SS-干燥综合症发病机制研究
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How about macrophages?
I FN α Autoanti gen
N Fκ B pathw ay dysfuncti on i n pSS pa O ne of the consequences of the stim ul im m unity is the acti vation ofnucl ear fac BAFF w hich can occur in a num ber of differe I FN γ salivary gland epithelialcells from pat I Cs hyperactivation of N Fκ B has been a decreased expression of one of the regu Th17 acti vation,A 20 (al so know n as TN F-α -i n 28 Bcel l [T N FA IP3]). Interestingly, defective acti vati on another gene invol ved in feedback regu B cel l TFH cel l N Fκ Bi nhi bi tor α (al so know n as Iκ Bα ),l e 29 m ent of a pSS phenotype in m ice. Fu Pl asm a G Cl i ke cel l first G W A S in pSS14 identified an assoc structure this disease and a gene (TN IP1) encod Figure 1 |S chem ati c representati on of the pathophysi ol ogy processes interacting protein 1,a protein that inte hypothesi zed to underl i e pS S ,based on Lin our current understandi Envi ronmRheum ental X, et al ng. Ann (2015) andDis. is involved in the regulation of N F factors such a vi rus or other acti vators of i nnate i m m uni ty cause epi thel i alcel land Together, these observations suggest D C acti vati on (see B ox 1 for a descri pti on of how vi ruses m i ght i nsti gate
TH 1 cel l
?
原发性干燥综合征 ---- 目前研究的挑战？ • 干燥综合征的动物模型: 继发性?
( Spontaneous
SS animal models)
1. NOD --- I 型糖尿病 2. (NZB+NZW)F1--- 红斑狼疮 3. Fas(lpr) --- 红斑狼疮
* 基因修饰的动物模型:
Vi rus?
O ther acti vator of i nnate i m m uni ty?
Epi thel i alcel l pD C NK cel l N Kcel l IL12 acti vati on IL12R DC Tcel l acti vati on
infil trate i n sal i va potenti a pSS cou retrovir be consi respons system . expressi responsi
干燥综合征的发病机制及转化研究
香港大学 吕力为
干燥综合征
(Sjögren's Syndrome)
• Dry eyes, dry mouth • A systemic disease
Karolinska Institutet
1933
干燥综合征是一种多发病
1993
张乃峥教授
Epidemiology of primary Sjögren’s Syndrome
泪腺炎症----淋巴细胞浸润，组织破坏
Tear Flow Rate (uL/15 min))
泪液
25 20 15 10 5 0 Ctrl
***
ESS
CD19 CD4 Hoechst
肺和肾间质纤维化及淋巴细胞浸润
CD19 GL-7
CD45 IgG IgM Hoechst
Infiltration of T and B cells in the salivary gland of ESS mice
constitutive: β1, β2, β5 immuno-proteasome: β1i, β2i, β5i (LMP7)
炎症中的免疫细胞 蛋白酶体表达增高
NF-kB pathway:
Survival, apoptosis, cytokine production …
IFN α Autoanti gen
Costa et al, Arthritis Res Ther 2015
N Fκ Bp O ne of im m uni BAFF w hich c IFN γ salivary ICs hyperac decrease Th17 acti vatio Bcel l [T N FA I acti vati on another B cel l TFH cel l N Fκ B in m ent of Pl asm a G Cl i ke cel l first G W structure this dise Figure 1 |Schem ati c representati on of the pathophysi ol ogy processes interact hypothesi zed to underl i e pS S,based on our current understandi ng. Envi ronm ental and is in Nocturne Mariette Nat Rheumatol . 2013 factors such a vi rus& or other acti vators of , i nnate i m mRev uni ty cause epi thel i alcel land Togethe D C acti vati on (see B ox 1 for a descri pti on of how vi ruses m i ght i nsti gate lated ac devel opm ent of pS S). pD C s can al so be acti vated by ICs form ed as a consequence suscepti of the adapti ve i m m une response. S uch sti m ul ati on of D C s prom otes acti vati on of
唾液流量
Serum Auto-antibodies (OD Value at 450 nm )
自身抗体
1.5 1.0 0.5 0.0 Ctrl-peptide M3R-peptide Anti-ANA SSA-peptide
*** *** ***
Ctrl
ESS
SG protein-immunized mice develop ESS with enhanced Th1 and Th17 cell responses
TH 1 cel l
原发性干燥综合征动物模型的应用 1. 研究SS发病机制 2. 发现治疗新靶标 3. 新药物的药效鉴定 4. 药物新功能的评估
（白芍,羟氯喹… ）
干燥综合征治疗的新靶标研究
蛋白酶体 --- Proteasome
Major function: degrade proteins 26S proteasome:3 catalytic subunits
Th17 cell transfer promotes Th1 and GC B cell responses in IL-17 KO mice
A critical Rrole EVIEW of S Th17 cells in ESS development
Vi rus? O ther acti vator of i nnate i m m uni ty?
