Молекулярно-генетическое исследование местного иммунитета
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» . . , » (03.03.03. – ) : , 2012 . ...................................... 4 ..................................................................................................... 6 1. , . ( ) ............................................................................................12 1.1 . - ........................................12 1.2 , ....................................................15 , 1.3 .....19 1.4 ......................26 1.5 ............................39 , ..................43 2. 2.1 .................................45 2.2 ...........................................46 2.3 .....................................52 ........57 3. 3.1 .................................................................................57 2 3.3 ............................................................................................................61 3.4 .............................63 3.5 ............................................................................................................78 ...........................93 3.6 4. ..........................................................................95 .....................................................................................................107 .........................................................................108 3 – – – – – – – – – – – – – – – – APC - antigen-presenting cell GNLY – granulysin HPV - human papillomavirus HSV – herpes simplex virus IFN - interferon IL – interleukin LIF - leukemia inhibitory factor MHC - major histocompatibility complex PAMP - pathogen-associated molecular patterns PRR - pattern recognition receptor TGF - transforming growth factor Th – T-helper 4 TLR – toll-like receptor TNF - tumor necrosis factor 5 . , - ( ) – , , , [30; 33; 73]. , [8]. , : ( , , -, ) . . , ( ), [8; 11]. , , , . 6 , . , - . , [14; 169]. , . [90; 122]. . , 2- 4- ) : ( , , , , . - , , . 7 - . 1. . 2. ( ) (IL1B, IL6, IL8, IL10, IL12A, IL15, IL18, IL23, TNF , IFNG, TGFB1 (TBX21, GATA3, FOXP3 LIF), RORC), Toll- (TLR2, TLR4, TLR9), (CD45, CD68, CD69, IL2R ) (GNLY) . 3. . 4. . 5. . 8 6. , . (IL1 , IL6, IL8, IL10, IL12A, IL15, IL18, IL23, IL2RA, GNLY, TNFA, TGFB1, LIF, IFNG, TLR2, TLR4, TLR9, TBX21, GATA3, RORC, FOXP3, CD45, CD68, CD69) . 14 (IL1B, IL8, IL10, D45, CD69, TLR2, TLR4, TNF , GATA3, CD68, IL12A, IL18, TGFB1, RORC) 24 . IL12A IL18, CD68 Th2- GATA3 , . , , IL1B, IL18, IL10, TLR4, CD68 GATA3 . . IL1B, IL8, IL10, TNFA, TLR2, 9 TLR4, CD45, CD69, GATA3, CD68, TGFB1, IL12A, RORC, IL18 . IL1B, IL18, IL10, CD68, TLR4 GATA3 96% 95% , . . . : , , . , , , , . , . 201147924 « 10 ». 7 , 5 , . « »( « , 2011 .), VI »( , 2012 .), V " . "( , 2012 .). 16.522.12.2009 29 2011 . 128 , , , , , , , 74 123 . 11 11 24 . 1. , . ( ) 1.1 . - . - [34; 52]. : , . , , , [41; 62]. , , : 28 60% [35]. [33; 48; 49; 73; 75; 88; 167]. ( 12 ), ( ) ( ) [4; 22; 52], . , , [4]. . , , , , , , . IUSTI (International Union against Sexually Transmitted Infections) 2011 [170] : (22-50% ), (17-39%) (4-35%), , . . Anderson M.R. 30% [80]. IUSTI, , , , [3; 13; 30; 34; 37; 45; 46; 58; 66]. 13 , , . , , , ) [8; 10; 11]. , , . , , , . , , . . . , , , . , , ( ). , . : ( , ), ), . 14 . , , , , , . 1.2 , , . , , , . , , , . , , : 3,8—4,5, . 108-109 1 – 105-108, , 95-98% – 106-109 . 15 – 103-105 . 