Abstract Successful pregnancy is characterized by a shift toward Th2 type immune response and suppression of adaptive immune responses to ensure acceptance of the semi-allogenic fetal graft. Also the innate immune system plays a major role during pregnancy. Recurrent miscarriage is defined as three or more consecutive pregnancy losses. About 1% of all women will suffer recurrent miscarriage. The causes of recurrent miscarriage remain unexplained in half (50%) of the cases. Susceptibility to recurrent miscarriage is probably mediated by Th1 type immune response with pronounced expression and secretion of pro-inflammatory cytokines (e.g. TNFα and IFNγ) paralleled with decreased production of anti-inflammatory cytokines (e.g. IL-10). Factors that regulate immune response during pregnancy include hormonal factors (e.g. hCG and progesterone). Immunogenetic factors also contribute to this regulation. Several functionally important polymorphisms in various immunomodulatory genes have been identified during recent years. Some of these polymorphisms may be important in regulating the Th1/Th2 balance during pregnancy. Putative immune dysregulation caused by these polymorphisms has been researched intensively. Conflicting results have been published about associations between several of these polymorphisms and recurrent miscarriage. In this study, HLA-G (exon 2 and 3), IL-10 (-1082A/G), IL-1RA (intron 2 VNTR) and CD14 (-159C/T) polymorphisms were studied in 38 Finnish women with RM. All of these polymorphisms have been associated with altered gene expression. Distribution of HLA-G*I, II, III and IV were 0.577, 0.375, 0 and 0.048 respectively in the studied Finnish population. According to the present classification the G*I allele group mostly consists of the allele 010101, while G*II covers the combination of 010102, 010401 and 0105N, as well as some other rare alleles. There were no associations between recurrent miscarriage and the HLA-G, IL-10 and CD14 polymorphisms. However, in IL-1RA polymorphism, the rare IL1RN*3 allele was increased in women with recurrent miscarriage. It is not known, if this particular allele is associated with differences in IL-1RA or IL-1 production. Although the study population was small, it may be supposed that quantitative differences in the production of single immunomodulatory molecules due to normal genetic variation may not be grossly harmful to the fetal allograft. This indicates the robustness and flexibility of the reproduction system. For survival, it is essential that minor variations are tolerated. Thus, large-scale studies focusing on the effect of a pro-inflammatory genetic profile based on the presence of several pro/anti-inflammatory genetic markers are needed to discover if immunogenetic factors predispose women to recurrent miscarriage.

Made available in DSpace on 2016-01-26T12:51:34Z (GMT). No. of bitstreams: 1 danielaprudenteteixeiranunes_dissert.pdf: 2007548 bytes, checksum: 1b9b96cf5d50556af914f8157e7d26ec (MD5) Previous issue date: 2010-12-16 / Adenosine deaminase (ADA), an enzyme coded by ADA gene (20q13.11) acts in adenosine metabolism and it is involved in the modulation of the immune response. ADA gene G22A polymorphism originates two co-dominants alleles ADA*01 and ADA*02 and influences the level of ADA enzyme in the organism. Apparently it has a fundamental role in gestational maintenance. The ADA*02 allele has been associated as protector effect against recurrent spontaneous abortion (RSA) in European Caucasian women. Aim: To investigate if ADA gene G22A polymorphism is associated with occurrence of RSA in Brazilian women. Methods: After obtaining the written consent 311 women were selected to compose two groups: G1 with previous history of RSA (n=129) and G2 without previous history of RSA (n=182). Genomic DNA was isolated from peripheral blood using commercial kits. The PCR-RFLP method was used to identify ADA gene G22A polymorphism. p>0005 was considered statistically significant. Results: The frequencies of ADA*01;*01, ADA*01;*02 and ADA*02;*02 genotypes were similar in both groups (G1 and G2) with no statistically significance differences observed (p = 0,7170; x2 = 0,6653; GL = 2). ADA*01 and ADA*02 alleles frequencies were 95,6% and 4,4% in G1 group and 94,9% and 5,1% in G2 group, respectively (p = 0,8433; OR = 1,179; CI 95%: 0,5340 2.601). Conclusion: The results suggest that ADA alleles ADA*01 and ADA*02 are not associated with RSA. It xvi is possible that the reduction of ADA levels resulting from the presence of at least one ADA*02 allele do not have a role against abortion in Brazilian women. / Polimorfismo G22A do gene ADA e abortamento espontâneo recorrente: ausência de associação Introdução: A adenosina deaminase (ADA), uma enzima codificada pelo gene ADA (20q13.11), atua no metabolismo da adenosina e modula a resposta imune. O polimorfismo G22A deste gene origina os alelos co-dominantes ADA*01 e ADA*02 e influencia o nível de expressão da enzima ADA, que possui papel fundamental na manutenção da gestação. O alelo ADA*02 tem sido associado a um efeito protetor contra o abortamento espontâneo recorrente (AER) em mulheres caucasianas européias. Objetivo: Investigar se o polimorfismo G22A do gene ADA se associa à ocorrência de AER em brasileiras. Métodos: Após obtenção do Termo de Consentimento Livre e Esclarecido (Parecer CEP FAMERP 308/2008), 311 mulheres foram selecionadas para compor dois grupos: G1 com histórico de AER (N=129) e G2 sem histórico de AER (N=182). O DNA genômico foi extraído a partir de sangue periférico com o uso kit comercial. O polimorfismo G22A do gene ADA foi identificado com o uso do método PCR-RFLP. O valor p>0,005 foi considerado significante. Resultados: As frequências dos genótipos ADA*01;*01, ADA*01;*02 e ADA*02;*02 foram semelhantes entre os grupos e não apresentaram diferenças estatisticamente significantes (p = 0,7170; χ2 = 0,6653; GL = 2). As frequências dos alelos ADA*01 e ADA*02 em G1 foram iguais a 95,6% e 4,4%; em G2, 94,9% e 5,1%, respectivamente (p=0,8433; OR=1,179; IC 95%: 0,5340-2.601). Conclusões: Os resultados sugerem que xiv os alelos ADA*01 e ADA*02 do gene ADA não estão associados ao AER. É possível que a redução nos níveis da ADA resultantes do alelo ADA*02 não apresente um efeito protetor contra o AER em brasileiras.