银屑病患者外周血单一核细胞对链球菌M6蛋白反应的研究
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摘要
背景与目的：银屑病是一种原因未明的疾病，有多种原因可诱发，现多认为点滴型银屑病是由T细胞介导的与A族β溶血性链球菌感染有关的炎症性皮肤病。有人提出链球菌M6蛋白作为一种细菌性超抗原在点滴型银屑病发病过程中发挥着重要作用。超抗原是一类具有强烈刺激T细胞增殖潜能的微生物蛋白家族，研究认为超抗原在其作用中是通过刺激T淋巴细胞大量增殖，继而释放大量细胞因子而发挥作用的。经研究发现链球菌M6蛋白与人类50KDI型角蛋白存在高度的氨基酸同源系列，这些同源序列主要包括构成α-螺旋结构的七肽重复序列。在以往的研究中，我们从点滴型银屑病患者咽部感染菌群中分离出β溶血性链球菌，从中鉴定培养并提纯了M6蛋白，并发现点滴型银屑病患者血清中M6蛋白抗体滴度明显高于斑块型银屑病患者和正常人，初步证实点滴型银屑病与链球菌M6蛋白可能相关。本实验目的为进一步研究探讨A族β溶血性链球菌M6蛋白在点滴型银屑病发病中是否具有细菌超抗原作用机制。
方法：1．应用已提纯的M6蛋白，刺激点滴型银屑病患者外周血单一核细胞(PBMC)，观察PBMC对极微量M6蛋白(100ng)的增殖反应，并与斑块型和正常人群进行对照；同时采用目前公认并研究较多的葡萄球菌肠毒素B(SEB)作为超抗原对照，以破伤风类毒素(TT)作为普通抗原对照，以RPMI-1640作为空白对照。具体如下：收集确诊的点滴型、斑块型银屑病病例各30例及正常体检人员30名，各抽取静脉血4mL，采用密度梯度离心法分离得到PBMC，用RPMI-1640培养液配制成1×10~9／L细胞悬液，每孔100μL加入40孔细胞培养板，分别加入浓度为1mg／L的M6蛋白、SEB、TT、RPMI-1640
第四军医大学硕士学位论文
各100pL，37℃、5％CO。饱和湿度下培养6d，于培养结束前4h，每孔加入MTT
20pL，培养结束后加入甲蹦50卜L，应用自动酶标仪坝定双波长（570urn，455urn）
光密度值。同时观察了其中 12例点滴型银屑病患者应用不同浓度门 mg／L。
Zing／L、4mg／L、sing／L）M6蛋白、SEB引起 PBMC增殖反应的变化。2．检坝g
20例点滴型银屑病患者PBMC经M6蛋白刺激72h培养上清中IFN－Y及IL4
含量变化。具体方法为：点滴型银屑病患者 20例，将所得细胞悬液，每孔 lmL
加入 24孔细胞培养板，分别加入 M6蛋白、RPMIq（空白对照）各 100pL，
收集培养72h上清液300HL，离心后毛0C冻存待测。检测采用双抗夹心
ABC＊LISA法，严格按照试剂盒要求进行操作。
结果：1．浓度 ling／L的 M6蛋白 100pL（100n）可引起点滴型银屑病
患者P＊＊C明显增殖，与＊T对比差异非常显著（平均光密度值分别为0二3土0．05、
0．IO士0刀3，P（0刀01），而＊T与空白对照组间无显著性差异；P＊＊C对＊6蛋
白的反应在点滴型银屑病与斑块型银屑病及正常对照组差异非常显著（分别为
0．2310．05与0．1510．06、0．1710．04，P（0．001）。SEB弓起点滴型及斑块型银屑
病组PBMC的增殖反应与正常对照组比较差异显著；M6蛋白和SEB引起点滴
型银屑病患者PBMC的增殖反应不因其浓度的增加而增强。二．点滴型银屑病患
者PBMC经M6蛋白刺激培养72h后IFN－Y明显增加，与空白对照组相比差异
非常显著（A4。。分另为0．7310．33、0．24f0．16，P（0刀of）。M6蛋白束激组及空
白对照组培养72h后IL－4含量无明显变化。
结论：1．极微量M6蛋白可致使点滴型银屑病患者PBMC明显增殖，而相
同量的普通抗原未能出现同样结果；这种增殖反应不因M6蛋白浓度增加而增
强。在点滴型银屑病发病中溶血性链球菌M6蛋白可能是作为细菌性超抗原刺
激T细胞大量增殖而发挥作用。2．M6蛋白刺激点滴型银屑病患者PBMC增殖
后引起了 TM细胞因子 IFN－Y含量明显增加，而 ThZ细胞因子巳－4无变化。
M6蛋白的作用可能是作为细菌性超抗原刺激淋巴细胞大量增殖并产生Thl细
5
第四军医大学硕士学位论文
胞因子而发挥作用的。
我们的研究显示：从点滴型银屑病患者咽部菌群中分离提纯的链球菌M6
蛋白与点滴型银屑病关系密切，其作用机制可能是作为一种细菌性超抗原刺激
点滴型银屑病患者淋巴细胞大量增殖并产生 IFN1等 Th细胞因子，破坏机体
Th／ThZ平衡而发挥作用的。
Background & Objectives: Psoriasis is a kind of skin disease with unclear causes, which can be triggered by many factors. It's widely acknowledged guttate psoriasis is a T-cell mediated inflammatory skin disease which has been associated with group A, (3 haemolytic streptococcal infections. There is hypothesis that streptococcal M6 protein, as a germ superantigen, play an key role in the pathogenesis of psoriasis. Superantigens belong to a family