400 150 [45]. , ), , ( ), [45; 60]. , , , . , [1; 126]. , , , . . ( ), - . , . , (3,8—4,5). , . , 16 . , , . , . III [64]. , . . (Lactobacillus), : L. acidophilus, L. jensenii, L. casei, L. gasseri, L. crispatus, L. plantarum, L. fermentum, L. cellobiosus, L. brevis L. Salivarius. : , , L. crispatus, L. jensenii, L. gasseri L. iners [104; 123; 142; 150; 162; 190; 196]. , – , [1; 193]. , , 46,5 , , , , . , 17 100%. . , . . [2] 5% , 37% – 61% – . , . 2 2 [7; 15; 45; 61; 65]: : ; ; ; . , . . 30 [28; 123]. , , , , , , , , ., 18 Candida. 15-20% [3; 104; 117; 193]. , - 400 . [10; 72; 142; 193] , . Atopobium spp., Megasphaera spp. Leptotrichia spp., , Lactobacillus, , . , , , . , , . Atopobium vaginae [169]. . , , [193; 195; 196]. 1.3 , . 19 , , ( , , , , .), ( , — , , , , , ; ; ( , , ); ; , .) [59]. , ( , ) [34; 55; 73]. , , . . — , . — , , ( ). — 20 , , , ). , , ). [16; 60]. ( ) . 5–60% . . , . , : , , , , , [37]. . (Gardnerella vaginalis, Mobiluncus spp., Bacteroides spp., Fusobacterium spp., Prevotella spp., Prophyromanas spp., Peptostreptococcus spp. Atopobium vaginae .) [115; 147; 159; 186]. , , 21 108-109 [13]. - 4,5, . , ( ), , , . , , . , « « » » [4; 16]. , [66]. , Amsel R. (1983 .). : , ; ; >4,5; " " [36; 114; 151; 159]. . , , Enterobacteriaceae (Escherichia coli, Klebsiella 22 spp.), Staphylococcus aureus, S. epidermidis, Streptococcus agalactiae, Enterococcus spp. (103-104 . , ) . . , « » , . [3; 22; 108; 138; 177]. , , Candida. , , — 10 79%, ( , , ) [19; 38; 63; 113; 170]. Candida spp. 104 . C.ablicans. , , , Candida spp. , [3; 4; 51]. . , 6,0-6,5, ( 2,5-3,0), . , . C.albicans . , . 23 C. albicans, — C. Glabrata [35; 39; 45; 161]. 3 : , , 104 ( ). Candida 15–30% - 40%). ( - ), , . , , [4; 67; 68; 70; 197]. 40% - . Ureaplasma spp. 50% ( - Mycoplasma hominis , 10% , Ureaplasma spp. 80%). Mycoplasma hominis , , . [24; 31; 57; 92; 139; 153; 187]. , . , . , 24 [18]. ) , [5] -, , , . [56]. , , . , [54]. , - , , , [8; 11; 30]. , , , , , , . : 3–4 25 , , [4; 9; 12; 31; 43; 47; 71; 147; 164; 177; 187]. 1.4 , . , , , , , . , . – , . . , , . , . , , . , , 26 . , , , , – [40]. - , . , , . , , , [47]. , : . . , , , . [7; 149]. – 27 . , . , . , , (lamina propria). : , , , , , , , ( 1). , , [160; 173]. . 1. : ( ) ( 28 ). ( ( ) ), . , CD8+ , , , . . , ( , , ( ), ). IgA+ , . . , , [74; 158]. . , , . – , . [42]. , . . , , , , , . , , , ( .). 29 , , , , , , [7; 29; 84; 100; 124; 182]. . , , . 2 2 , . , . , , « . » , , IgA [178], , , , , [91]. . . , [122; 172], – , [74; 93]. . , , . (TNF , IL-1 , IL-6, IL-8 .), . 30 , , ( , - 2) [128]. . (APC). . APC, [96; 119; 134; 154] . 2. . ( , , , .) - (pattern-recognition receptor – PRR ), [125; 129; 131; 155]. 31 . ( - - pathogen-associated molecular pattern – PAMP ). PAMP , ( , , , , , , , .), ( , , ), , , « , » [78]. PRR PAMP, , , [129; 184]. PRR, (TLR – toll-like receptor), RIGreceptor), NOD- (RLR – RNA-like (NLRs - Nucleotide Oligomerization Domain-like receptor), , , [99]. TLR . TLR. 10 , -TLR1, -2, -4, -5 , TLR3, -7, -8 , ( 3) [83; 94]. 32 -6 -9, TLRs , . , TLR2 - TLR1 TLR6 . . . 3. TLR . TLRs c , . MyD88 ( 88), NF-kB, (TNFa TLR3 TLR4 IL-6) . MyD88- , 3 (IRF-3). 33 I ( 4) [137; 143; 152; 192]. Kaei Nasu [152] TLRs, TLR1 , TLR10. TLR2 , , . TLR4 , (IL-1 , IL-8, TNF ). TLR9 CpG- . [152; 190]. . 4. TLRs ( ) [114; 116; 149] TLR2, -4, -6, (IL-1 , IL-6, IL-8, TNF ) . 34 , PAMP [181] , , (antigen- presenting cell – APC ), , MHC II (major histocompatibility complex class II– CD4+ ) 2 CD8+ . , . [101]. PAMP, , . TGF , , IL-10 – , . D4+ . . – Th1 2 Th2 (Th – T-helper). Th1- TBX21) IL-2, TNFA, TNFB IFNG, , , , Th2- GATA3) 4, IL-5, IL-10 IL-6, IL- ., , ( ). , IL-4 Th1- Th2- (IFNG ) . 