狼疮模型鼠各脏器TCR Vβ基因的表达及T细胞克隆性分析
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摘要
系统性红斑狼疮(SLE)是一种累及多系统、多器官的典型的自身免疫性疾病，其主要特点为淋巴细胞功能异常引起多种自身抗体的产生和免疫复合物的沉积。T细胞所参与的免疫应答是SLE机体整个免疫调节的核心。大量证据表明，T淋巴细胞尤其是CD4~+T细胞在SLE的发病中发挥重要作用。MRL／lpr和(NZB×NZW)F1两种狼疮模型小鼠具有多种与人类SLE相似的临床表现和病理生理学特征，因而常被用于研究人类SLE。
研究发现，CD4~+T细胞广泛浸润在受累组织中；去除CD4~+T细胞或MHCⅡ类分子基因敲除的MRL／lpr小鼠，可出现淋巴结病，但无自身抗体产生，且不出现狼疮肾炎表现；应用抗CD4单克隆抗体可改善两种狼疮模型鼠的发病症状。这些结果均表明CD4~+T细胞在狼疮鼠的发病中具有重要作用。但目前为止，克隆扩增并广泛浸润的致病性CD4~+T细胞克隆尚未被鉴定。SLE疾病中的抗原特异性T细胞的本质也尚不清楚。致病性CD4~+T细胞克隆的检出和鉴定将有利于阐明CD4~+T细胞克隆在SLE抗原特异性免疫反应中的作用，并有助于了解引起SLE发病的自身抗原的特点，从而为特异性免疫调节治疗提供靶点和新途径。本研究以致病性T细胞克隆为研究对象，通过对幼年未发病狼疮鼠和成年发病狼疮鼠的各脏器中浸润的T细胞克隆性的比较，发现广泛浸润的T细胞克隆，并分析其克隆扩增的特点及其细胞来源，进而通过对该细胞克隆TCR Vβ基因的测序，来分析其抗原特异性，从而揭示其在SLE中的致病作用及其所针对的自身抗原的结构特点，为特异性免疫调节治疗提供靶点和新途径。
采用RT-PCR-SSCP法分析MRL／lpr和(NZB×NZW)F1两种SLE模型小鼠各脏器中TCR Vβ1-19基因亚家族的表达及T细胞的克隆性；对广泛浸润在各脏器中的T细胞克隆的TCR Vβ6 CDR3片段进行DNA测序分析；并联合交叉应用磁珠细胞分离法、流式细胞仪细胞分选法和RT-PCR-SSCP分析法，来确定广泛浸润在各脏器中的T细胞表型。
本研究的主要结果如一F:
1.成年发病的MRL月pr和伽zBxNzw)Fl狼疮模型鼠中，存在广泛浸润在多脏器中
的相同的T细胞克隆，以双肾、脑、肺、小肠及淋巴结最为明显，各周龄、各TCR vp亚家
族中出现相同的T细胞克隆带的数量分别为:22周龄的MRL月Pr小鼠的TcR vpZ、TcR vp6、
TcR vps.l、TeR vpls的T细胞中分别出现3条相同的克隆带，TeR vpl6中出现2条，兀R
v印。中出现4条:26周龄的MRL月pr小鼠的TcRv两中出现2条，TCR vp10中出现3条;
40周龄的伽zBxNzW)FI小鼠的TCRV助和TCRv田中分别出现2条;47周龄的
伽zB、Nz幼Fl小鼠的TcRv呀中出现1条，TcRv阶中出现3条。而幼年未发病狼疮鼠各
脏器中虽可见T细胞克隆扩增带，但未见相同的T细胞克隆。
2.克隆扩增的T细胞呈TcR vp限制性:此广泛浸润的共同的T细胞克隆呈TcR vp
限制性扩增，即TCR vp基因存在优势取用:MRLllPr发病鼠存在v阳，v陌，v阶.1，v印0，vp16，
v印8的优势取用，困zBxNz钧Fl发病鼠仅存在v时和vp7基因的优势取用。
3.克隆扩增广泛浸润的T细胞为cD4+T细胞:c以+T细胞去除的细胞群及cD4+T
细胞和CDS+T细胞都去除的细胞群中，此共同浸润的T细胞克隆电泳带大多消失，而单纯
CDS+T细胞去除的细胞群中，此电泳带仍然存在。表明该两种狼疮发病鼠中克隆扩增并广泛
浸润的T细胞来源于CD4十T细胞。
4.克隆扩增并广泛浸润的T细胞为CD4+ CD69+T细胞:用队CS方法分选47周龄成
年发病的困zBxNzw)FI小鼠右侧肾脏中的eo4+en69+T细胞，经Rl;peR·sseP法分析，
发现CD4+ CD69+T细胞与左侧肾脏及其它脏器的总体T细胞存在相同的克隆扩增带，表明
此克隆扩增并广泛浸润的T细胞为活化的T细胞表型-一一毛D4十cO69+T细胞。
5.成年发病狼疮鼠中TcRv郎亚家族CDR3片段编码的氨基酸序列特点:该广泛浸
润的T细胞克隆的TcRv助cDR3片段，在不同个体的成年发病的狼疮鼠之间，存在相同的
氨基酸基序:四个个体中都出现‘r即异亮氨酸;三个个体出现‘G’即甘氨酸;四个个体中都出
现带阴离子电荷的酸性氨基酸，其中三个个体出现‘D’即天门冬氨酸，另外一个个体出现‘E’
即谷氨酸。提示该广泛浸润的T细胞克隆针对特定的自身抗原。
6.应用scion Imag。软件分析ssCP胶片上肾脏或脑组织中的各条电泳带的密度分布比
例。分析所得出的J‘一泛扩增的T细胞克隆在浸润于该组织中的T细胞总体中所占比例，分别
与实际DNA测序所得的比例相比，结果相近。表明实际的测序结果可靠。
一2-
幻
本研究的主要结论为:
1 .MRL八Pr和困zBxNzw)F1两种狼疮模型鼠在sLE发病时，cD4+T细胞被活化、呈
克隆性扩增，并厂‘泛浸润于多个脏器，表明其在狼疮肾炎和狼疮中枢神经系统损害的发病中
发挥重要作用。
2.此广泛浸润的cD4+T细胞克隆来源于cD4十cD69+T细胞，其克隆扩增呈TcR vp
限制性。
3.不同的狼疮模型鼠个体，在该特定的cD4+T细胞克隆的TcR vp基因c0R3区中
存在相同的氨基酸基序，表明其识别某种特定的自身抗原，参与SLE的特异性免疫应答。
本研究的主要创新点为:选择性地以狼疮模型鼠的致病性T细胞为研究对象，并非研