of immunoglobulin proteins which greatly stimulate the proliferation potential of T-cells. Study shows that streptococcal M6-protein share high ammal acid sequence homology with 50 kDa type-I human epidermal keratin. The consensus sequences mainly include highly repeated 7-peptide sequences which comprise of α-helical structure. In former studies, β-haemolytic streptococci were separated from throat infection isolates of psoriasis patients. They were cultured and the M6-protein were purified. It was
found that the titer of antibodies to M6-protein was apparently higher in serum of guttate psoriasis patients than plaque psoriasis patients and normal group, preliminarily proving the close association between streptococcal M6 protein and guttate psoriasis patients. The purpose of this paper is to further explore if there is a mechanism of group A, β-type streptococcal M6 protein as superantigen in the pathogenesis of guttate psoriasis. Methods:
we applied purified M6 protein to stimulate peripheral blood mononuclear cells(PBMC) from guttate psoriasis patients, observing PBMC's proliferation response to trace M6-protein (100ng).Comparation was done to plaque psoriasis and normal group, with staphylococcal enterotoxin (SEB) as superantigen which is widely recognized, and tetanus toxin (TT) as ordinary antigen, PRMI-1640 as negative control. Detail methods were as follows: during May 2001 to June 2002, totally 30 confirmed guttate psoriatic patients and 30 normal controls, were selected, 4mL venous blood were extracted from each of the above individual. PBMCs were seperated by means of density gradient centrifugal method, and 1 × 109 /L cells were suspended in
RPMI-1640 culture medium. Each 100uL of cell suspension was added into each well of 40-well plate. Then lOOuL of each of the following reagents (1mg/L for all): M6-protein ,SEB,TT,RPMI-1640 was added into each well respectively and cultivated at 37℃, 5% CO2, saturated relative humidity for 6d. 4 hours before culturing ending, 20uL MTT was added to each of the well. After culturing, 150uL of formazan was further added (to each well) . A microplate reader was employed to measure the absorbance of light with doubwave lengthes (570nm , 455nm) . Observations were made on the proliferation changes among 20 guttate psoriatic patients at different concentration (1mg/L, 2mg/L, 4mg/L, 8mg/L) of M6 and SEB.
