本文選題：格林-巴利綜合征 + 白細胞介素-22��； 參考：《鄭州大學》2014年碩士論文

【摘要】：研究目的與背景 格林—巴利綜合征(Guillain—Barre Syndrome,GBS)是一種常見的多發(fā)性脊神經和周圍神經的脫髓鞘疾病，由體液免疫及細胞免疫共同介導，又稱為對稱性多神經根炎或急性特發(fā)性多神經炎。臨床上表現為進行性上升性對稱性麻痹、四肢軟癱，以及不同程度的感覺障礙。細胞因子在自身免疫損傷中起到啟動、維持和調節(jié)的作用，細胞因子在GBS及其動物模型ENA中的作用受到越來越多的學者關注，經大量實驗研究表明，免疫性疾病的發(fā)展與轉歸是由促炎性細胞因子及抑炎性細胞因子介導的Th1/Th2型細胞間平衡的改變造成的。白細胞介素-22(Interleukin-22,IL-22)是最近發(fā)現的IL-10細胞因子家族中的成員之一，NK細胞、γδT細胞、LTi細胞、Th17細胞、Th22細胞均可產生IL-22，其中Th17細胞是一種CD4+T效應細胞，可分泌多種細胞因子，如IL-2、IL-17A、IL-17F、IL-22，在實驗性自身免疫性腦炎的小鼠模型（EAE）中，IL-17mRNA基因水平和蛋白質水平均升高，IL-22及IL-17在多種體外試驗及動物模型中被證實可相互協(xié)同，共同參與促炎性免疫反應，同時，在腫瘤細胞中，IL-22可誘導結合珠蛋白、血清淀粉樣蛋白、α1抗胰凝乳蛋白酶等急性反應期蛋白的產生。白介素-37（Interleukin-37,IL-37）是IL-1細胞因子家族中的成員之一，IL-37在巨噬細胞或上皮細胞內表達，可以抑制TLR誘導的促炎因子IL-1α、IL-1β、IL-18、IFN-γ和TNF-α的產生、釋放以及促進樹突狀細胞的活性，也可以促進CD4+CD25+調節(jié)性T細胞的表達，從而有效的抑制免疫應答。此次研究通過檢測GBS患者急性期及恢復期血清中IL-22及IL-37的濃度，探討這兩種細胞因子在GBS發(fā)病及轉歸的過程中可能起到的作用，為新的GBS治療方案提供進一步的理論基礎。 資料和方法 收集2012年9月至2014年2月間在鄭州大學第一附屬醫(yī)院神經內科住院的GBS患者共51例，其中男性患者30例，女性患者21例，年齡8~74歲，平均(42.00±18.23)歲。所有入選的GBS患者均經過我院神經內科兩名以上醫(yī)師詳細詢問病史、神經系統(tǒng)�？企w檢、肌電圖檢查及腦脊液檢測，檢查結果符合Asbury等于1990年制定的診斷標準，然后對所有入選患者進行Hughes評分來評測疾病的嚴重程度。選取同一時期在我院門診體檢的健康志愿(Healthy Control，HC)者31例為對照組，其中男性19例，女性12例，年齡8~66歲，平均(40.61±18.23)歲。抽血前無手術史、免疫治療史，無感染性疾病、腫瘤、心腦血管疾病等。實驗組和對照組年齡及性別差別無統(tǒng)計學意義。 在采血前，每位健康人及患者需禁食、禁水10小時以上。在第二日清晨抽取肘靜脈血3ml，隨后置于真空采血管中（無抗凝劑），，放入-80℃冰箱備用。GBS患者組均于急性期（起病l～14天）和恢復期（起病30～60天）分別采集肘靜脈血標本。健康對照組僅采集一次靜脈血標本。采用雙抗體夾心酶聯免疫吸附方法(Enzyme Linked Immunosorbent Assay,ELISA)測定血清中IL-22和IL-37的水平。采用SPSSl7．0軟件包處理所有數據，應用均數±標準差(x±s)表示定量資料。運用兩獨立樣本t檢驗進行兩組定量資料的比較，運用Spearman相關系數分析兩組定量資料的相關性，運用單因素方差分析進行多組定量資料的比較，隨后采用組間比較(LSD檢驗)法，若P0.05，表示差異有統(tǒng)計學意義。 結果 1.GBS患者組急性期、恢復期與對照組血清IL-22水平的比較：GBS患者組急性期血清IL-22水平(110.70±24.37)ng/L較恢復期(78.32±11.68)ng/L顯著升高，P=0.001；較對照組(75.62±15.00)ng/L顯著升高，P=0.000；GBS患者組恢復期血清IL-22水平雖有所下降，但仍較對照組升高，P=0.030。 2.GBS患者組恢復期、急性期與對照組血清IL-37水平的比較：GBS患者組恢復期血清IL-37水平(84.38±6.67)ng/L較急性期(62.80±9.29)ng/L顯著升高，P=0.004；較對照組(57.82±16.11)ng/L顯著升高，P=0.000；GBS患者組急性期血清IL-37水平雖較恢復期降低，但仍較對照組升高，P=0.039。 3.GBS患者急性期血清IL-22及IL-37水平與疾病嚴重程度的關系：GBS患者急性期血清中IL-22水平與Hughes評分顯著相關，r=0.803，P=0.001；GBS患者急性期血清中IL-37水平與Hughes評分無明顯相關性，r=-0.246，P=0.082。 4.GBS患者恢復期血清IL-22及IL-37水平與疾病嚴重程度的關系：GBS患者恢復期血清中IL-22水平與Hughes評分無明顯相關性，r=0.029，P=0.839；GBS患者恢復期血清中IL-37水平與Hughes評分顯著相關，r=-0.766，P=0.000。 5.各類型GBS患者急性期血清IL-22及IL-37水平的比較：脫髓鞘+軸索型GBS患者急性期血清IL-22水平(141.13±23.45)ng/L較軸索型(108.41±9.25)ng/L升高，P=0.002，較脫髓鞘型(90.45±3.62)ng/L顯著升高，P=0.000,軸索型GBS患者急性期血清IL-22水平較脫髓鞘型升高,P=0.004；脫髓鞘+軸索型、軸索型、脫髓鞘型患者急性期血清中IL-37水平的差異無統(tǒng)計學意義，F=3.098P=0.054。 6.