35 , IFNG Th1- – Th2- , , IL4 . , Th1- IL-12, IL-23 IFNG, IL18, IL-27. , TNFA, TNFB IFNA. Th2- IL-4 Th2- IL-13, IL-10, IL-6, IL-2, IL-19 p40 IL-12. [140; 172] , . [79; 81; 85; 90; 114; 121; 151] IL-1A, IL-1B, IL-6, IL-8, TNFA , , , , Neisseria gonorrhoeae, Chlamydia trachomatis. IL-12 IFNG , Th1[79; 164] [81; 90; 179]. IL-10 , . . [79; 85; 149; 164]. , 36 [44; 65; 104], . CD4+-T, : ( ) . CD8+ FoxP3, , - TGFB, IL-10 , . , , . , T CD8+ . [6; 20; 74; 130; 166]. CD4+ lamina pripria . CD8+ ) ( , , [158]. , , . . T- , T, IFNG, TNFA IL-17. , . , [36; 74]. 37 , – IgM- , . . IgA. IgA , . . . [9] [46] . . , IgA, IgG IgM . . [17] . IgA . . [23] , , A, M, G, , . , . , . . (IL1B, IL18, IL12A, TNFA, IL23), IL10, IL15), (IL6) TLR (TLR2, -4, -9), , Th1- (GATA3), Th17- (RORC), , 38 (TGFB, (FOXP3), (TBX21), Th2- (CD45 – , CD68 – , CD69 – , IL2RA – ), (GNLY), . 1.5 , : , . . . , , , , , . [14; 169]. » , , . : , , , , ) ( [8; 10]. 39 7 ( ., .) . . [2; 4] : , ( , , ( ( . , ), ), )( ). [21] , 4 : 1. , , , , « » . . 2. – , , . ( 10), . , , , , . 3. , , , « ». , . . 40 4. ( ) – ( 10), , , . [88; 151; 171], . . 16S , , , [8; 11; 72; 76; 97; 162; 185]. , . . . , . , , , - [25; 112; 120; 188]. , 41 , . , , . , . , , . 42 2. 295 . , . » 16.522.12.2009. 194 19 18 45 40 101 37 41 . . 3-5- . , , ( ). , , , ( 10 ). (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium) 1 2 , , . , . 43 « » . « »( , 2009/04663) . . (2011). (n=194) : (n=40), (n=115); 10 : (n=14), 103 ( Candida spp. ) , 104 Ureaplasma spp. (n=10) (n=15). (n=101) : (n=42), (n=24); 10 : Candida spp. (n=11), 103 , 104 Ureaplasma spp. (n=8). (n=16) , ( ) , . . 44 : 1. , , . 2. . : 1. . 2. . 2.1. , . 2.2. « ». 2.3. . 3. . 2.1 : , , . , , , , , , , , . , , , . , , 45 . 2.2 . . . : – , , , « » ( , , ), ), , , , ), , , . [2; 4]. , ; – ; ; – , , . , , 46 « »; , , ( , ); – , ; ; . 3 Candida . 1. (Candida ) , ; (10-15 ) (30-50 ); ; , , . 2. , « »; ; – , ; , / ; . 3. ; 47 , ; ; , . , ; ( 10 ); ; ; – (+) . ( ) , « » ; 10 ; ; . « ». ( ) . 13000 10 100 . « », . ). 48 » (« - , , . 100 . (« , », ) ( )), Lactobacillus spp. 14 , (Enterobacterium spp., Streptococcus spp., Staphylococcus spp)., (Gardnerella bivia/Porphyromonas spp., Eubacterium spp., vaginalis/Prevotella Sneathia spp./Leptotrihia spp./Fusobacterium spp., Megasphaera spp./Veillonella spp./Dialister spp., Lachnobacterium spp./Clostridium spp., Mobiluncus spp./Corynebacterium spp., Peptostreptococcus spp., Atopobium vaginae), Mycoplasma hominis, Ureaplasma spp. Candida spp. : Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis , (HSV-1, HSV -2, CMV) ). 35 :1 – 94º 30 94º , 64º 15 « – 80º 30 ; 45 , 94º 1 – 94º 10 -964» (« », 30 ;5 , 10º – ). 64º FAM, HEX ROX. . « » , [11], » ». . 49 . . , , . , . 104 , 104 , . , . ( ). - , , . . 106 – 108 , – 105 – 107 – . , , , , . . Lactobacillus ( ). , 106–108 , – 105 – 107 – 50 . -, -, Candida. , Candida, . , Ureaplasma spp 104 Mycoplasma hominis . Candida spp 103 « » Candida spp. : 1. – , : Gardnerella vaginalis /Prevotella bivia/Porphyromonas spp; Atopobium vaginae; Eubacterium spp; Sneathia spp /Leptotrihia spp/Fusobacterium spp; Megasphera spp/Veilonella spp/Dialister spp; Lachnobacterium spp/Clostridium spp; Mobiluncus spp/Corynebacterium spp; Peptostreptococcus spp. 2. – , : Enterobacteraceae, Streptococcus spp 3. - Staphylococcus spp. , , Candida. . (IL1B, IL6, IL8, IL10, IL12A, IL15, IL18, IL23, TNF , IFNG, TGFB1, LIF), (TBX21, GATA3, FOXP3, RORC), Toll(TLR2, TLR4, TLR9), CD69, IL2RA) (CD45, CD68, (GNLY) 51 . ( », « », « ). , . 