神经梅毒与免疫炎症性损伤
周平玉
上海市皮肤病医院
中国的梅毒流行病现状
1980s: 梅毒出现
1990s: 梅毒流行
2000s: 梅毒发病率不断上升
2012:
429，677 例
胎传梅毒: 12,477例 (活产数)
20年来成人梅毒上升了200倍，胎传梅毒上升了6000倍
Source: China CDC
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
报告发病率(1/10万)
历年全国梅毒与淋病发病趋势
35
30
梅毒
淋病
25
20
15
10
5
0
年份
2010估计的全球新发梅毒病例：1300万
100, 000
东欧和中亚
140, 000
欧洲
100, 000
？？？
北美洲
东亚和太平洋地区
370, 000
北非和中东
4 Million
南亚和东南亚
3 Million
拉丁美洲和加勒比海地区
4 Million
非洲（撒哈拉沙漠以南）
10, 000
澳大利亚和新西兰
神经梅毒的概况
• 早期感染即可出现中枢神经系统的侵犯(≥40%)
• 中枢神经系统的侵犯并不意味着发病，
• 即使不治疗也只有约20%的患者发展成为有症状的神经
梅毒
• 提示：机体的免疫状况在其中起作用
TP
Humoral and cellular responses can be induced after T.Pallidum
infection.
梅毒螺旋体的致病机制
临床表现多样化
特有的侵袭性与免疫逃逸性
能在有强体液、细胞免疫应答下在组织中繁殖，经
血循环播散（秘密病原体， stealth pathogen）
夹膜样物质-酸性粘多糖（来自宿主？利用原料自行
合成？），保护菌体，抗吞噬
酸性粘多糖吸附，然后通过粘多糖酶分解宿主细胞
（血管内皮细胞）的粘多糖， 合成夹膜，分解粘多
糖，引起血管坍陷、炎症、坏死、溃疡。
虽然是古老的疾病，而且基因组1，5 Mb已解析15年，但致病
机制基本不清，体外不能长时间培养
Molecular structure of T. pallidum envelope structure
BamA
analogue
Pore-forming
lipoprotein
OM缺乏脂多糖，炎症反应低下；缺乏插入的蛋白，
对宿主诱生免疫应答低下；主要蛋白免疫原难以被
抗体作用； OM中的TprK, TP0136在胞浆外间隙中
体外试验虽然证明抗体可与螺旋体作用，但未
能揭示抗体与螺旋体直接结合
Cox et al INFECTION AND IMMUNITY, Dec. 2010, p.
5178–5194
梅毒螺旋体的致病机制
认为细胞免疫可能是控制疾病过程的重要因素
硬下疳-大量巨噬细胞浸润， 吞噬、消化梅毒螺旋体，T细胞介导IV型变态
反应
在神经系统内不受T细胞攻击，故梅毒螺旋体可以长期潜伏，发展为神经
梅毒
 IV型变态反应的强弱决定梅毒临床发展，一般 1/3 发展至二期，1/3 发展
至三期梅毒，细胞免疫低下，而细胞免疫应答中度者，病原体可长期潜伏，
但抗体阳性
梅毒的免疫特性
 未经治疗患者，出现硬下疳后有一定的免疫力，机体可持续数年带
有梅毒螺旋体，有感染性， 不断排入血液可构成持续抗原刺激，表
现为有免疫应答。 （带菌免疫）
家兔试验提示，2期梅毒患者血清有抑制淋巴细胞功能的物质， 认
为粘多糖可能有利于梅毒螺旋体在体内繁殖产生2期梅毒。
先天性梅毒患者和感染梅毒螺旋体的家兔淋巴结或脾脏的T细胞有
耗竭的表现， 梅毒患者对梅毒螺旋体抗原出现迟发型变态反应。
（细胞免疫重要）
体液免疫应答，检测 （VDRL, 制动抗体，粘多糖抗体， 多肽抗
体），免疫复合物-------2 期肾脏损伤
TP
Humoral and cellular responses can be induced after T.Pallidum
infection.
Treg
T.pallidum antigen TpF1 can promote the differentiation of Treg.
Babolin C et al. J I mmunol.2011.187:1377-1384.