各類型GBS患者恢復期血清IL-22及IL-37水平的比較：脫髓鞘+軸索型、軸索型、脫髓鞘型患者恢復期血清中IL-22水平的差異無統(tǒng)計學意義，F=0.473P=0.626；脫髓鞘型GBS患者恢復期血清IL-37水平(90.10±3.72)ng/L，較軸索型(84.44±3.06)ng/L升高，P=0.010，較脫髓鞘+軸索型(75.52±3.30)ng/L顯著升高，P=0.000軸索型GBS患者恢復期血清IL-37水平，較脫髓鞘+軸索型升高，P=0.005。 結論 1.IL-22在GBS患者急性期與恢復期血清中的表達水平均較對照組顯著升高，推測IL-22可能參與GBS免疫應答。GBS患者急性期IL-22水平較恢復期升高更顯著，考慮IL-22可能主要在免疫應答起始階段起促炎作用。 2.IL-37在GBS患者急性期與恢復期血清中的表達水平均較對照組顯著升高，考慮IL-37可能參與GBS免疫應答。GBS患者恢復期IL-37水平較急性期升高更顯著，考慮IL-37可能主要在疾病恢復期起抑炎性作用。 3.IL-22在GBS患者急性期血清中的表達水平與疾病嚴重程度呈正相關，IL-22水平越高，病情越重；IL-37在GBS患者恢復期血清中的表達水平與疾病嚴重程度呈負相關，IL-37水平越高，病情越輕。 4.GBS患者急性期IL-22升高可能參與髓鞘脫失及軸索的損害，其顯著升高可能提示預后不良，GBS患者恢復期IL-37升高可能參與髓鞘及軸索的修復，其顯著升高可能提示預后較好。
[Abstract]:Research purpose and background
Green Barre syndrome (Guillain Barre Syndrome, GBS) is a common multiple spinal and peripheral nerve demyelinating disease, which is mediated by humoral immunity and cell immunity. It is also known as symmetric multiple neuropathy or acute idiopathic multiple neuritis. It is clinically manifested as progressive symmetrical paralysis and soft paralysis of the limbs. As well as different degree of sensory disturbance. Cytokine plays the role of initiation, maintenance and regulation of autoimmune injury. The role of cytokines in GBS and its animal model ENA is concerned by more and more scholars. A large number of experimental studies have shown that the development and outcome of immune diseases are derived from proinflammatory cytokines and anti inflammatory cells. Factor mediated changes in the balance between Th1/Th2 type cells. Interleukin-22 (IL-22) is one of the members of the recently discovered IL-10 cell factor family, NK cells, NK cells, LTi cells, Th17 cells, Th22 cells can produce IL-22, and Th17 cells are a kind of effector cells, which can secrete a variety of cytokines. Such as IL-2, IL-17A, IL-17F, IL-22, in the mouse model of experimental autoimmune encephalitis (EAE), the IL-17mRNA gene level and protein level are increased. IL-22 and IL-17 have been confirmed in a variety of in vitro experiments and animal models to cooperate with each other to participate in the inflammatory response, and in the tumor cells, IL-22 can induce the combination of Pearl eggs. White, serum amyloid, alpha 1 anti - pancreatic chymotrypsin and other acute reaction proteins. -37 (Interleukin-37, IL-37) is one of the members of the IL-1 cell factor family. IL-37 is expressed in macrophages or epithelial cells, which inhibits the production of TLR induced proinflammatory cytokines, IL-1 a, IL-1 beta, IL-18, IFN- gamma, and TNF- alpha. And promoting the activity of dendritic cells can also promote the expression of CD4+CD25+ regulatory T cells, and thus effectively inhibit the immune response. This study explored the possible role of these two cytokines in the pathogenesis and return of GBS by detecting the concentrations of IL-22 and IL-37 in the serum of GBS patients at acute and convalescent stages, as a new GBS. The treatment scheme provides a further theoretical basis.