To further study the mechanism of PBMC proliferation in response to M6-protein in psoriasis, we tested the concentration change of IFN-γ and IL-4 in supernant of PBMC from 20 guttate psoriatic patients after M6-protein stimulation. For guttate psriatic patients, 1mL of above supernatant, lOOuL of M6, RPMI-1640 was added to each well of a 24 -well plate respectively. 300uL of supernatant was collected after 72 hr cultivation. After centrifugation, the supernatant was freezed at -20℃for storage, or tested by ABC-ELISA.
Results:
long M6-protein resulted in significant proliferation of PBMC in guttate psoriasis patients, which was obvious higher than that of tetanus toxin(TT) and RPMI-1640 at same concentration(P<0.001); It was also observed there existed signigicant difference of PBMC proliferation in response to M6-protein among guttate psoriasis, plaque psoriasis and normal group (P<0.001); significant difference of PBMC proliferation in response to SEB among guttate psoriasis, plaque psoriasis and normal group; no difference of PBMC proliferation in response to varied concentration of M6-protein and SEB among guttate psoriasis. That showes very low concentration M6-protein results in significant P
方法：1．应用已提纯的M6蛋白，刺激点滴型银屑病患者外周血单一核细胞(PBMC)，观察PBMC对极微量M6蛋白(100ng)的增殖反应，并与斑块型和正常人群进行对照；同时采用目前公认并研究较多的葡萄球菌肠毒素B(SEB)作为超抗原对照，以破伤风类毒素(TT)作为普通抗原对照，以RPMI-1640作为空白对照。具体如下：收集确诊的点滴型、斑块型银屑病病例各30例及正常体检人员30名，各抽取静脉血4mL，采用密度梯度离心法分离得到PBMC，用RPMI-1640培养液配制成1×10~9／L细胞悬液，每孔100μL加入40孔细胞培养板，分别加入浓度为1mg／L的M6蛋白、SEB、TT、RPMI-1640
第四军医大学硕士学位论文
各100pL，37℃、5％CO。饱和湿度下培养6d，于培养结束前4h，每孔加入MTT
20pL，培养结束后加入甲蹦50卜L，应用自动酶标仪坝定双波长（570urn，455urn）
光密度值。同时观察了其中 12例点滴型银屑病患者应用不同浓度门 mg／L。
Zing／L、4mg／L、sing／L）M6蛋白、SEB引起 PBMC增殖反应的变化。2．检坝g
20例点滴型银屑病患者PBMC经M6蛋白刺激72h培养上清中IFN－Y及IL4
含量变化。具体方法为：点滴型银屑病患者 20例，将所得细胞悬液，每孔 lmL
加入 24孔细胞培养板，分别加入 M6蛋白、RPMIq（空白对照）各 100pL，
收集培养72h上清液300HL，离心后毛0C冻存待测。检测采用双抗夹心
ABC＊LISA法，严格按照试剂盒要求进行操作。
结果：1．浓度 ling／L的 M6蛋白 100pL（100n）可引起点滴型银屑病
患者P＊＊C明显增殖，与＊T对比差异非常显著（平均光密度值分别为0二3土0．05、
0．IO士0刀3，P（0刀01），而＊T与空白对照组间无显著性差异；P＊＊C对＊6蛋
白的反应在点滴型银屑病与斑块型银屑病及正常对照组差异非常显著（分别为
0．2310．05与0．1510．06、0．1710．04，P（0．001）。SEB弓起点滴型及斑块型银屑
病组PBMC的增殖反应与正常对照组比较差异显著；M6蛋白和SEB引起点滴
型银屑病患者PBMC的增殖反应不因其浓度的增加而增强。二．点滴型银屑病患
者PBMC经M6蛋白刺激培养72h后IFN－Y明显增加，与空白对照组相比差异
非常显著（A4。。分另为0．7310．33、0．24f0．16，P（0刀of）。M6蛋白束激组及空
白对照组培养72h后IL－4含量无明显变化。
结论：1．极微量M6蛋白可致使点滴型银屑病患者PBMC明显增殖，而相
同量的普通抗原未能出现同样结果；这种增殖反应不因M6蛋白浓度增加而增
强。在点滴型银屑病发病中溶血性链球菌M6蛋白可能是作为细菌性超抗原刺
激T细胞大量增殖而发挥作用。2．M6蛋白刺激点滴型银屑病患者PBMC增殖
后引起了 TM细胞因子 IFN－Y含量明显增加，而 ThZ细胞因子巳－4无变化。
M6蛋白的作用可能是作为细菌性超抗原刺激淋巴细胞大量增殖并产生Thl细
5
第四军医大学硕士学位论文
胞因子而发挥作用的。
我们的研究显示：从点滴型银屑病患者咽部菌群中分离提纯的链球菌M6
蛋白与点滴型银屑病关系密切，其作用机制可能是作为一种细菌性超抗原刺激
点滴型银屑病患者淋巴细胞大量增殖并产生 IFN1等 Th细胞因子，破坏机体
Th／ThZ平衡而发挥作用的。
