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Graves’ disease and pregnancy
Csaba Balázs MD, DSc
Department of Medicine & Endocrinology, Polyclinic of the Hospitaller Brother’s of St. John of God in Buda, Budapest

Graves’disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism caused by stimulating autoantibodies directed against the TSH receptor (TSH-R). The appearance of anti-TSH-R antibodies is a consequence of a breakdown in self-tolerance to the TSH-R. Both humoral and cellular immune reactions are responsible for induction and perpetuation of disease. The precise mechanisms for breakdown of immune tolerance to the TSHR remain unclear, however, it appears to be influenced by protective and permissive environments in genetically susceptible individuals1, 2, 3 (Table 1.)
EPIDEMIOLOGY
GD is one of the most common autoimmune diseases. Women are affected more than men, most frequently between the ages of 20 and 40 years, but the disease can occur at any age. The incidence of GD was found to be 30 cases per 100,000 annually. The distribution of GD around the globe, so far as data are available, appears to be relatively equal, affecting all countries and races. It is most typically a disease of adult women and has an incidence roughly eight times greater in women than in men. Aside from the infrequent occurrence of postnatal thyrotoxicosis due to maternal antibodies, the incidence of spontaneous GD in children before the age of ten is most unusual, but the incidence climbs with each decade until about age 60.4,5,6 One possibility of this preponderance is that female reproductive activity somehow stresses the thyroid and/or during pregnancy the fetal Y positive cells pass the placenta and can bring about the micro-chimerism in the mother which resamble the graft versus phenomenon.7, 8
STRUCTURE OF TSH-R
TSH-R is one of the 7-transmembrane domain G protein-coupled glycoprotein hormone receptors, which is the master switch in regulation of the thyroid gland and also a major autoantigen in autoimmune thyroid disorders, especially in GD. The identification and characterization of intra- and intermolecular signaling determinants as well as signaling mechanisms are prerequisites to gaining molecular insights into functions and dysfunctions of TSH-R. The TSH-R gene located on chromosome 14q, has long been thought of as a likely-specific susceptibility gene for GD. TSH-R consist of 10 exons which encode a 764 amino acid protein of approximately 95 kD including a 21 amino acid signal peptide which later cleaved a mature TSH-R of 743 amino acids 9,10,11,12. TSH-R consists of an "A" and "B" subunit. A subunit represents a large extracellular domain which is composed of 394 amino acids encoded by 1-9 exons. The "B" subunit is in the trans-membrane regions consisting of 349 amino acids encoded by exon 10. Cleavage of event on "A" subunit results in the removal of a 50 amino acid peptide between 316-366 13, 14,15 (Fig. 1). Intensive study on soluble TSH-R (sTSH-R) revealed that a metalloproteinase (ADAM10) might be responsible for this mechanism16.These observations confirmed that the "A" subunit of TSH-R is a critical autoantigen, cleavage and shedding of TSH-R "A" subunit may influence the production of autoantibodies. Shedding of TSH-R "A" subunit could trigger the autoimmune response in individuals processing TSH-R self-reactive T cells. Isolation of human and mouse TSH-R has shown that binding occurs between amino acid 1-261corresponding the extracellular domain.16. The increased shedding of TSH-R may, therefore, trigger the autoimmune response in the production of anti-TSH-R antibodies. The concentration of circulating antigen (sTSH-R) in individuals possessing self-reactive T cells is likely to be a key factor in the breakdown of self tolerance. A higher concentration of TSH-R immunogen region increases the chances of presentation by antigen presenting cells such as macrophages or activated (HLA-DR positive) thyrocytes to self-reactive lymphocytes, thus triggering an autoimmune response.17, 18, 19 The physiologic immune regulation can prevent the autoimmune mechanism since a high concentration of sTSH-R may also induce activation of T regulatory (Treg) cells (CD4+CD25+ FoxP3+) and able to abolish the autoimmune process.20
GENETIC FACTORS OF GD
TSH-R