50 . 40 33 ( ). . 40º 30 , 95º 5 . 5 . . . TBP, B2M, GUSB. 3 , 600 1 10 180 . 15 36 ( p), 10-50 108 . (« », ). . . 2.3 . «SPSS Statistics 17.0 for Windows». 52 - . . , — (25- ), 75- . , (Cp) . ( Cq) 3 . 3 (NF) – Cp ( = ( )+ Expression(x) = 2 ( ( 2 )+ ( ) ) ( . )) x : . . , . « « » (box-and-whisker plot). » 1 . 3 (x25, x75) – . (x1, x2), : = max( = min , , 1,5 ( + 1,5 ( )), ) . 53 « » ( . 5. 5 ). . , . . ) . . <0,05. .) % . ( 2). <0,05. (OR), 95% 54 . p<0,05. , , . ( ), . = + + + , m=1,…, n, k=1,…,g ( . - m x ) k; m– k. , . «SPSS Statistics 17.0 for Windows». , . . cut off) ROC- (Receiver Operator Characteristic) . ROC- , . 55 (AUC - Area Under Curve) 1). 1. AUC AUC 0,9-1,0 0,8-0,9 0,7-0,8 0,6-0,7 0,6 cut off . . . 56 3. 3.1 . 194 128 (66,0%), - 62 (48,4%), – 66 (51,6%). (n=62) 6%, 94%, (104 Candida spp. 103 ) . 66 28 104 Ureaplasma spp. , 103 Candida spp. (43,5%) 56 (84,8%) , 18 (28,1%) . 20% . 80%. 66 (34,0%) 194 , 75% . 1% 94% 8 (12,1%) . 62% . 30% 1% 99% . Streptococcus spp. Enterobacterium spp. Ureaplasma spp. 30% 99%. 104 57 3 . 30% 80% (n=66) (45,5%) . 20% 79% 30 . 1% . : 63% 20 - Gardnerella vaginalis/Prevotella bivia/ Porphyromonas spp. 99%, 23,3% - Eubacterium spp. 20 30%, 20,0% - Lachnobacterium spp./Clostridium spp. 25 99%, 16,7% - Atopobium vaginae 20 80%, spp./Leptotrihia spp./Fusobacterium spp. 21 (70,0%) - Sneathia 40% . Ureaplasma spp, 104 28 20 26,7% 5 – M. hominis . 66 (42,4%) , 20% , 103 Candida spp. . 50% 32 99% . – 20 104 Ureaplasma spp. 103 Candida spp. 80%. 3 , 18 - . (n=115) 6): (n=22), Candida spp. (n=42), (n=8), (n=15) (n=28). 58 , . 6. . 3.2 (n=101) . 95 (94,1%). 59 (62,1%), – 36 (37,9%). 36 18 (50,0%) 104 Ureaplasma spp. , 103 Candida spp. 20 (55,6%) , 2 . 6 (5,9%) 101. – 60%. : Enterobacterium spp. Streptococcus spp. 25%. 59 30% , . (n=24) ( 7): (n=9), (n=9), 103 Candida spp. , (n=6). Ureaplasma spp. , Candida spp. [51; 197]. 2. . 7. 60 2. (n=194) (n=101) 40 42 115 24 14 11 10 16 15 - - 8 ) : ) Candida spp. > 103 <10 : Ureaplasma spp. > 10 <10 , 4 <10 , <10 3.3 : (IL1B, IL6, IL8, IL10, IL12 , IL15, IL18, IL23, IFNG, TNFA, TGFB1, LIF); 61 (TBX21, GATA3, FOXP3, RORC2); (CD45, CD68, CD69, IL2RA(CD25)); (TLR2, TLR4, TLR9); (GNLY). , ( 8). 100,00 10,00 1,00 0,10 0,01 0,00 IL8 IL1B IL18 TGFB1 CD68 GATA3 TNFA CD45 IL12a IL23 TLR2 TLR4 CD69 RORC IL10 IL15 FOXP3 LIF TLR9 GNLY TBX21 IFNG IL6 IL2Ra B2M GUS TBP 0,00 . 8. ( ). 3 : 106 105 (IL8, IL1B, IL18, TGFB1, CD68, GATA3); 105 103 62 (TNFA, CD45, IL12A, IL23, TLR2, TLR4, CD69, RORC, IL10) 103 - (IL15, FOXP3, LIF, TLR9, GNLY, TBX21, IFNG, IL6, IL2RA). , , . 180-600 106 . 3.4 , . 3. 1 . . <0,05. 103 (IL15, FOXP3, LIF, TLR9, GNLY, TBX21, IFNG, IL6, IL2RA) . 2( ). 4 ( ) 5 2 . <0,05. , IL1B 63 4,0, IL8 5,7, TLR2 4,4, TLR4 4,8 . ( , , TNFA , .). IL23 9). 0.01 0.1 1 10 100 ( IL1B* IL8* TNFA TLR2* . 9. TLR4* IL23 IL1B, IL8, TNFA, TLR2, TLR4, IL23 , ( 1 , * <0,05) , CD45 CD69 3,5 3,3 64 10). IL10 3,6 10). 0.01 0.1 1 10 100 ( CD45* CD69* . 10. IL10* CD45, CD69, IL10 , ( 1 , * <0,05). , 65 : IL12A GATA3 8, RORC2 2, TGFB1 8, CD68 3, 2 11). 0.001 0.01 0.1 1 10 ( 4, IL18 CD68* IL12A* IL18* GATA3* . 