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of pathogenic autoantibodies and tissue deposition of immune complexes, which result in multiple organ damage. The MRL/lpr and (NZBNZW)F1 mouse that spontaneously develop a lupus syndrome closely resembling human SLE are considered to be excellent models for investigating the pathogenesis of the human disease.
It has been suggested that T-cell-dependent antigen-specific immune responses play a key role in the pathogenesis of these two strains. Published data have documented the involvement of T cells, especially CD4+ T cells, in lupus in the mouse. This involvement includes: 1) The infiltration of affected tissues with predominantly CD4+ T cells; 2) The development of lymphadenopathy but not autoimmune renal disease or autoantibodies in CD4+ T cell-deficient or MHC class II-deficient lupus mice; 3) Improvement in the disease manifestations following treatment with anti-CD4 mAb. These results suggest that CD4+ T cells play an important role in the development of lupus. Although the participation and importance of CD4+ T cells in lupus mice has been emphasized, the pathogenic CD4+ T cell clonotypes that expanded in different sites of these murine models have not yet been identified and characterized. Also, the nature of antigen-specific T cells in SLE still remains poorly defined. Detection and characterization of t
he pathogenic T cell clonotypes that expanded in lupus mice may help to illustrate the contribution of CD4+ T cell clones to the antigen-specific immune responses in SLE, give insight into the nature of the T cell Ags involved and provide possible immunoregulatory therapeutic way to SLE as well.
-1-
In order to address these questions and to further investigate the pathogenic role of CD4+ T cells clonally expanded in SLE, we compared the T cell clonality in different organs derived from young and nephritic (NZBNZW)F1 as well as MRL/lpr mice using the established RT-PCR-SSCP study in combination with CDR3 sequence analysis of the TCR VP family. Furthermore we use MACS and FACS cell sorting method combined with RT-PCR-SSCP analysis to identify the phenotype of the T cell commonly infiltrating in different organs. To test the accuracy of CDR3 sequence, we also perform the density analysis of T cell clonality based on SSCP image using Scion Image software.