Since the TSH-R is the primary autoantigen in GD it has been the focus of several genetic studies over the last 20 years. The GD is known to be specific human disease, because the similar spontaneously manifesting disorder has not been observed in animals, therefore, it was assumed that the human TSH-R should have specific mutation(s) or polymorphism(s),therefore,an intensive research has been started for finding structural differences and polymorphism in TSH-R. Previously we found phylogenetic differences in molecular structure between human and animal TSH-R, however, these observations have provided inconclusive evidence for manifestation of GD in human being.21 (Fig.2.) To date, three common germline single nucleotide polymorphisms (SNPs) of the TSH-R have been described. Two of these SNPs reside in the extracellular domain of the TSH-R, they are an aspartic acid to histidine substitution at position 36 (D36H), and a proline to threonine substitution at position 52 (P52T).The third SNP, a relatively conservative substitution of glutamic acid for aspartic acid (D727E). The P52T, located in the extracellular domain was first reported to be associated with GD21, 23, 24, 25. Unfortunately, the association of these polymorphisms with GD were not replicated in any subsequent case-control study21, 25. Most recently a 40Kb region of TSH-R intron 1.has been found and showed to have the strongest evidence of association with GD.14, 25 It is likely that genetic variants within the TSH-R may influence post-translational changes in TSH-R and/or gene expression, and increase the risk of the TSHR becoming an immune target.14
HLA
The HLA-region located on chromosome 6p21, extends over 7.6Mb and is particularly gene dense with at least 252 genes, most of which are involved in different aspects of immune function. Over 30 years ago we were the first who demonstrated the association of variants within HLA class I, particularly HLA-A and HLA-B with GD.26 Subsequent studies demonstrated stronger associations within HLA class II genes, leading to more focused efforts within this region. The strongest GD associations within HLA class II were the DRB1*03, DQA1*0501 and to a lesser extent DQB1*02, which together make up the DR3 susceptibility haplotype and a protective DR7 haplotype, consisting of DRB1*07-DQB1*02-DQA1*0201. Later, amino acid mapping based on the alleles genotyped at DRB1 identified 13 amino acid positions that were associated with GD, the DRB1 74 showing strongest evidence for association with GD. The DRB1*03 allele which is part of the predisposing DR3 haplotype encodes an arginine at 74, whereas DRB1*07 part of the protective DR7 haplotype encodes glutamine at 74, suggesting amino acid changes at 74 may drive the associations.25, 26, 27, 28, 29, 30 ,31 Consequently, variants within HLA class I (HLA-C and HLA-B) and HLA class II (DRB1 and DQA1) are likely to interfere with antigen binding and subsequent presentation of antigens to CD4+ or CD8+ T cells. It is possible, that certain HLA class I or II alleles associated with GD such as DRB1 74 may increase affinity for TSH-R autoantigen and so initiate an autoimmune response as seen in GD.25 Moreover, aberrant expression of the MHC class II antigens on thyrocytes and activated lymphocytes in GD was also observed 25. This observation that thyroid follicular cells have the capability to express HLA class II molecules suggests that thyrocytes might be able to present autoantigene(s) by themselves to T cells and contribute to the pathogenesis of the disease. Various factors including cytokines (i.e, IFN-γ), infection and chemicals have been found to express HLA-DR antigens. In addition, we published that the anti-TSH-R autoantibodies are able by themselves for inducing HLA-DR expression and methimazole can modulate it.32 (Table 1.)
CTLA4
Cytotoxic T-Lymphocyte Antigen 4 also known as CD152 is a protein that plays an important regulatory role in the immune system. The human CTLA4 protein is encoded by the CTLA4 gene is a potent inhibitor of T lymphocytes but it is unclear exactly how CTLA4 inhibits T cell function. CTLA4 polymorphisms were first associated with GD and have since been linked with other autoimmune diseases. The CT60 SNP revealed strongest association with GD and it is important that the associated genotypes of CT60 were linked with reduced mRNA levels of a soluble CTLA4 isoform. The recently published results suggest that the G allele at position +49 in exon 1 of the CTLA-4 gene is associated with GD. Two of hypotheses have been assumed for the role of CTLA-4 molecule. First, it is possible that a CTLA-4 gene polymorphism in the leader sequence (exon 1) may influence the level on pattern of expression of the protein. Thus, T cells from G/G-expressing patients would be expected to have reduced levels of CTLA-4 molecules following T cell activation as compared with T cells from A/A-expressing patients. Second, a reduced function of CTLA-4 in cells from G/G-expressing individuals are decreased activation by CTLA-4 ligation of a downstream signaling inhibitory pathway.23, 25