11. TGFB1* RORC* CD68, IL12A, IL18, GATA3, TGFB1, RORC2 , ( 1 , * <0,05) 66 3. ( 1 ) (n=115) (n=40) Med (0.250.75) spp. Ureaplasma 104 (n=10) Candida spp. 103 (n=14) (n=15) Med (0.250.75) * Med (0.250.75) * Med (0.250.75) * Med (0.250.75) * IL8 1 (0.26-2.26) - 5.7 (2.64-12.93) 3.11*10-11 4.9 (1.30-8.62) 0.02 2,0 (0.40-3.89) 0.38 1.5 (0.56-3.80) 0.27 IL1B 1 (0.47-1.56) - 4.0 (1.76-7.69) 2.03*10-9 2.4 (1.36-4.54) 0.02 0.8 (0.24-2.67) 0.95 1.4 (0.74-3.53) 0.21 CD68 1 (0.56-1.78) - 0.3 (0.17-0.54) 1.13*10-9 0.5 (0.20-0.78) 0.03 0.8 (0.42-2.25) 0.98 0.4 (0.24-1.14) 0.02 IL18 1 (0.72-1.64) - 0.1 (0.04-0.24) 8.50*10-17 0.3 (0.12-0.62) 0.01 0.8 (0.33-2.62) 0.67 0.2 (0.12-0.49) 0.0001 TGFB1 1 (0.68-1.72) - 0.6 (0.39-1.22) 0.003 0.9 (0.44-1.39) 0.24 1.8 (1.25-2.93) 0.02 1.1 (0.65-1.75) 0.91 GATA3 1 (0.56-1.50) - 0.1 (0.04-0.24) 1.90*10-17 0.5 (0.11-0.69) 0.01 1,0 (0.32-1.89) 0.60 0.3 (0.08-0.82) 0.001 CD45 1 (0.34-2.11) - 3.5 (1.76-5.43) 2.43*10-8 2.8 (1.59-3.36) 0.04 0.8 (0.20-1.83) 0.70 1.1 (0.45-2.46) 0.71 3 (n=115) (n=40) Med (0.250.75) Ureaplasma spp. 104 (n=10) Candida spp. 103 (n=14) (n=15) Med (0.250.75) * Med (0.250.75) * Med (0.250.75) * Med (0.250.75) * TNFA 1 (0.59-1.85) - 1.2 (0.53-2.62) 0.35 0.9 (0.46-1.20) 0.39 1.6 (0.42-2.98) 0.49 1.1 (0.39-1.52) 0.64 TLR2 1 (0.54-2.73) - 4.4 (2.24-6.96) 8.39*10-9 5.1 (2.34-8.18) 0.004 1,0 (0.11-3.67) 0.69 2.2 (0.86-3.96) 0.14 TLR4 1 (0.29-1.72) - 4.8 (2.63-7.19) 3.14*10-12 2.5 (1.19-7.16) 0.018 0.6 (0.19-0.88) 0.45 1.8 (0.62-3.75) 0.10 IL23 1 (0.54-2.28) - 0.9 (0.39-2.70) 0.89 1.1 (0.46-1.71) 0.67 2,0 (0.34-6.58) 0.43 0.5 (0.19-1.24) 0.11 CD69 1 (0.62-2.56) - 3.3 (1.67-7.05) 1.59*10-9 3.1 (1.82-7.00) 0.005 1.5 (0.25-2.18) 0.99 1.6 (0.49-2.13) 0.68 IL12A 1 (0.68-1.89) - 0.3 (0.09-0.77) 7.55*10-9 0.4 (0.21-1.72) 0.05 1.0 (0.76-1.39) 0.73 0.4 (0.26-0.56) 0.001 IL10 1 (0.38-2.21) - 3.6 (2.01-6.86) 5.82*10-9 3.1 (1.59-4.77) 0.06 0.9 (0.04-3.97) 0.87 1.6 (1.07-2.25) 0.20 RORC 1. (0.46-1.96) - 0.2 (0.12-0.49) 2.87*10-10 0.7 (0.24-0.77) 0.07 0.7 (0.34-1.49) 0.35 0.8 (0.29-1.25) 0.27 * p - . 68 4. 103 (n=40) (n=115) Ureaplasma spp. 104 (n=10) , Candida spp. 103 (n=14) - (n=194) (n=15) LIF 25 (63%) 70 (61%) 8 (80%) 6 (43%) 9 (60%) 118 (61%) IL15 17 (43%) 69 (60%) 8 (80%) 6 (43%) 9 (60%) 109 (51%) IL6 14 (35%) 96 (84%) 9 (90%) 3 (21%) 11 (73%) 133 (69%) GNLY 24 (60%) 100 (87%) 9 (90%) 7 (50%) 11 (73%) 151 (78%) TLR9 33 (83%) 108 (94%) 10 (100%) 8 (57%) 12 (80%) 171 (88%) FOXP3 35 (88%) 106 (92%) 9 (90%) 10 (71%) 14 (93%) 175 (90%) IFNG 25 (63%) 92 (80%) 7 (70%) 8 (57%) 10 (67%) 142 (73%) IL2RA 11 (28%) 69 (60%) 6 (60%) 3 (21%) 7 (47%) 96 (49%) TBX21 21 (53%) 108 (94%) 7 (70%) 8 (57%) 11 (73%) 155 (80%) 69 5. 2 (n=115) 2 103 Ureaplasma spp. 104 (n=10) 2 , - Candida spp. 103 (n=14) 2 (n=15) 2 LIF 0,0 1,00 0,5 0,50 0,9 0,34 0,0 1,00 IL15 3,0 0,08 3,1 1,00 0,0 1,00 0,7 0,39 IL6 31,5 0,001 7,7 0,007 0,4 0,54 5,0 0,026 GNLY 11,9 0,001 2,0 0,16 0,1 0,74 0,4 0,55 TLR9 3,4 0,06 0,8 0,36 2,4 0,12 0,0 1,00 FOXP3 0,3 0,57 0,0 1,00 1,0 0,33 0,0 0,39 IFNG 4,0 0,045 0,0 0,94 0,0 0,97 0,0 1,00 IL2RA 11,3 0,002 2,5 0,12 0,0 0,93 1,1 0,31 TBX21 33,6 0,4 0,52 0,0 1,00 1,2 0,16 0,001 2 p<0,05 3,84. 70 103 , IL6, GNLY, TBX21, IL2RA, IFNG. , , Th1- 14 . 103 Candida spp. , ( 10). , 2 TGFB1, , . 10 104 Ureaplasma spp , ( 10). , , TLR2 2,4, IL8 3,3 4,9, CD45 GATA3 2,8, CD69 3,1 , 5,1, TLR4 2,5, IL1B - CD68 2,0, IL18 2,2 . IL6. . 15 ( 10). CD68 IL18 4,8, GATA3 4,0 IL12A 2,5, 2,5 . . IL6. , , , ( ) , . : 1]/[ p1 2] = E2Cp2/E1Cp1, p2- , 1 2– . (IL15, FOXP3, LIF, TLR9, GNLY, TBX21, IFNG, IL6, IL2RA) , ( ) . IL1B/CD68, IL10/IL18 12). , . 72 TLR4/GATA3 , . , , , : (n=78) (n=77). (n=40) (n=115) . 2 : 0.001 0.01 0.1 1 10 100 1000 . IL10/IL18* . IL1B/CD68* TLR4/GATA3* 12. , ( 1 , *p<0,05). 