제일병원 양광문 교수
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Transcript of 제일병원 양광문 교수
Immunologic concern of Recurrent Spontaneous
Abortion
관동대학교 의과대학 · 제일병원 산부인과
양 광 문
Definition of RSA
• 3 or more clinically recognized pregnancy losses before 20 weeks.
• Occurs in about 1 in 300 pregnancies.• Clinical investigation should be initiated after 2
consecutive spontaneous abortions
especially, 1. Fetal heart activity is identified
2. Older than 35 years of age
3. Difficulty conceiving Novak’s Gynecology, 14th ed, 2007
Etiology of RSA in Cheil General Hospital
Unexplained
Genetic Translocation 60.3%
Anatomic Synechia 64.3% Ut. Septum 14.3%
Autoimmune Anti-thyroid 83.3% APA 16.7%
Endocrine Hyperthyroidism 71.4%Infection
Ureaplasma 89.5%
N = 881(2005. 1.1 - 2009. 12. 31)
Brief summary of Immunologic concern in RSA
1. Genetic Cause Thrombophilic Gene mutation
3. Infection
2. Autoimmune disease
4. Semi-allogenic graft rejection HLA expression
Microvasculi thrombosis in placental bed
Immune cells Cytokines
Pro- , anti-inflammatory cytokines
T cell (T reg cell), NK cell, Dendritic cell, Macrophage
Disruption of coagulation pathway
Direct injury to vascular endothelial cell
Non-Pregnancy Endometrium Early Pregnancy Decidua Peripheral Blood
Proliferation phase
Secretory phase Decidua Decidua Basalis
Decidua Parietalis
T cell 40-50 % 30-35% 10-15 % 12 % 6 % 70 %
CD4+ T cell 15-20 % 10-15 % 5-7 % 6 % 3 % 40-45 %
CD8+ T cell 20-25 % 15-20 % 7-10 % 5 % 3 % 30-40 %
Type 2 cell/T cell 0.5% 1.4 % 15-20 % 22 % 16 % 3 %
Type 1 cell/T cell 60 % 40 % 10-15 % ? ? 20 %
NK cell
CD16+ NK cell 2% 4 % 2 % 2 % 2 % 10-15 %
CD 16-CD56bright 20 % 40-50 % 60-70 % 69 % 64 % < 1 %
NKT cell ? ? 0.4 % ? ? 0.05 %
B cell ~ 5 % ~ 5 % 2 % 2 % 2 % 8-10 %
Dendritic cell ? ? 1 % ? ? 0.8 %
Monocyte/macropgage
10% 10 % 20 % 30 % 20 % 8-10 %
Populations of lymphocytes and monocytes in uterus and peripheral blood
Allo-immunity as a cause of RSA
Inflammatory cells
NK cell T cell (Th1 cells)
Trophoblastic cell apoptosis
Thrombosis of Placental vessel
Anti-inflammatory cells T cells (Th2 cells) Regulatory T cells Dendritic cells
Pro-inflammatory cytokines
Pro-inflammatory cytokines
Unexplained
pbNK ≥ 15%
Unknown
???
pbNK cells as a markers for predicting risk of RSA
최지영 , 양광문 등 . 대한생식의학회지 . 2010년 3 월 .
Immune modulation treatment using IVIG
9
Peripheral Blood NK Cells Reflect Changes in Decidual NK Cells in Women With Recurrent Miscarriages
Park DW and Yang KM et al, AJRI 2010
pbNK cell cytolytic activity assay
55.8%
36.7%
24.3%
2.1%PBMC (NK) K562 cell
Count of dead K562 cell (%)
by different
Effecter (E) : Target (T) ratio
2 hrs
48.3
31.3
37.0 20.2
23.5 12.4
50:1 25:1 12.5:1
Increased pNK cell cytolytic activities in unexplainedRSA
RSA Control
최지영 , 양광문 등 . 대한생식의학회지 . 2010년 3 월 .
Increased pNK cell cytolytic activities in unexplained RSA
최지영 , 양광문 등 . 대한생식의학회지 . 2010년 3 월 .
42.7
33.0
25.1
*
* P > 0.05
E:T ratio, 50:1 (n=17)
Decreased pbNK cytolytic activities by using PDS and IVIG
Preliminary data
Pb T lymphocytes as a markers for predicting risk of RSA
Mean ratio of TNF-α or INF- γ to IL-10 expression on CD3+/4+ Cells
1 2
TNF- α / IL- 10 expression on CD3+/4+ cells
10
20
30
40
50
60
p = 0.02
1 2
INF- γ / IL- 10 expression on CD3+/4+ cells
10
20
30
40
50
60
p > 0.05
한애라 , 양광문 등 . 대한생식의학회지 . 2010년 6 월 .
Mean ratios of expressing lymphocyte activation markers (CD154 or CD69) expressing cells among
CD4+ and CD8+ T lymphocytes
한애라 , 양광문 등 . 대한생식의학회지 . 2010년 6 월 .
Treatment of immune cause RSA
%pbNK
pbNKA
Th1 cell
Trophoblastic cell apoptosis
Coagulation and Thrombosis
Low dose aspirin
LMWH 20-40mg
Pro-inflammatoryCytokines
PDS 10mg/day F.U after 2 weeks
IVIG
High dose progesterone (600mg/day)
Immunologic Factors involved in Human Reproduction
Shormila R. et al., HR Update, 2000
RIF
RSA
IUGR
Pre-eclampsia
Fertilization failure
Further researchGenetic InfectionEnvironmental
(Drug)
Development of disease 1. Reproductive failure (Infertility, RSA, OB complication) 2. Gynecologic disease Endometriosis etc
Immunologic disruption as a pathogenesis of various disease Research about
• Diagnostic markers• Treatment by immune modulation
Immunogenetics
Questions &
Answers