Tregs:
 Immune escape of pathogens
 Avoid the immune damage
Part Ⅰ Treg frequency and function in syphilis patients without
neurological involvement
Part Ⅱ Treg in Blood and Cerebrospinal Fluid of neurosyphilis
Patients
Part Ⅰ Treg frequency and function in syphilis patients without
neurological involvement
Part Ⅱ Treg in Blood and Cerebrospinal Fluid of neurosyphilis
Patients
100 healthy donors
71 patients with primary syphilis,
136 patients with secondary syphilis,
127 patients with latent syphilis,
97 patients with serofast syphilis
100 Neurosyphilis (52: asymptomatic Neurosyphilis ; 10 : Meningealneurosyphilis ;
34:General paresis ; 4: Tabes dorsalis )
Treg Numbers Are Elevated in the Peripheral Blood of Syphilis Patients
Treg Suppressive Function Are Increased in Secondary and Serofast
Syphilis Patients
18
Serum TGF-β
D
Positive correlation between Treg and TGF-β
19
Association of circulating Treg numbers with serum RPR titers of syphilis
patients.
20
Conclusion

Treg Numbers Are Elevated in the Peripheral Blood of Primary,
Secondary, Latent and Serofast Syphilis Patients
 Treg
Suppressive Function Are Increased in the Peripheral Blood of
Secondary and Serofast Syphilis Patients
 Serum RPR Titers Are Positively Correlated to Treg
Frequencies in Secondary, Latent and Serofast Syphilis
Part Ⅰ Treg frequency and function in syphilis patients without
neurological involvement
Part Ⅱ Treg in Blood and Cerebrospinal Fluid of neurosyphilis
Patients
Treg frequency in peripheral blood of neurosyphilis patients
Analysis of CD4+ CD25high Tregs in CSF
The laboratary fetures in CSF derived from different types of syphilis patients
Type
Non-neurosyphilis
Asymptomatic
Meningeal
Parenchymal
Leukocytes
Cells/µL
4±1
14±32a
35±15ab
16±4ac
CD4+
%d
29.7±2.4
41.8±2.3a
49.7±2.6
46.4±2.1a
CD4+ CD25high
%e
22.0±1.0
20.0±1.1
12.5±1.4ab
12.0±1.2ab
Cells/µL
0.1±0.1
1.2±0.2a
0.9±0.3a
0.5±0.1ab
ng/ml
8.2±1.7
10.7±2.0
3.4±0.9ab
2.8±0.5ab
CD4+ CD25high
TGF-β
NOTE. a v.s. syphilis patients without neurological involvement; b v.s. asymptomatic neurosyphilis
c v.s. meningeal neurosyphilis patients; d percentage (%) among CD45 + leukocytes;
patients;
e percentage (%) among CD4 + T cells.
25
Conclusion
 Circulating Treg Numbers Are Higher in Neurosyphilis Patients than Syphilis
Patients without Neurological Involvement
 CD4+ T Cells Predominates in the Cerebrospinal Fluid of Neurosyphilis Patients
 CSF Treg Numbers Are Reduced in Symptomatic Neurosyphilis Patients
Treg
T.pallidum antigen TpF1 can promote the differentiation of Treg.
Babolin C et al. J I mmunol.2011.187:1377-1384.
Increased Interleukin-17 Correlates With Disease Progression of
Neurosyphilis
Methods
 Th17 in peripheral blood from 69 syphilis patients
without neurological involvement, 103 neurosyphilis
patients and 70 healthy donors were analyzed by flow
cytometry.
 The level of IL-17 in cerebrospinal fluid was
quantified by ELISA.
 One-year follow up for 44 neurosyphilis patients
was further monitored to investigate the role of
Th17/IL-17 in neurosyphilis.
Conclusions
 Th17 response may be involved in central nervous
system damage and the associated clinical symptoms
in neurosyphilis patients.
 Th17/IL-17 may be used as an alternative surrogate
marker for assessing the efficacy of clinical treatment
of neurosyphilis patients.
Results
Increased Interleukin-17 Correlates With Disease Progression of
Neurosyphilis
Methods
 Th17 in peripheral blood from 69 syphilis patients
without neurological involvement, 103 neurosyphilis
patients and 70 healthy donors were analyzed by flow
cytometry.
 The level of IL-17 in cerebrospinal fluid was
quantified by ELISA.
 One-year follow up for 44 neurosyphilis patients
was further monitored to investigate the role of
Th17/IL-17 in neurosyphilis.
Conclusions
 Th17 response may be involved in central nervous
system damage and the associated clinical symptoms
in neurosyphilis patients.
 Th17/IL-17 may be used as an alternative surrogate
marker for assessing the efficacy of clinical treatment
of neurosyphilis patients.
Results
Thanks
Dr. Haikong Lu
Dr. Xin Gu
Dr.Mei Shi
Dr.Gaoyin
Dr. Zhifang Guan
Dr. Weimin Gong
Dr. Yihong Qian
Dr. Zhe Cai
Cuini Wang Ph.D.
Kang Li M.S
Ling Zhu Li M.S
Shufang Zhang M.S
Zixiao Gao M.S
Thank You!
Pingyu Zhou, M.D., Ph.D.
zhoupingyu@medmail.com.cn