73 ( ), : y 0,2 lg IL1B CD 68 0,2 lg IL10 IL18 [IL1B], [CD68], [IL10], [IL18], [TLR4] ( 0,3 lg TLR 4 GATA3 1,0 , [GATA3] – ) . . 95% (19 20) 93% (54 58) ( 13). 4,0 3,0 2,0 1,0 ,0 -1,0 -2,0 -3,0 -4,0 -5,0 -6,0 cut off . 13. . , (n=77). 74 , 95% (73 : 95% (19 96% (55 20) 57) . ROC- ( ROC- (AUC) . 14). 0,98 (p<0,05) ( 15). « ». 25 20 , % 15 10 5 0 -5 -3 -1 1 3 5 cut off . 14. . 75 77) ROC- . 15. ROC( ). ( cut off) , , -0,61. 96% 95% . cut off . : , 40% 86% 47% 6). 76 6. , , , 4 Candida spp. > 10 (n=14) Ureaplasma spp. > 104 (n=10) (n=15) 86% (12 14) 14% (2 14) 40% (4 10) 60% (6 10) 47% (7 15) 53% (8 15) cut off 16. . 16. . 77 3.5 , , , . 7. 1 . . <0,05. 103 (IL15, FOXP3, LIF, TLR9, GNLY, TBX21, IFNG, IL6, IL2RA) . 2( ). 8 ( 9 ) 2 . <0,05. , , LIF IL15 , , 2 . , 78 IL1B TLR2 8,0, TLR4 9,4, IL8 6,0, 7,3 . , TNFA 5,3 IL15 2,3, LIF 2,5 . ( , , , NK- , .). IL23 17). 0.01 0.1 1 10 100 ( IL1B* IL8* TNFA* . 17. TLR2* TLR4* IL23 IL1B, IL8, TNFA, TLR2, TLR4, IL23 , ( 1 ). 79 7. ( 1 ) (n=42) Med (0.250.75) * IL8 1 (0.41-0.98) IL1B , Ureaplasma spp. 104 (n=16) (n=24) Candida spp 103 (n=11) Med (0.25* 0.75) (n=8) Med (0.250.75) * 0.03 0.7 (0.45-1.43) 0.60 0.7 (0.50-1.47) 0.21 1.2 (0.74-3.29) 0.50 0.07 0.6 (0.38-0.73) 0.004 1.2 (1.08-1.45) 0.10 0.7 (0.37-1.54) 0.38 0.6 (0.42-0.90) 0.01 1.2 (1.19-1.49) 0.21 0.0004 1.2 (0.60-1.94) 0.91 0.7 (0.44-0.78) 0.02 2.4 (1.11-2.81) 0.29 0.3 (0.16-0.39) 4.11*10-8 0.9 (0.48-1.31) 0.31 0.5 (0.37-0.76) 0.004 2.3 (1.77-4.34) 0.008 - 5.7 (4.18-9.46) 4.96*10-8 0.8 (0.39-1.41) 0.27 0.9 (0.49-1.54) 0.39 0.9 (0.60-3.54) 0.76 - 2.3 (1.49-4.02) 0.0009 1.3 (0.65-3.09) 0.49 0.8 (0.58-1.10) 0.28 0.8 (0.48-1.73) 0.40 Med (0.25-0.75) * Med (0.25-0.75) * - 6,0 (2.71-11.84) 3.18*10-7 1.3 (0.29-2.19) 0.70 0.5 (0.41-0.57) 1 (0.58-2.36) - 9.4 (6.61-11.90) 2.01*10-9 1.4 (0.41-2.02) 0.84 CD68 1 (0.67-1.59) - 0.4 (0.22-0.56) 5.75*10-7 0.7 (0.48-1.09) IL18 1 (0.63-1.54) - 0.2 (0.14-0.45) 4.98*10-8 TGFB1 1 (0.59-2.51) - 0.4 (0.23-0.87) GATA3 1 (0.65-1.40) - CD45 1 (0.46-2.08) TNFA 1 (0.63-1.86) 7 (n=42) Med (0.250.75) * TLR2 1 (0.45-2.15) TLR4 , Ureaplasma spp. 104 (n=16) (n=24) Candida spp 103 (n=11) Med (0.25* 0.75) Med (0.25-0.75) * Med (0.250.75) * - 8,0 (4.97-12.44) 1.07*10-7 1.1 (0.17-3.15) 0.50 0.9 (0.27-1.04) 1 (0.32-2.34) - 7.3 (4.90-12.74) 9.09*10-8 1.1 (0.22-2.34) 0.76 IL23 1 (0.48-2.53) - 1.5 (0.51-6.11) 0.18 0.6 (0.36-1.60) CD69 1 (0.39-3.43) - 5.4 (2.15-14.82) 0.00098 IL12A 1 (0.72-1.48) - 0.5 (0.26-0.91) IL10 1 (0.55-2.24) - RORC (n=8) Med (0.250.75) * 0.09 0.8 (0.37-1.39) 0.35 0.6 (0.43-1.34) 0.45 1.3 (0.64-2.08) 0.67 0.43 0.9 (0.70-4.34) 0.37 0.4 (0.26-0.93) 0.09 1.5 (0.39-1.26) 0.11 1.0 (0.73-2.11) 0.80 2.8 (1.85-5.28) 0.09 0.0003 0.9 (0.63-1.57) 0.67 0.6 (0.50-1.15) 0.08 1.1 (0.96-1.82) 0.55 4.2 (3.33-7.98) 5.98*10-8 1.9 (0.89-4.70) 0.06 2.1 (1.54-3.30) 0.02 1.3 (0.60-1.86) 0.82 1 (0.64-2.90) 0.2 (0.09-0.71) 0.00003 0.7 (0.32-2.00) 0.23 0.3 (0.18-0.96) 0.02 3.3 (2.08-6.13) 0.07 LIF 1 (0.40-2.48) 5.3 (2.94-35.54) 0.0001 0.8 (0.40-2.55) 0.49 0.3 (0.10-0.43) 0.001 1.1 (0.75-2.61) 0.98 IL15 1 (0.63-2.36) 2.5 (1.57-3.50) 0.01 3.1 (1.43-5.47) 0.02 1.9 (1.47-3.22) 0.09 1.8 (1.19-2.76) 0.17 * p . 81 8. 103 (n=42) (n=24) LIF 42 (98%) 24 (100%) Ureaplasma spp. 104 (n=16) 16 (100%) IL15 42 (100%) 24 (100%) IL6 27 (64%) GNLY , 3 Candida spp 10 (n=11) (n=101) 11 (100%) (n=8) 8 (100%) 101 (100%) 16 (100%) 11 (100%) 8 (100%) 100 (100%) 23 (96%) 11 (69%) 10 (91%) 6 (75%) 76 (75%) 31 (74%) 24 (100%) 10 (63%) 6 (55%) 4 (50%) 75 (74%) TLR9 36 (86%) 24 (100%) 10 (63%) 8 (73%) 4 (50%) 82 (81%) FOXP3 36 (86%) 19 (79%) 14 (88%) 8 (73%) 4 (50%) 81 (80%) IFNG 24 (57%) 17 (71%) 11 (69%) 10 (91%) 0 (0%) 62 (61%) IL2RA 19 (45%) 21 (88%) 6 (38%) 6 (55%) 5 (63%) 57 (56%) TBX21 24 (57%) 18 (75%) 10 (63%) 8 (73%) 4 (50%) 64 (63%) 9. 