Minor salivary gland biopsy - Effector B cell -AutoAbs -GC-like structure in SG -B lymphoma CD3 / CD20 Effector T cell -Infiltration -Cytokine storm
Lymphocytic infiltration
Prevalence (%) 3.3 2.7 1.56 1.0 0.8 0.77 0.6 0.6 0.44 0.3 0.17 0.1 0.09
SS论文: 1.4万
(pห้องสมุดไป่ตู้S: 5千)
Greece France
原发性干燥综合征发病机理目前不清楚
Dry eyes, dry mouth
CD4
CD20
EVIEW S Pathogenesis of primaryR Sjögren’s syndrome
Epi thel i alcel l pD C NK cel l N Kcel l I L12 acti vati on I L12R DC Tcel l acti vati on
infil trates,butinterestingl ywi thoutany d i n sal i vary gl ands atthe onsetofautoi mm potenti alexpl anation for the el usi veness o pSS could be that overexpression of som retroviralsequences has been overlook be considered instead ofsearching for an responsibl e for disease-associated activa system .For exam pl e,epigenetic abnorm expression ofendogenous retroviralel e responsibl e for acti vation ofthe type I IF
Kinetic changes of Th17/Th1 responses in CLN and SG during ESS development
CLN Th1
Th17
SG
IL-17KO mice are resistant for ESS induction
Th17 cell transfer restores SS pathology in IL-17 KO mice
( Gene-modified SS animal models)
IL-12-Tg, BAFF-TgId3-KO, IL-14a-Tg
我们的目标: 建立原发性干燥综合征动物模型
SG protein Immunization
SG protein-immunized mice develop ESS with reduced saliva secretion and increased autoantibody production
患病率
Countries UK Sweden Turkey Canada Denmark China Slovenia USA Norway Italy Brazil
Qin B et al, Ann Rheum Dis . 2015 Sherine E Gabriel et al. Arthritis Res Ther. 2009
I FN α Autoanti gen
N Fκ B pathw ay dysfuncti on i n pSS pa O ne of the consequences of the stim ul im m unity is the acti vation ofnucl ear fac BAFF w hich can occur in a num ber of differe I FN γ salivary gland epithelialcells from pat I Cs hyperactivation of N Fκ B has been a decreased expression of one of the regu Th17 acti vation,A 20 (al so know n as TN F-α -i n 28 Bcel l [T N FA IP3]). Interestingly, defective acti vati on another gene invol ved in feedback regu B cel l TFH cel l N Fκ Bi nhi bi tor α (al so know n as Iκ Bα ),l e 29 m ent of a pSS phenotype in m ice. Fu Pl asm a G Cl i ke cel l first G W A S in pSS14 identified an assoc structure this disease and a gene (TN IP1) encod Figure 1 |S chem ati c representati on of the pathophysi ol ogy processes interacting protein 1,a protein that inte hypothesi zed to underl i e pS S ,based on Lin our current understandi Envi ronmRheum ental X, et al ng. Ann (2015) andDis. is involved in the regulation of N F factors such a vi rus or other acti vators of i nnate i m m uni ty cause epi thel i alcel land Together, these observations suggest D C acti vati on (see B ox 1 for a descri pti on of how vi ruses m i ght i nsti gate
TH 1 cel l
?
原发性干燥综合征 ---- 目前研究的挑战？ • 干燥综合征的动物模型: 继发性?
( Spontaneous
SS animal models)
1. NOD --- I 型糖尿病 2. (NZB+NZW)F1--- 红斑狼疮 3. Fas(lpr) --- 红斑狼疮
* 基因修饰的动物模型:
Vi rus?
O ther acti vator of i nnate i m m uni ty?