Our RT-PCR-SSCP study of TCR Vp chain demonstrated that there were some identical T cell clonotypes expanded and accumulated in different organs in aged diseased mice. Most of these identical clonotypes were CD4+ T cells in both of the two strains. In contrast, young lupus mice exhibited little accumulation of common clone in different organs. The TCR VP usage of these identical clonotypes was limited in Vp2, VP6, VfJS.l, vpio, VP16, Vpl8 in MRL/lpr mouse and Vp6, VP? in (NZBNZW)F1 mouse respectively. Furthermore, some conserved amino acid motifs such as I and D were observed in CDR3 loops of TCR Vp from these identical CD4+ clonotypes in (NZBNZW)F1 mice. Likewise, I, G and D or E were also found in MRL/lpr mice. Density analysis of T cell clonality based on SSCP image using Scion Image software revealed the accurate result of CDR3 sequence analysis. The T cell phenotypic analysis showed the existence of the activated CD4+ T cell populations in different organs in aged (NZBNZW)F1 mouse and the FACS sorted CD
4+CD69+ cells from right kidney of this strain displayed the identical expanded clonotypes with the left kidney and other organs from the same individual.
These findings suggest that activated and clonally expanded CD4+ T cells commonly accumulated in different tissues in aged murine lupus models, and these CD4+ T cell clonotypes might recognize restricted T cell epitopes on autoantigens and are involved in specific immune responses of SLE, thus playing a pathogenic role in these lupus mice.
研究发现，CD4~+T细胞广泛浸润在受累组织中；去除CD4~+T细胞或MHCⅡ类分子基因敲除的MRL／lpr小鼠，可出现淋巴结病，但无自身抗体产生，且不出现狼疮肾炎表现；应用抗CD4单克隆抗体可改善两种狼疮模型鼠的发病症状。这些结果均表明CD4~+T细胞在狼疮鼠的发病中具有重要作用。但目前为止，克隆扩增并广泛浸润的致病性CD4~+T细胞克隆尚未被鉴定。SLE疾病中的抗原特异性T细胞的本质也尚不清楚。致病性CD4~+T细胞克隆的检出和鉴定将有利于阐明CD4~+T细胞克隆在SLE抗原特异性免疫反应中的作用，并有助于了解引起SLE发病的自身抗原的特点，从而为特异性免疫调节治疗提供靶点和新途径。本研究以致病性T细胞克隆为研究对象，通过对幼年未发病狼疮鼠和成年发病狼疮鼠的各脏器中浸润的T细胞克隆性的比较，发现广泛浸润的T细胞克隆，并分析其克隆扩增的特点及其细胞来源，进而通过对该细胞克隆TCR Vβ基因的测序，来分析其抗原特异性，从而揭示其在SLE中的致病作用及其所针对的自身抗原的结构特点，为特异性免疫调节治疗提供靶点和新途径。
采用RT-PCR-SSCP法分析MRL／lpr和(NZB×NZW)F1两种SLE模型小鼠各脏器中TCR Vβ1-19基因亚家族的表达及T细胞的克隆性；对广泛浸润在各脏器中的T细胞克隆的TCR Vβ6 CDR3片段进行DNA测序分析；并联合交叉应用磁珠细胞分离法、流式细胞仪细胞分选法和RT-PCR-SSCP分析法，来确定广泛浸润在各脏器中的T细胞表型。
本研究的主要结果如一F:
1.成年发病的MRL月pr和伽zBxNzw)Fl狼疮模型鼠中，存在广泛浸润在多脏器中
的相同的T细胞克隆，以双肾、脑、肺、小肠及淋巴结最为明显，各周龄、各TCR vp亚家
族中出现相同的T细胞克隆带的数量分别为:22周龄的MRL月Pr小鼠的TcR vpZ、TcR vp6、
TcR vps.l、TeR vpls的T细胞中分别出现3条相同的克隆带，TeR vpl6中出现2条，兀R
v印。中出现4条:26周龄的MRL月pr小鼠的TcRv两中出现2条，TCR vp10中出现3条;
40周龄的伽zBxNzW)FI小鼠的TCRV助和TCRv田中分别出现2条;47周龄的
伽zB、Nz幼Fl小鼠的TcRv呀中出现1条，TcRv阶中出现3条。而幼年未发病狼疮鼠各
脏器中虽可见T细胞克隆扩增带，但未见相同的T细胞克隆。
2.克隆扩增的T细胞呈TcR vp限制性:此广泛浸润的共同的T细胞克隆呈TcR vp
限制性扩增，即TCR vp基因存在优势取用:MRLllPr发病鼠存在v阳，v陌，v阶.1，v印0，vp16，
