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