Information and methods
A total of 51 GBS patients were hospitalized in the Department of Neurology of the First Affiliated Hospital of Zhengzhou University from September 2012 to February 2014. There were 30 male patients, 21 female patients, age 8~74 years, average (42 + 18.23) years old. All the selected GBS patients were examined by more than two physicians in the Department of Neurology in our hospital. The results of electromyography and cerebrospinal fluid examination were in accordance with the diagnostic criteria of Asbury equal to 1990, and then Hughes scores were used to evaluate the severity of the disease. 31 cases of Healthy Control (HC) in the same period of our hospital were selected as the control group, including 19 males and 12 females. The average age of 8~66 years was (40.61 + 18.23) years old. There was no history of operation, history of immunotherapy, no infectious disease, tumor, cardiovascular and cerebrovascular diseases before blood extraction. There was no statistical difference between the age and sex of the experimental group and the control group.
Before the blood collection, every healthy person and patient need to fasting and prohibit water for more than 10 hours. Extraction of 3ml in the elbow vein blood on the early morning of second, then placed in the vacuum blood vessel (no anticoagulant), and put into the acute phase (L to 14 days) and the recovery period (30~60 days of the onset of disease) to collect the blood specimens of the elbow vein, and the healthy control group. Only one venous blood specimen was collected. The level of IL-22 and IL-37 in serum was measured by Enzyme Linked Immunosorbent Assay (ELISA). All data were processed with SPSSl7.0 software package, and the quantitative data were expressed by mean standard deviation (x + s). Two groups of quantitative data were carried out by two independent sample t test. In comparison, the correlation of two groups of quantitative data was analyzed with Spearman correlation coefficient, and the comparison of multiple quantitative data was carried out by single factor analysis of variance. Then group comparison (LSD test) method was used, if P0.05, the difference was statistically significant.