v印8的优势取用，困zBxNz钧Fl发病鼠仅存在v时和vp7基因的优势取用。
3.克隆扩增广泛浸润的T细胞为cD4+T细胞:c以+T细胞去除的细胞群及cD4+T
细胞和CDS+T细胞都去除的细胞群中，此共同浸润的T细胞克隆电泳带大多消失，而单纯
CDS+T细胞去除的细胞群中，此电泳带仍然存在。表明该两种狼疮发病鼠中克隆扩增并广泛
浸润的T细胞来源于CD4十T细胞。
4.克隆扩增并广泛浸润的T细胞为CD4+ CD69+T细胞:用队CS方法分选47周龄成
年发病的困zBxNzw)FI小鼠右侧肾脏中的eo4+en69+T细胞，经Rl;peR·sseP法分析，
发现CD4+ CD69+T细胞与左侧肾脏及其它脏器的总体T细胞存在相同的克隆扩增带，表明
此克隆扩增并广泛浸润的T细胞为活化的T细胞表型-一一毛D4十cO69+T细胞。
5.成年发病狼疮鼠中TcRv郎亚家族CDR3片段编码的氨基酸序列特点:该广泛浸
润的T细胞克隆的TcRv助cDR3片段，在不同个体的成年发病的狼疮鼠之间，存在相同的
氨基酸基序:四个个体中都出现‘r即异亮氨酸;三个个体出现‘G’即甘氨酸;四个个体中都出
现带阴离子电荷的酸性氨基酸，其中三个个体出现‘D’即天门冬氨酸，另外一个个体出现‘E’
即谷氨酸。提示该广泛浸润的T细胞克隆针对特定的自身抗原。
6.应用scion Imag。软件分析ssCP胶片上肾脏或脑组织中的各条电泳带的密度分布比
例。分析所得出的J‘一泛扩增的T细胞克隆在浸润于该组织中的T细胞总体中所占比例，分别
与实际DNA测序所得的比例相比，结果相近。表明实际的测序结果可靠。
一2-
幻
本研究的主要结论为:
1 .MRL八Pr和困zBxNzw)F1两种狼疮模型鼠在sLE发病时，cD4+T细胞被活化、呈
克隆性扩增，并厂‘泛浸润于多个脏器，表明其在狼疮肾炎和狼疮中枢神经系统损害的发病中
发挥重要作用。
2.此广泛浸润的cD4+T细胞克隆来源于cD4十cD69+T细胞，其克隆扩增呈TcR vp
限制性。
3.不同的狼疮模型鼠个体，在该特定的cD4+T细胞克隆的TcR vp基因c0R3区中
存在相同的氨基酸基序，表明其识别某种特定的自身抗原，参与SLE的特异性免疫应答。
本研究的主要创新点为:选择性地以狼疮模型鼠的致病性T细胞为研究对象，并非研
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of pathogenic autoantibodies and tissue deposition of immune complexes, which result in multiple organ damage. The MRL/lpr and (NZBNZW)F1 mouse that spontaneously develop a lupus syndrome closely resembling human SLE are considered to be excellent models for investigating the pathogenesis of the human disease.
It has been suggested that T-cell-dependent antigen-specific immune responses play a key role in the pathogenesis of these two strains. Published data have documented the involvement of T cells, especially CD4+ T cells, in lupus in the mouse. This involvement includes: 1) The infiltration of affected tissues with predominantly CD4+ T cells; 2) The development of lymphadenopathy but not autoimmune renal disease or autoantibodies in CD4+ T cell-deficient or MHC class II-deficient lupus mice; 3) Improvement in the disease manifestations following treatment with anti-CD4 mAb. These results suggest that CD4+ T cells play an important role in the development of lupus. Although the participation and importance of CD4+ T cells in lupus mice has been emphasized, the pathogenic CD4+ T cell clonotypes that expanded in different sites of these murine models have not yet been identified and characterized. Also, the nature of antigen-specific T cells in SLE still remains poorly defined. Detection and characterization of t
he pathogenic T cell clonotypes that expanded in lupus mice may help to illustrate the contribution of CD4+ T cell clones to the antigen-specific immune responses in SLE, give insight into the nature of the T cell Ags involved and provide possible immunoregulatory therapeutic way to SLE as well.