Epi thel i alcel l pD C NK cel l N Kcel l IL12 acti vati on IL12R DC Tcel l acti vati on
infil trate i n sal i va potenti a pSS cou retrovir be consi respons system . expressi responsi
干燥综合征的发病机制及转化研究
香港大学 吕力为
干燥综合征
(Sjögren's Syndrome)
• Dry eyes, dry mouth • A systemic disease
Karolinska Institutet
1933
干燥综合征是一种多发病
1993
张乃峥教授
Epidemiology of primary Sjögren’s Syndrome
泪腺炎症----淋巴细胞浸润，组织破坏
Tear Flow Rate (uL/15 min))
泪液
25 20 15 10 5 0 Ctrl
***
ESS
CD19 CD4 Hoechst
肺和肾间质纤维化及淋巴细胞浸润
CD19 GL-7
CD45 IgG IgM Hoechst
Infiltration of T and B cells in the salivary gland of ESS mice
constitutive: β1, β2, β5 immuno-proteasome: β1i, β2i, β5i (LMP7)
炎症中的免疫细胞 蛋白酶体表达增高
NF-kB pathway:
Survival, apoptosis, cytokine production …
IFN α Autoanti gen
Costa et al, Arthritis Res Ther 2015
N Fκ Bp O ne of im m uni BAFF w hich c IFN γ salivary ICs hyperac decrease Th17 acti vatio Bcel l [T N FA I acti vati on another B cel l TFH cel l N Fκ B in m ent of Pl asm a G Cl i ke cel l first G W structure this dise Figure 1 |Schem ati c representati on of the pathophysi ol ogy processes interact hypothesi zed to underl i e pS S,based on our current understandi ng. Envi ronm ental and is in Nocturne Mariette Nat Rheumatol . 2013 factors such a vi rus& or other acti vators of , i nnate i m mRev uni ty cause epi thel i alcel land Togethe D C acti vati on (see B ox 1 for a descri pti on of how vi ruses m i ght i nsti gate lated ac devel opm ent of pS S). pD C s can al so be acti vated by ICs form ed as a consequence suscepti of the adapti ve i m m une response. S uch sti m ul ati on of D C s prom otes acti vati on of
唾液流量
Serum Auto-antibodies (OD Value at 450 nm )
自身抗体
1.5 1.0 0.5 0.0 Ctrl-peptide M3R-peptide Anti-ANA SSA-peptide
*** *** ***
Ctrl
ESS
SG protein-immunized mice develop ESS with enhanced Th1 and Th17 cell responses
TH 1 cel l
原发性干燥综合征动物模型的应用 1. 研究SS发病机制 2. 发现治疗新靶标 3. 新药物的药效鉴定 4. 药物新功能的评估
（白芍,羟氯喹… ）
干燥综合征治疗的新靶标研究
蛋白酶体 --- Proteasome
Major function: degrade proteins 26S proteasome:3 catalytic subunits
Th17 cell transfer promotes Th1 and GC B cell responses in IL-17 KO mice
A critical Rrole EVIEW of S Th17 cells in ESS development
Vi rus? O ther acti vator of i nnate i m m uni ty?
Minor salivary gland biopsy - Effector B cell -AutoAbs -GC-like structure in SG -B lymphoma CD3 / CD20 Effector T cell -Infiltration -Cytokine storm
Lymphocytic infiltration
Prevalence (%) 3.3 2.7 1.56 1.0 0.8 0.77 0.6 0.6 0.44 0.3 0.17 0.1 0.09
SS论文: 1.4万
(pห้องสมุดไป่ตู้S: 5千)
Greece France
原发性干燥综合征发病机理目前不清楚
Dry eyes, dry mouth
CD4
CD20
EVIEW S Pathogenesis of primaryR Sjögren’s syndrome
Epi thel i alcel l pD C NK cel l N Kcel l I L12 acti vati on I L12R DC Tcel l acti vati on
infil trates,butinterestingl ywi thoutany d i n sal i vary gl ands atthe onsetofautoi mm potenti alexpl anation for the el usi veness o pSS could be that overexpression of som retroviralsequences has been overlook be considered instead ofsearching for an responsibl e for disease-associated activa system .For exam pl e,epigenetic abnorm expression ofendogenous retroviralel e responsibl e for acti vation ofthe type I IF
Kinetic changes of Th17/Th1 responses in CLN and SG during ESS development
CLN Th1
Th17
SG
IL-17KO mice are resistant for ESS induction
Th17 cell transfer restores SS pathology in IL-17 KO mice
( Gene-modified SS animal models)
IL-12-Tg, BAFF-TgId3-KO, IL-14a-Tg
我们的目标: 建立原发性干燥综合征动物模型
SG protein Immunization
SG protein-immunized mice develop ESS with reduced saliva secretion and increased autoantibody production
患病率
Countries UK Sweden Turkey Canada Denmark China Slovenia USA Norway Italy Brazil
Qin B et al, Ann Rheum Dis . 2015 Sherine E Gabriel et al. Arthritis Res Ther. 2009