PTPN22
Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) is a protein which in humans is encoded by the PTPN22 gene located on chromosome 1p13. This gene is responsible for production of a signalling molecule (lymphoid tyrosine phosphatase= LYP), which can inhibit the activation of T cells.14, 15 Alternative splicing of PTPN22 gene results in two transcript variants encoding distinct isoforms. The common 1858T (rs2476601) nonsynonymous single nucleotide polymorphism located in the PTPN22 gene frequency was found in autoimmune disorders, including GD. The other missence single-nucleotide polymorphism (SNP) in PTPN22 gene known as R620W (rs2476601) was recently reported to be associated significantly with GD.14, 33

ENVIRONMENTAL AND ENDOGENOUS FACTORS
These factors in opposite to unavoidable (genetic) factor are avoidable. In regions of iodine deficiency, iodine supplementation precipitates Graves' hyperthyroidism and other types of autoimmune thyroid disease (Hashimoto’s thyroiditis). In some patients, adverse events (such as divorce, and job loss) precede the onset of Graves' disease, supporting the possibility of a role for stress as an initiating factor in the disease by means of neuroendocrine pathways. Smoking is weakly associated with Graves' hyperthyroidism and strongly associated with the development of ophthalmopathy. Infections and increased level of interferons have been shown to induce GD via stimulating HLA-DR expressing on thyrocytes. We published that this expression is decreased by methimazole and selenium and can be important in reduction of autoimmun processes.25, 34
THE PATHOMECHANISM OF GD
The consequence of impaired tolerance to TSH-R is the production of anti-TSH-R autoantibodies by B lymphocytes. Unlike other antibodies (e.g. anti-thyroperoxidase and anti-thyroglobulin antibodies), TSH-R antibodies are directly involved in the pathogenesis of Graves’ disease, as demonstrated by the occurrence of transient hyperthyroidism in neonates whose mothers have thyroid-stimulating antibodies. According the effect on thyroid function the anti-TSH-R antibodies can be classified.10, 18
• Thyroid over-activity in Graves’ disease is due to autoantibodies to the TSH-R which activate the receptor in a similar way to the TSH. These autoantibodies are usually described as thyroid-stimulating autoantibodies (TSAb).
• The small part of anti-TSH-R antibodies can block the stimulating effects of TSH (TSBAb) and result in hypothyrodisim by anti-human IgG antibodies in vitro.
• Converting type of anti-TSH-R antibodies. These antibodies can be converted to the stimulating type by anti-human IgG antibodies in vitro. The results suggest that the blocking and stimulating types bind to the same epitope(s) of TSH-receptor related antigens.35 (Fig.3)
The anti-TSH-R antibodies are experimentally proved to be anti-TSH idiotype antibodies. Rabbit anti-rat anti-human TSH anti-idiotypic antibodies have been raised. These antibodies were active at the thyrotropin (TSH) receptor, they inhibited 125I-labeled bovine TSH binding to thyroid plasma membranes and stimulated adenylate cyclase activity.36, 37 (Fig.4) Later we found that the autologous sera from patients with remission were able to suppress significantly the titre of anti-TSH-R antibodies, whereas the controls were capable of a less remarkable inhibition. On the basis of this observation the autologous sera could have therapeutical implication in an accelerated remission of hyperthyroidism in Graves' disease.38 The the most important development in our understanding of peripheral tolerance to TSH-R in the last 20 years has been the characterization of regulatory T (Treg) cells, which emerged from the wreckage of the older concept of suppressor T cells39, 40. By 1990, the existence of general and TSH-R specific suppressor T cells had been published but later questioned. Recently, the rehabilitation of the idea of suppressor T cells as regulators of autoreactive T cells started with the characterization of the T cell subsets that can prevent experimental autoimmune disease. The first of these subsets to be characterized is phenotypically CD4+CD25 cells, other important characteristics of these Treg cells are their expression of FoxP3 (forkhead foxP3) genes41, 42. Numerous experiments attest to the importance of such Treg cells in maintaining tolerance to self, especially in Graves’disease and animal models such as experimental autoimmune thyroiditis42.