-1-
In order to address these questions and to further investigate the pathogenic role of CD4+ T cells clonally expanded in SLE, we compared the T cell clonality in different organs derived from young and nephritic (NZBNZW)F1 as well as MRL/lpr mice using the established RT-PCR-SSCP study in combination with CDR3 sequence analysis of the TCR VP family. Furthermore we use MACS and FACS cell sorting method combined with RT-PCR-SSCP analysis to identify the phenotype of the T cell commonly infiltrating in different organs. To test the accuracy of CDR3 sequence, we also perform the density analysis of T cell clonality based on SSCP image using Scion Image software.
Our RT-PCR-SSCP study of TCR Vp chain demonstrated that there were some identical T cell clonotypes expanded and accumulated in different organs in aged diseased mice. Most of these identical clonotypes were CD4+ T cells in both of the two strains. In contrast, young lupus mice exhibited little accumulation of common clone in different organs. The TCR VP usage of these identical clonotypes was limited in Vp2, VP6, VfJS.l, vpio, VP16, Vpl8 in MRL/lpr mouse and Vp6, VP? in (NZBNZW)F1 mouse respectively. Furthermore, some conserved amino acid motifs such as I and D were observed in CDR3 loops of TCR Vp from these identical CD4+ clonotypes in (NZBNZW)F1 mice. Likewise, I, G and D or E were also found in MRL/lpr mice. Density analysis of T cell clonality based on SSCP image using Scion Image software revealed the accurate result of CDR3 sequence analysis. The T cell phenotypic analysis showed the existence of the activated CD4+ T cell populations in different organs in aged (NZBNZW)F1 mouse and the FACS sorted CD
4+CD69+ cells from right kidney of this strain displayed the identical expanded clonotypes with the left kidney and other organs from the same individual.
These findings suggest that activated and clonally expanded CD4+ T cells commonly accumulated in different tissues in aged murine lupus models, and these CD4+ T cell clonotypes might recognize restricted T cell epitopes on autoantigens and are involved in specific immune responses of SLE, thus playing a pathogenic role in these lupus mice.
引文
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2. Giese T, Davidson WF. Evidence for early onset, polyclonal activation of T cell subsets in mice homozygous for lpr. J Immunol. 1992 Nov 1;149(9):3097-106.
3. Koh DR, Ho A, Rahemtulla A, et al. Murine lupus in MRL/Ipr mice lacking CD4 or CD8 T cells. Eur J Immunol. 1995 Sep;25(9):2558-62.
4. Jevnikar AM, Grusby M J, Glimcher LH. Prevention of nephritis in major histocompatibility complex class Ⅱ-deficient MRL-Ipr mice. J Exp Med. 1994 Apt 1;179(4): 1137-43.
5. Merino R, Iwamoto M, Fossati L, et al. Polyclonai B cell activation arises from different mechanisms in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice. J Immtmol. 1993 Dec 1;151(11):6509-16.
6. Jabs DA, Burek CL, Hu Q, et al. Anti-CD4 monoclonal antibody therapy suppresses autoimmune disease in MRL/Mp-lpr/lpr mice. Cell Immunol. 1992 May;141(2):496-507.
7. O'Sullivan FX, Ray C J, Takeda Y, et al. Long-term anti-CD4 treatment of MRL/Ipr mice ameliorates immunopathology and lymphoproliferation but fails to suppress rheumatoid factor production. Clin Immunol Immunopathol. 1991 Dec;61(3):421-35.
8. Santoro TJ, Portanova JP, Kotzin BL. The contribution of L3T4+ T cells to lymphoproliferation and autoantibody production in MRL-lpr/lpr mice. J Exp Med. 1988 May 1;167(5):1713-8.
9. Wofsy D, Seaman WE. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonai antibody to L3T4. J Exp Med. 1985 Feb 1;161(2):378-91.
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