Background & Objectives: Psoriasis is a kind of skin disease with unclear causes, which can be triggered by many factors. It's widely acknowledged guttate psoriasis is a T-cell mediated inflammatory skin disease which has been associated with group A, (3 haemolytic streptococcal infections. There is hypothesis that streptococcal M6 protein, as a germ superantigen, play an key role in the pathogenesis of psoriasis. Superantigens belong to a family of immunoglobulin proteins which greatly stimulate the proliferation potential of T-cells. Study shows that streptococcal M6-protein share high ammal acid sequence homology with 50 kDa type-I human epidermal keratin. The consensus sequences mainly include highly repeated 7-peptide sequences which comprise of α-helical structure. In former studies, β-haemolytic streptococci were separated from throat infection isolates of psoriasis patients. They were cultured and the M6-protein were purified. It was
found that the titer of antibodies to M6-protein was apparently higher in serum of guttate psoriasis patients than plaque psoriasis patients and normal group, preliminarily proving the close association between streptococcal M6 protein and guttate psoriasis patients. The purpose of this paper is to further explore if there is a mechanism of group A, β-type streptococcal M6 protein as superantigen in the pathogenesis of guttate psoriasis. Methods:
we applied purified M6 protein to stimulate peripheral blood mononuclear cells(PBMC) from guttate psoriasis patients, observing PBMC's proliferation response to trace M6-protein (100ng).Comparation was done to plaque psoriasis and normal group, with staphylococcal enterotoxin (SEB) as superantigen which is widely recognized, and tetanus toxin (TT) as ordinary antigen, PRMI-1640 as negative control. Detail methods were as follows: during May 2001 to June 2002, totally 30 confirmed guttate psoriatic patients and 30 normal controls, were selected, 4mL venous blood were extracted from each of the above individual. PBMCs were seperated by means of density gradient centrifugal method, and 1 × 109 /L cells were suspended in
RPMI-1640 culture medium. Each 100uL of cell suspension was added into each well of 40-well plate. Then lOOuL of each of the following reagents (1mg/L for all): M6-protein ,SEB,TT,RPMI-1640 was added into each well respectively and cultivated at 37℃, 5% CO2, saturated relative humidity for 6d. 4 hours before culturing ending, 20uL MTT was added to each of the well. After culturing, 150uL of formazan was further added (to each well) . A microplate reader was employed to measure the absorbance of light with doubwave lengthes (570nm , 455nm) . Observations were made on the proliferation changes among 20 guttate psoriatic patients at different concentration (1mg/L, 2mg/L, 4mg/L, 8mg/L) of M6 and SEB.
