ＩＬ－６受体结合实验表明，ｋｄ＝４．７ｎｍ，每个细胞ＩＬ－６Ｒ数为４０００左右；Ｎｏｒｔｈｅｒｎ－Ｂｌｏｔ发现该细胞的ＲＮＡ与￣（３２）Ｐ标记的１．５ｋｂ的ＩＬ－６ＲｃＤＮＡ探针呈明显的杂交信号，证明我们已成功地建立了高表达人ＩＬ－６Ｒ的ＬＴ１２－ＩＬ－６Ｒ￣＋的大鼠急性白血病细胞模型。

关键词：白血病电转基因表达白细胞介素6

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深入开展脐血干细胞的基础与临床研究

中华血液学杂志 1999年第8期20卷 397-398页

作者：奚永志唐佩弦军事医学科学院附属医院北京100039 军事医学科学院基础医学研究所

bcr/abl反义RNA片段启动人Ph~+白血病细胞凋亡过程

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中华血液学杂志 1996年第12期17卷 623-625页

作者：郝秀娟奚永志唐佩弦杜德林毛宁吴文北京军事医学科学院基础医学研究所中国医学科学院中国协和医科大学肿瘤研究所

为探讨ｂｃｒ／ａｂｌ融合基因对维持细胞生存方面的作用，通过脂质体介导的方法将表达ｂｃｒ／ａｂｌ融合区反义ＲＮＡ片段的重组质粒导入Ｋ５６２和ＢＶ１７３细胞系，对细胞的超微结构、细胞大小的改变以及核ＤＮＡ降解等进行观察。... 详细信息

为探讨ｂｃｒ／ａｂｌ融合基因对维持细胞生存方面的作用，通过脂质体介导的方法将表达ｂｃｒ／ａｂｌ融合区反义ＲＮＡ片段的重组质粒导入Ｋ５６２和ＢＶ１７３细胞系，对细胞的超微结构、细胞大小的改变以及核ＤＮＡ降解等进行观察。结果：表达ｂｃｒ／ａｂｌ反义ＲＮＡ片段的细胞呈典型的细胞凋亡形态，细胞核ＤＮＡ降解。证实ｂｃｒ／ａｂｌ反义ＲＮＡ片段启动人Ｐｈ＋白血病细胞系凋亡过程。提示ｂｃｒ／ａｂｌ融合基因是Ｐｈ＋白血病细胞存活能力增强的重要因素。

关键词：基因重排反义RNA 细胞凋亡白血病

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MHC结构与功能的研究进展

中国实验血液学杂志 2000年第3期8卷 227-230页

作者：孙玉英孔繁华奚永志军事医学科学院附属医院免疫学研究室北京100039

MHC分子首先作为主要组织相容性抗原被发现 ,进而依此命名。随着其抗原结合分子及T细胞信使生物学功能本质的揭示 ,MHC为什么是主要组织相容性抗原的谜底就昭然于世。约10年前 ,MHC分子的抗原结合骨架结构首次被阐明 ,关于MHC结构与功... 详细信息

MHC分子首先作为主要组织相容性抗原被发现 ,进而依此命名。随着其抗原结合分子及T细胞信使生物学功能本质的揭示 ,MHC为什么是主要组织相容性抗原的谜底就昭然于世。约10年前 ,MHC分子的抗原结合骨架结构首次被阐明 ,关于MHC结构与功能的研究就进入了一个方兴未艾的崭新时代 ,并在这一领域中取得了许多可喜的成果。对此。

关键词： MHC HLA T细胞信使NK细胞抗原结合骨架