II. PREGNANCY
Two decades ago, it was suggested for women with Graves’ disease to avoid pregnancy due to increased risks to the mother and the child. In contrast, newer epidemiological data demonstrated that advances in the treatment of autoimmune diseases and the management of pregnant women with these diseases have similarly improved the prognosis for mother and child. In particular, if pregnancy is planned during periods of inactive or stable disease, the result often is giving birth to healthy full-term babies without increased risks of pregnancy complications. Pregnancy is characterized by a complex series of antigenspecific and nonspecific immunological changes that prevent rejection of the fetal semi-allograft. The generalized reduction of maternal immune responsiveness occurs during pregnancy, which is caused by hormonal and immune mechanisms. Several hormonal influences, mostly increased levels of progesterone give the ‘suppressive’ milieu to maintain a state of tolerance to fetal alloantigens as long as the pregnancy continues 34, 43 . Adaptation of the maternal immune response to accommodate the semi-allogeneic fetus is necessary for pregnancy success and disturbances in maternal tolerance are implicated in infertility, reproductive and post-partum pathologies. During pregnancy, the balance of Th1 (cell-mediated immunity) and Th2 (humoral immunity) cytokines is characterized by an initial prevalence of Th2 cytokines, followed by a progressive shift toward Th1 predominance in the late gestation. If this shift is abnormal it may initial and intensify the cascade of inflammatory cytokine production involved in adverse pregnancy outcomes 44, 45 (Fig.5a, 5b). The characterization of Treg cells has enabled investigation of their function in pregnancy and it is now apparent that these cells play a vital part in preventing rejection of the fetal allograft. The animal studies quickly led to an evaluation of the role of Treg cells in human pregnancy and it is clear from these studies that CD4+CD25+FoxP3+ T cells are increased in number, both in the circulation and in the uterus, during the first and (in most studies) second trimester and decline in the postpartum period44,45. Furthermore, during pregnancy the HLA-G molecules have been detected to modulate the immune system 46, 47, 48. These molecules belong to a non-classical human MHC class I molecules, but distinct from them with low polymorphism. HLA-G molecules are expressed on placenta, thymus, however, at the maternal-fetal interface, trophoblasts do not express major classical MHC class I molecules (HLA-A and B), to prevent normal T cell response. HLA-G is expressed, secreted and can suppress a wide range of immune responses by binding to inhibitory immune cells surface receptors (Fig.6). Experimentals results provide strong evidence in support of the hypothesis that HLA-G dimers play a role in immune suppression at the maternal-fetal interface. The disturbances in HLA-G molecule secretion can result in the termination of pregnancy. Further in-depth investigation will help to clarify the precise mechanism of HLA-G receptor recognition and signaling in vivo and the role of these interactions in successful reproduction.
PREVENTION OF GD
During pregnancy, Graves’ disease typically improves during the second and third trimesters due to progressive fall in anti-TSH-R antibodies which could be explained by Treg mediated suppression, therefore, it is usually possible to reduce and then stop antithyroid drug treatment. However, in those women with the highest levels of antibodies against the TSH-R, there may be sufficient passage of these antibodies across the placenta to cause fetal hyperthyroidism. Such babies are born with neonatal GD that resolves over the first 1-2 months of life as maternal antibodies disappear from the baby’s circulation.49.
The prevention and therapy of GD is possible by following ways:
• Ideally, women with Graves' hyperthyroidism should avoid pregnancy until their hyperthyroidism is adequately treated, because the rate of fetal loss in untreated women is high. The screening and follow up of anti-TSH-R levels is recommended.
• When Graves' hyperthyroidism occurs or recurs during pregnancy, an antithyroid drug should be given in the lowest dose necessary to maintain the woman's serum free thyroxine concentration in the upper part of the normal reference range or just above this range. Combination therapy with an antithyroid drug and thyroxine must be avoided because the dose of antithyroid drug needs to be higher in patients who are also receiving thyroxine therapy, and little of the thyroxine reaches the fetus, resulting in fetal hypothyroidism.50
• Properly monitored treatment with an antithyroid drug is safe in pregnant women. There is little difference between propylthiouracil and methimazole in terms of the potential of causing fetal hypothyroidism, despite the theoretically lower risk of transplacental transfer of propylthiouracil as a result of higher levels of drug binding to serum proteins 50
• If the thyrotoxicosis is relapsed the IVIG therapy can decrease the level of TSAb.38, 54
• Intrathyroid injection of dexamethasone on the relapse rate of hyperthyroidism in patients with GD was evaluated anf found that this combined therapy was helpful to prevent relapse of hyperthyroidism in GD after medical therapy withdrawal.51
• Selenium has been shown to increase the number and function of Treg cells. During pregnancy the therapy of selenium is considered .52, 53.


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