To further study the mechanism of PBMC proliferation in response to M6-protein in psoriasis, we tested the concentration change of IFN-γ and IL-4 in supernant of PBMC from 20 guttate psoriatic patients after M6-protein stimulation. For guttate psriatic patients, 1mL of above supernatant, lOOuL of M6, RPMI-1640 was added to each well of a 24 -well plate respectively. 300uL of supernatant was collected after 72 hr cultivation. After centrifugation, the supernatant was freezed at -20℃for storage, or tested by ABC-ELISA.
Results:
long M6-protein resulted in significant proliferation of PBMC in guttate psoriasis patients, which was obvious higher than that of tetanus toxin(TT) and RPMI-1640 at same concentration(P<0.001); It was also observed there existed signigicant difference of PBMC proliferation in response to M6-protein among guttate psoriasis, plaque psoriasis and normal group (P<0.001); significant difference of PBMC proliferation in response to SEB among guttate psoriasis, plaque psoriasis and normal group; no difference of PBMC proliferation in response to varied concentration of M6-protein and SEB among guttate psoriasis. That showes very low concentration M6-protein results in significant P
引文
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[30] Baker BS, Brown DW, Fischetti VA, Ovigne JM, Porter W, Powles A, Fry L. Skin T cell proliferative to M protein and other cell wall and membrane protein of group A streptococci in chronic plaque psoriasis. Clin Exp Immunol, 2001; 124(3): 516-521.
[31] Brown DW, Baker BS, Ovigne JM, Hardman C, Powles AV, Fry L. Skin CD4~+ T cells produce interferon-gamma in vitro in response to streptococcal antigens in chronic plaque psoriasis. J Invest Dermatol, 2000; 114(3): 576-580.
[32] Frankel DH. Skin cancer. Lancet, 1996; 347(9002): 634
[33] Telfer NR, Chalmers RJ, Whale K. The role of streptococcal infeection in the initiation of guttate psoriasis. Arch Dermatol, 1992; 128(1): 39-42
[34] Valdimarsson H, Sigmundsdottir H, Jonsdottir I. Is psoriasis induced by streptococcal superantigens and maintained by M-protein-specific T cells that cross-react with keratin? Clin Exp Immunol, 1997; 107 (S1): 21-24
[35] 赵广，冯晓玲，江永强等。聚合酶链式反应检测银屑病患者咽部菌群中M6蛋白。临床皮肤科杂志，2000，29(2)：87-89．
[36] 赵广，冯晓玲，那爱华等。银屑病患者血清中链球菌M6蛋白抗体的检测。临床皮肤科杂志，2002，31(4)：213-214．
[37] 张峻岭，陈学荣，殷金珠。银屑病患者淋巴细胞对葡萄球菌和链球菌超抗原刺激的反应。中华皮肤科杂志，1999，32(2)：126。
[38] Valdimarsson H, Baker BS, Jonsdottir I, et al. Psoriasis: a T-cell mediatedated autoimmune disease induced by steptococcal superantigens? Immunol Today, 1995; 16(3): 145-149
[39] Leung DM, Travers JB, Norris DA, et al. The role of superantigens in skin
disease. J Invesl Dermatol, 1995; 105(1 suppl): 39s-42s.
[40] Singh VK, Mehrotra S, Agarwal SS. The paradigm of Th1 and Th2 cytokines: its relevance to autoimmunity and allergy. Immunol Res, 1999; 20 (2): 147-161。
[41] Mozzanica N, Cattaneo A, Trabattoni D, et al. Production of type-1 and type-2 cytokines by peripheral blood mononuclear cells of psoriasis patients. Immunology, 1995; 86 (3):422-426.
[42] Austin LM, Ozawa M, Kikuchi T, et al. The majority of epidermal T cells in psoriasis vulgaris lesions can produce type-1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and Thleffector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol, 1999; 113 (5):752-759.
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