Result
In the acute phase of 1.GBS patients, the comparison of serum IL-22 levels in the acute phase and the control group: the level of serum IL-22 in the acute phase of the GBS patients (110.70 + 24.37) ng/L was significantly higher than that in the recovery period (78.32 + 11.68) ng/L, P=0.001; the ng/L was significantly higher than the control group (75.62 + 15) ng/L, P=0.000, although the serum IL-22 level in the recovery period of the GBS patients decreased, but still remained. Higher than the control group, P=0.030.
In the convalescent period of 2.GBS patients, the comparison of serum IL-37 levels between the acute phase and the control group: the level of serum IL-37 in the convalescent period of the GBS patients (84.38 + 6.67) was significantly higher than that in the acute phase (62.80 + 9.29) ng/L, P=0.004; the ng/L was significantly higher than the control group (57.82 + 16.11) ng/L, and the serum IL-37 level in the acute phase of the GBS patients was lower than the recovery period, but the level of serum IL-37 was lower than that of the control group, but the serum IL-37 level was lower than the recovery period. It is still higher than the control group, P=0.039.
The relationship between serum IL-22 and IL-37 levels in the acute phase of 3.GBS and the severity of the disease: the level of IL-22 in serum of patients with GBS was significantly correlated with the Hughes score, r=0.803, P=0.001, and there was no significant correlation between the IL-37 level and Hughes score in the acute phase of GBS patients.
The relationship between the level of serum IL-22 and IL-37 and the severity of the disease in the convalescent period of 4.GBS patients: there was no significant correlation between the serum IL-22 level and the Hughes score in the recovery period of GBS patients, r=0.029, P=0.839, and the IL-37 level in the serum of GBS patients was significantly related to the Hughes score. R=-0.766
5. comparison of serum IL-22 and IL-37 levels in acute phase of GBS patients: the level of serum IL-22 in patients with demyelinating + axonal GBS (141.13 + 23.45) ng/L was higher than that of axonal type (108.41 + 9.25) ng/L, P=0.002, and demyelinating type (90.45 + 3.62) ng/L increased significantly. P=0.000, the serum IL-22 level of axonal GBS patients was higher than demyelinating type. There was no significant difference in serum IL-37 level between the high and P=0.004, demyelination + axonal type, axonal type and demyelinating patients, F=3.098P=0.054.
6. the comparison of serum IL-22 and IL-37 levels in the recovery period of all types of GBS patients: the difference in serum IL-22 levels in demyelinating + axonal type, axonal type and demyelinating patients was not statistically significant, F=0.473P=0.626; the serum IL-37 level (90.10 + 3.72) ng/L in demyelinating GBS patients was higher than that of axonal type (84.44 + 3.06) ng/L, P=0.010, Compared with demyelination + axonal type (75.52 + 3.30) ng/L, the serum IL-37 level of P=0.000 axonal GBS patients was higher than that of demyelination + axonal type, P=0.005.
conclusion
The expression level of 1.IL-22 in the acute and convalescent serum of GBS patients was significantly higher than that in the control group. It is suggested that IL-22 may participate in the acute phase of GBS immune response to.GBS patients with higher level of IL-22 than that of the recovery period, and IL-22 may be used primarily in the initial stage of the immune response.
The expression level of 2.IL-37 in the acute and convalescent serum of GBS patients was significantly higher than that in the control group. Considering that IL-37 may participate in the GBS immune response of.GBS patients, the level of IL-37 was more significant in the convalescence period, and IL-37 might be mainly in the recovery period of the disease.
The expression level of 3.IL-22 in the acute phase of GBS patients was positively correlated with the severity of the disease, the higher the level of IL-22, the heavier the disease, and the negative correlation between the serum level of IL-37 in the recovery period of GBS patients and the severity of the disease, the higher the level of IL-37, the lighter the disease was.
The elevation of IL-22 in patients with 4.GBS may be involved in myelin loss and axonal damage. The significant increase may indicate poor prognosis. The increase of IL-37 in the recovery period of GBS may be involved in the repair of myelin and axon, which may suggest a better prognosis.

【學位授予單位】：鄭州大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R744

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