2 103 (n=24) 104 Ureaplasma spp. (n=16) 2 2 , 3 Candida spp 10 (n=11) 2 (n=8) 2 IL6 6,7 0,01 0,0 0,99 4,0 0,045 0,0 0,86 GNLY 5,8 0,02 0,2 0,60 0,7 0,39 0,8 0,36 TLR9 2,2 0,13 1,2 0,27 0,3 0,57 3,3 0,07 FOXP3 0,1 0,73 0,0 1,00 0,3 0,57 3,3 0,07 IFNG 4,0 0,045 0,2 0,61 3,8 0,08 6,6 0,01 IL2RA 9,7 0,003 0,1 0,81 0,1 0,83 0,2 0,61 TBX21 1,4 0,24 0,0 0,94 0,3 0,55 0,0 1,00 2 p<0.05 3,8 83 , CD45 5,7 CD69 5,4 18). 0.01 0.1 1 10 100 ( CD45* CD69* IL10* . 18. LIF* IL15* CD45, CD69, IL10, LIF, IL15 , ( ). IL10 ( 4,2 18). CD68 2,5, IL12A 1 2,0, IL18 5,0, GATA3 3,3, TGFB1 2,5 RORC 19). 0.001 0.01 0.1 1 10 ( 5,0 CD68* IL12A* IL18* GATA3* . 19. TGFB1* RORC* CD68, IL12A, IL18, GATA3, TGFB1, RORC , ( 1 ). 103 , IL6, GNLY, IL2RA IFNG. . 11 103 Candida spp. 85 , ( 10). IL8 2,0, IL18 1,6, TGFB1 – IL10 1,4, GATA3 2,0, RORC 3,0 LIF 4,0 2,1 . IL6. 16 104 Ureaplasma spp , ( 10). , , IL15, 2 . (n=8) , GATA3, 2 , . , : IL1B/CD68, IL10/IL18 TLR4/GATA3. , , ( ) . 86 10. 10. ( 1 ) (n=40) (n=42) (0,25-0,75) * (0,25-0,75) * IL1B 1 (0,45-1,56) - 0,6 (0,30-1,40) 0,09 IL8 1 (0,28-2,41) - 0,9 (0,37-1,81) 0,52 IL10 1 (0,39-2,23) - 2,4 (1,32-5,45) 0,004 IL12A 1 (0,69-1,89) - 1,8 (1,32-2,72) 0,021 IL18 1 (0,69-1,73) - 0,8 (0,52-1,28) 0,002 TNFA 1 (0,59-1,90) - 0,6 (0,34-1,01) 0,001 TGFB1 1 (0,69-1,81) - 12,7 (7,55-31,82) 1,2*10-13 CD45 1 (0,31-2,11) - 0,5 (0,23-1,04) 0,01 TLR2 1 (0,54-2,73) - 0,6 (0,25-1,20) 0,07 TLR4 1 (0,29-1,72) - 0,6 (0,19-1,40) 0,46 IL23 1 (0,54-2,28) - 0,9 (0,45-2,38) 0,84 GATA 3 1 (0,56-1,50) - 0,8 (0,52-1,12) 0,34 CD68 1 (0,56-1,78) - 1,6 (1,08-2,56) 0,005 CD69 1 (0,62-2,56) - 1,3 (0,49-4,39) 0,84 * p . 87 IL10 2,4, IL12A 18, TGFB1 12,7 IL18 1,2, TNFA 1,8 CD68 CD45 1,6 , 2,1 ( 20). , , 0 .1 1 10 ). IL1B IL8 IL10* IL12A* IL18* TNFA* TGFB1* CD45* TLR2 TLR4 IL23 GATA3 CD68* . 20. , . 1 (*p<0,05) . : y 0,5 lg IL1B CD 68 0,3 lg IL10 IL18 88 0,04 lg TLR 4 GATA3 1,3 , CD69 [IL1B], [CD68], [IL10], [IL18], [TLR4] ( [GATA3] – ) . , , 0.001 0.01 0.1 1 10 100 1000 21. IL10/IL18* . IL1B/CD68* TLR4/GATA3* 21. , ( (*p<0,05)). 95% (40 96% (23 24) . ( 22). 89 42) 1 35 30 25 ,% 20 15 10 5 0 -3 -2 -1 0 1 2 3 4 5 6 cut off . 22. . ROC(AUC) . 0,993 (p<0,05) ( ROC- 23). ». ( cut off) , . 0,65. 96% 95% . cut off . 90 ROC- . 23. ROC( ). : 82% Ureaplasma spp. , 75% 104 , ( 11). 91 11. , , , 4 Candida spp. > 10 (n=11) Ureaplasma spp. >104 (n=16) (n=8) 82% (9 11) 18% (2 11) 75% (12 16) 25% (4 16) 100% (8 8) 0% (0 8) cut off 24. . 24. 92 3.6 , (p=1,3*10-5, =10,4 3,28-32,94). , ( 12). 12. (n=42) 7 % 16,7 7 (n=24) % 29,2 1 2,4 7 29,2* , 3 7,1 6 25,0* , 3 7,1 4 16,7 9 21,4 2 13 8,3* 54,2* . . : *– ( <0,05) : (7,8%) 7 (29,2%) (p=0,012, 16.10). 93 6 =4.87, 1.48- 6 (25,0%) , 6 (7,8%) ( =0,033, =3.94, 1.16-13.44). , . 7 , 9 (77,7%) 104 Candida spp. . , Candida spp. . IL1B, IL8, IL10, D45, CD69, TLR2, TLR4, TNF , GATA3, CD68, IL12A, IL18, TGFB1, RORC ( , ) ( , ) . , , . 94 4. . , , , , [47]. , [4]. . , : ), . , . , , , [109; 110]. , , L. crispatus, L. iners, L. jensenii L.gasseri [150]. , . , . , , , , [16; 60]. 95 . [50; 53; 58]. , [16; 60]. , [102; 146; 168], , : , , - . , , , . , 81% , Streptococcus spp., Enterobacterium spp., Gardnerella vaginalis/Prevotella bivia/Porphyromonas spp., Eubacterium spp., Lachnobacterium spp./Clostridium spp., Atopobium vaginae, Sneathia spp./Leptotrihia spp./Fusobacterium spp.) . 