Mapping susceptibility genes for complex diseases can better our understanding of their pathogenesis. However, even when a complex disease gene is mapped, unravelling the mechanisms underlying its association with disease is not straightforward. In contrast to classical monogenic diseases where a genetic mutation usually inactivates a gene or causes unchecked activation of a gene, in complex diseases such as AITD the associated genetic variants may cause subtle changes in the function of one or more genes. Therefore, even when a gene associated with a complex dis ease is mapped it can be challenging to prove that a certain variant changes the function of the gene in a way that will promote the development of the disease. However, considerable progress has been made in dissecting some of the mechanisms by which AITD associated genes predispose to disease.

HLA

The mechanisms by which HLA associations confer disease susceptibility in many autoimmune diseases are now well understood. For T cells to recognize and respond to an antigen they require inter action with a molecular complex consisting pf an antigenic peptide and an HLA class II molecule. It is thought that different HLA alleles have different affinities for peptides derived from the processing of autoantigens (e.g. such as Tg and the TSHR) and which are then recognized by T- cell receptors. Thus, certain alleles may have a preferential affinity for a particular autoantigen because the peptide is able to f it in the antigen binding groove inside the HLA molecule allowing it to be recognized by the T- cell receptor while other HLA molecules may not have the same binding pocket structure. This would deter mine if an autoimmune response to that antigen peptide will develop.

Studies have demonstrated that DRβ- Arg74 is a critical HLA- DR pocket amino acid associated with GD. Position 74 of the DRβ chain is located in pocket 4 (P4) of the DR peptide- binding cleft. Structural modelling analysis demonstrated that the change at position 74, from the common neutral amino acids (Ala or Gln) to a positively charged hydrophilic amino acid (Arg), significantly modified the three dimensional structure of the P4 peptide- binding pocket thus altering the peptide- binding properties of the pocket and favouring peptides able to induce GD. A similar pocket HLA- DR amino acid signature has been strongly associated with HT.

For thyroid autoantigens to be presented by HLA molecules to T cells, a mechanism of autoantigen presentation must exist within the target tissue. One potential mechanism not utilizing professional APCs may be through aberrant expression of HLA class II molecules on the target tissue cells. Indeed, thyroid epithelial cells from patients with AITD have been shown to express HLA class II antigen molecules which are normally expressed only on APCs such as macrophages and dendritic cells [54]. This aberrant expression of HLA molecules on thyroid cells, could initiate thyroid auto immunity via direct thyroid autoantigen presentation.

CTLA- 4

CTLA- 4 is a negative regulator of T cells and a polymorphism that de creases CTLA- 4 function and/ or cell surface expression would cause enhanced T- cell activation potentially contributing to the development of an autoimmune condition as seen when treating patients with anti- CTLA- 4. Several CTLA- 4 variants have been analysed in detail for their effect on CTLA- 4 function and/ or expression and a comprehensive analysis of the CTLA- 4 gene locus reported that the CT60 SNP of CTLA- 4 (rs3087243) showed the strongest association with GD, suggesting that it might be the causative SNP.

CD40

CD40 is an important costimulator of T- cell activation associated with a number of autoimmune diseases. The CC genotype of a CD40 5’UTR SNP was shown to be associated with GD. This CD40 SNP resides in a region which can influence the initiation of translation and, therefore, the expression of CD40. Indeed, the C- allele of the 5’UTR SNP was shown to increase the translation of CD40 mRNA transcripts, by 20– 30% compared to the T- allele. At least two potential mechanisms can explain how the C- allele of the CD40 5’UTR SNP increases the risk for GD: (1) The C- allele may increase CD40 expression and function on B cells, thereby potentially lowering the threshold of activation of thyroid autoreactive B cells; and/ or (2) The C- allele may increase the expression of CD40 in the thyroid gland itself. CD40 signalling in thyrocytes can result in cytokine secretion (e.g. IL- 6). Thus, overexpression of CD40 on thyroid cells may, under certain conditions (e.g. infection), result in increased secretion of cytokines by thyroid cells causing local inflammation and activation of autoreactive T cells that were dormant or suppressed by peripheral regulatory mechanisms. This mechanism is known as a bystander mechanism of induction of autoimmunity and is seen in experimental thyroiditis. Studies with transgenic mice overexpressing thyroid CD40 indicate that the development of GD after TSHR immunization was more profound confirming the potential role of this costimulator.

PTPN22

 The lymphoid tyrosine phosphatase (LYP) encoded by the PTPN22 gene belongs to a family of protein tyrosine phosphatases that are expressed in both immature and mature B- and T- lymphocytes. LYP is a powerful inhibitor of the T- cell antigen receptor signalling pathway. LYP binds to the C terminal of the protein kinase, Csk, restricting the response to antigens by disrupting protein tyrosine phosphorylation events that control cell activation and differentiation. This negative control mechanism prevents spontaneous T- cell activation.

The exact mechanism by which the associated R620W variant of the PTPN22 gene predisposes to autoimmunity is not known. The substitution of arginine with tryptophan at this position interferes with the interaction of LYP with Csk. In vitro experiments show that only LYP with arginine at position 620 forms a complex with Csk whereas LYP with tryptophan at this position binds less efficiently. One study suggested that the tryptophan variant is a gain- of- function change that makes the protein an even stronger inhibitor of T cells. Thus, the disease- associated tryptophan variant would be expected to suppress T- cell activation and proliferation. Reduced T- cell receptor signalling could lead to a tendency for self- reactive T cells to escape thymic deletion and thus remain in the periphery.