19% . 63% , . 96 37% - (IL1B, IL6, IL8, IL10, IL12A, IL15, IL18, IL23, TNF , IFNG, TGFB1, LIF, TBX21, GATA3, FOXP3, RORC, TLR2, TLR4, TLR9, CD45, CD68, CD69, IL2R , GNLY) ( - ). , , , , , . , TLR2, TLR4, IL1B, IL8, IL6, IL10, CD45, CD69, IL2RA, IFNG GNLY, CD68, IL12A, IL18, GATA3, RORC, TGFB1 . LIF, IL15 TNFA , – TBX21 . , . . , PAMP, : , , , , [131]. PRR TLRs, APC, [174]. 97 , TLRs [111; 124]. PAMP TLR1, -2, -4, -6, [144; 191]. [144; 163; 171; 189] , , , , , , TLR2, -4, -6, TLR2 TLR4. PRR , , ), . , TLRs , (NF-kB), (NF-kB) , , , . , IL1A, IL1B, IL8, IL6, IL18, IL12, TNFA [26; 85; 105; 107; 157], IL6 [106; , 120]. ( , , NK- .) . IL8. , , , , . 98 (IL1B, IL6, IL8, TNFA) , , . . , – NK- - . [103; 136], , . GNLY. ( TLRs, ) , . , , APC MHC - [102; 172]. [27; 165; 175] CD68, . CD68 . , , CD68. 99 . TBX21 INFG - . INFG, , . – , CD8+-T- – Th1- . TBX21 , Th0Th1- , - [132; 180]. TBX21, IFNG , IL18, , IL12 Th0, . IL12A IL12, Th1, IL18. , , [87; 101; 118]. , IL2Ra, CD69, CD45 . , . . 2-3 CD69 – 100 , CD25, - a- - IL-2 [74; 158]. - CD45 , , , [127; 176]. IL15 . IL-15 , . , : CD8+ , IFNG - , TNFA [77; 82; 89]. IL10, [79; 141; 194]. , , IL10, , , . , IL10 , , CD4+ , IL10 - CD8+ NKCD4+ - – , (IL2, IFNG, IL4, IL5, TNFA), – : MHC II (IL1A . IL10 , B, IL6, IL12, IL18, TNFA) 101 ; , . , IL10 [98]. IL10, , Th17- . RORC , [183]. 40% Candida spp. , , . , Candida spp. , IL10 TGFB1[69]. IL10 TGFB1 . , , , [86; 148]. , TGFB1 . , , , [133], , , . GATA3, Th2- , , ( 102 ) [95; 135]. GATA3 . , , IL10, IL12A, TGFB1 TNFA, CD45 – CD68, IL18, , . LIF, IL15, GNLY IFNG . NK- , [145; 156]. , , . , (GNLY, IL2RA, IL15, IFNG, TBX21, IL6, LIF, FOXP3) , , , , . , (p=1,3*10-5, =10,4 3,28-32,94). , IL1B, IL8, IL10, D45, CD69, TLR2, TLR4, TNF , GATA3, CD68, IL12A, IL18, TGFB1, RORC 5-3 103 , . , . 7 , 9 (77,7%) . , , 40% , [170], . IL1B, CD68, IL10, IL18, TLR4 96% GATA3 95% , . . , , , . , , , , , , [32]. 104 , . , , , . , « », - : , 104 Ureaplasma spp. . , . , : 14% , 60% 53% . , IL1B, CD68, IL10, IL18, TLR4 GATA3 . , , . 105 , , . . 106 1. , . 2. (24 14 (IL1B, IL8, IL10, ) D45, CD69, TLR2, TLR4, TNF , GATA3, CD68, IL12A, IL18, TGFB1, RORC) . 3. ( IL1B, IL8, IL10, TLR2, TLR4, TNF RORC , D45, CD69, GATA3, CD68, IL12A, IL18, TGFB1, ), . 4. IL10, IL12A, TGFB1, CD68 – IL18, TNFA, CD45 . 5. IL1B, IL8, IL10, D45, CD69, TLR2, TLR4, TNF , GATA3, CD68, IL12A, IL18, TGFB1, RORC ( , ) ( , ) . 6. IL1B, IL18, IL10, CD68, TLR4 GATA3 96% , 95% . 107 1. . ., . ., . : . / ., . .: « . », 2009. - 1200 c. 2. . . ./ 3. . .: " ., ", 2009. - 73 c. . . // 2001 - . 3 4. . ., . 2. . 24-27 . . //Concilium medicum. 2005. - . 51-64. 5. . . – //Consilium Medicum 2011 - . 13 6. . 4. . 7-11 ., . . : . / .: " ", 2008. - 256 . c. 7. . . . // 8. . 2010. - . 12 . ., . 3. . 4-6. ., . . - . //Consilium medicum. 2009. 9. 6. . 47-51. . ., . ., . . . // 10. . 2005. . 3. . 65-69. ., . 108 ., . . . . 2009. - . 27 11. . // 4. . 114–116. ., . ., . ., . . . ., : ? // . 2011. - 12. . ., . 1. . 57-65. ., . . - . 2009 - 1. . 34-36 13. . . . // . 2007. - . 4 1. . 6- 8. 14. . ., . . . 2009. - . . // 1. . 19-22. 15. . ., . // 16. ., . . . . 2007. - ., . 2. . 11-12. . . // 17. . ., . 2008. - 1. . 7-9. . . // , . 2001. - 4. . 89-93. 18. . . ., . . ., . 2012 . 3. . 88-93 . // . . . 2003. - . 11 17. . 985-989. 20. ., . // 19. ., . ., . 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