Thyroglobulin

 Thyroglobulin (Tg) is a 660 kDA homodimeric protein that serves as a precursor and storehouse for thyroid hormones. Tg is one of the main targets of the immune response in both HT and GD and by immunization is able to induce experimental autoimmune thyroiditis (EAT) in a variety of animal models, most notably the mouse [65]. EAT, like HT is characterized by a diffuse cellular infiltrate of the thyroid with anti- Tg T- cell responses as well as hightitres of Tg autoantibodies. This indicates that Tg is a critical thyroid- specific antigen involved in the aetiology of AITD.

It is not surprising, therefore, that the Tg gene is an AITD susceptibility gene. Three amino acid substitutions in Tg were first reported to be significantly associated with AITD [40] and several mechanisms have been postulated to explain the association. Clearly the presentation of a Tg peptide by APCs to T cells must be involved and since peptide antigens are presented within HLA class II molecules, as discussed earlier, this mechanism would imply that there exist a more potent interaction between certain Tg variant peptides related to the as sociated SNPs and certain HLA- DR variants in susceptible patients pre disposing them to AITD. This was shown for one such peptide which had a strong statistical interaction with the Arg74 polymorphism of HLA- DR, resulting in a high odds ratio of 15 for susceptibility to GD. Supporting this hypothesis was a study which identified specific HLA- DR bound Tg peptides within the thyroid glands from Graves’ patients. Moreover, studies in ‘humanized’ mice expressing HLA- DR3 have shown that certain Tg peptides can induce EAT in these mice. Another variant in the Tg promoter (- 1623A/ G) was also found to be associated with AITD. Functional analysis showed that the nucleotide substitution introduced by this Tg promoter SNP created a binding site for interferon regulatory factor- 1 (IRF- 1), causing up- regulating Tg promoter activity upon IRF- 1 binding. These data suggest an at tractive mechanism for environmental– genetic interaction whereby during viral infections local production of interferon alpha can lead to upregulation of Tg transcription via IRF- 1 in individuals carrying the risk (G) allele of the Tg promoter SNP but not in individuals carrying the protective (A) allele.

TSH Receptor (TSHR)

 All the TSHR SNPs which are consistently associated with GD are intronic. Therefore, the mechanism by which they predispose to GD is more challenging to dissect. It has been postulated that these intronic SNPs may influence the expression of the TSHR through regulatory elements. For example, intrathymic TSHR expression was decreased in individuals homozygous for a particular associated SNP (rs12101261) compared with carriers of the disease- protective allele. Furthermore, such repression was enhanced by interferon alpha acting through an epigenetic mechanism. Alternatively, SNPs may be associated with changes in the alternative splicing of the TSHR although how this alters the immune response is uncertain but changes in thymic expression may be involved.

The X Chromosome

There are a number of possible mechanisms whereby the X chromo some could influence the development of AITD. One mechanism is probabilistic. Females have two X chromosomes (one paternal and one maternal) while males have only one X chromosome (maternal). Therefore, females are twice as likely to inherit an X chromosome AITD susceptibility gene as males. Several immune regulatory genes are located on the X chromosome including the FOXP3 gene which was associated with AITD in Caucasians. FOXP3 is the master regulator gene of T regulatory cell differentiation hinting at a mechanism for the female preponderance of AITD.

Another possible mechanism involves X- inactivation. X- inactivation in females results in the production of two classes of cells that differ in the transcription of X- chromosome encoded genes including genes coding for self- antigens. If these two cell classes extend to the thymic cells responsible for tolerizing T cells in embryonic life, some lymphocytes may not be tolerized to one of the two self- antigens encoded by the X chromosome. Such lymphocytes would be autoreactive to that antigen and could induce an autoimmune response. Supporting this hypothesis are data showing skewing of X- inactivation in females with AITD.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الخدمية يواصل جهوده في توزيع الماء لزائري مرقد أبي الفضل العباس (عليه السلام)

قسم شؤون المعارف يجري القرعة الإلكترونية الخاصة بمشاهدي (مسابقة معارف التراث)

قسم الشؤون الفكرية يواصل برنامجه الصحي التوعوي في مدارس بغداد

من خدمة الزائرين إلى إغاثة المنكوبين.. العتبة العباسية المقدسة حاضرة في كل الميادين

المزيد

الآخبار الصحية

كوب قبل النوم.. مشروب طبيعي يحارب الأرق

دون أدوية.. طريقة طبيعية لخفض ضغط الدم بفعالية مذهلة

المعكرونة ليست عدوك.. كيف تصبح جزءا من وجبة صحية متوازنة؟

دراسة: تناول القهوة يوميا يخفض خطر الإصابة بالاضطرابات النفسية

المزيد

الآخبار التكنلوجية

علماء روس يخططون لبناء منشأة للكشف عن المادة المظلمة

ثاني أكسيد الكربون ليس تهديدا للمناخ فقط.. بل لصحة الإنسان أيضا!

ديدان الأرض تكشف تلوث التربة بالمعادن الثقيلة

خبير أرصاد جوية: ظاهرة النينيو القادمة قد تكون الأقوى خلال 10 سنوات

المزيد

مواضيع ذات صلة

Genetics of Autoimmune Thyroid Disease : Non- HLA Genes in AITD

Genetics of Autoimmune Thyroid Disease : The Primary Role of HLA Genes

Genetic Susceptibility to Autoimmune Thyroid Disease (AITD)

Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome

Genetic Screening in Populations

Genetic Counseling for Preconception and Prenatal Diagnosis and Screening

Fetal Surgical and Medical Interventions

X-Linked Inheritance

Preconception Genetic Screening and Testing

Problems in Prenatal Chromosome Analysis and Gene Sequencing

Introduction to Cytogenetics and Genome Analysis

Methods to Detect Fetal Chromosomal Abnormalities