Autoimmune diseases are a heterogeneous group of disorders. Epidemiological studies demonstrate that a complex interaction of genetic and environmental factors underlies their aetiopathogenesis. Autoimmune diseases that result from single gene mutations, although rare, provide a powerful means of studying the potential mechanisms responsible for the development of autoimmunity. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (OMIM 240300) or autoimmune polyendocrine syndrome Type 1 (APS1) is an autosomal recessive disease caused by mutations in the AIRE gene. This disorder has been a powerful model to address the question as to how a tolerant state is achieved or maintained, and to explore how tolerance is lost in the context of autoimmunity (reviewed in 1). AIRE has been proposed to function as a ‘non classical’ transcription factor, strongly implicated in the regulation of organ-specific antigen expression in thymic medullary epithelial cells (MECs), and the imposition of T cell tolerance. Nevertheless, given the complexity of AIRE function in autoimmunity many key questions remain unanswered (1). It has been suggested that genetic variability in the AIRE locus may play an additional role in more common organ-specific autoimmune diseases, such as Type 1 diabetes (T1D) and Hashimoto’s thyroiditis. It has been hypothesised that heterozygous loss-of-function mutations might favour development of certain organ-specific autoimmune disorders by causing inefficient presentation of self-antigens in the thymus and borderline tolerance. Predisposition to develop autoimmunity can also be enhanced by sequence polymorphisms in the coding sequence of AIRE. This heterozygous effect has been reported in mice and humans: a heterozygous AIRE’ variant (G228W) is thought to be responsible for a high prevalence of autoimmune thyroiditis in an Italian kindred (2). Interestingly, a novel G228W-knockin mouse model has been established showing that this variant acts in a dominant-negative manner to cause a unique autoimmune syndrome; this provides evidence that autoimmune predisposition to phenotypes distinct from APECED can be mediated in a dominant-negative fashion by AIRE (3). So far no significant association was found between genetic variation of AIRE and common disorders such as vitiligo and Addison’s disease (1). Recent experimental data regarding the pathogenesis of T1D suggest that the expression of T1D-associated autoantigens in AIRE-expressing cells is needed in order to maintain self-tolerance, in contrast to initial data obtained in epidemiological studies (1). It has also been suggested that graded thymic dysfunction plays a role in insulin deficiency by induction of insulin resistance and an increased number of proinsulin-specific autoreactive T cells in mice (4). Recently, deletion of insulin in the mouse thymus resulted in development of diabetes, which indicates the importance of self-antigen expression in AIRE-expressing cells (5). Variability in the function of the insulin gene (INS) promoter, conferred by the VNTR polymorphism, produces a failure to induce or to maintain self-tolerance to insulin because of reduced INS expression within the thymus and lymphoid tissues (6,7). Variability of expression due to polymorphisms is probably reinforced by the complex actions of AIRE in modulating autoantigen expression (1). In support of this hypothesis, deficiency of AIRE expression is also observed in severe immunodeficiencies characterised by abnormal T cell development, such as Omenn syndrome (8); as a consequence, the few residual T cell clones that develop may escape negative selection and therefore expand in the periphery, causing massive autoimmune reactions.Two recently published papers (9, 10) reported novel heterozygous AIRE mutations in patients affected by organ-specific autoimmune disorders. Cervato et al (9) described a novel heterozygous c.1411C>T mutation in exon 12, causing substitution of arginine at position 471 by cysteine (R471C). This mutation lies in one of the zinc fingers of the AIRE plant homeodomain (PHD), which is known to be involved in chromatin-mediated regulation of transcription (1). The mutation was described in a patient with chronic hypoparathyroidism, transient diabetes insipidus, chronic thyroiditis and evidence of circulating parietal cell antibodies (PCA) (9). The novel heterozygous IVS9+6G>A DNA change was described by Toth et al (10) in a patient with Sjőgren syndrome, autoimmune thyroiditis and psoriasis (5). These single heterozygous DNA changes were also detected in a few controls and therefore considered ‘not disease causing’. Nevertheless it has to be emphasised that, in the same paper, the compound herozygous state IVS9+6G>A /c.1411C>T was found in an additional patient with multi-organ autoimmune disease including adrenal failure and autoimmune thyroiditis (Type 2 polyendocrinopathy or Schmidt syndrome) (10). This fact also emphasises the importance of looking at AIRE DNA changes, mutations and polymorphisms that, when present as compound heterozygote changes, could be responsible for organ-specific autoimmune manifestations other than APECED. In this regard, we cannot exclude that some patients with single heterozygous AIRE changes may harbour a second AIRE mutation in the non-coding region, thus making their apparent phenotype in the ‘heterozygous’ state a false impression. Investigations based on biological systems are needed to verify the effect of mutated AIRE proteins compared to wild type proteins. Functional experimental evidence is required to prove whether missense dominant negative AIRE mutations, well-documented at the molecular level, can indeed generate an altered protein that interacts with the remaining wild-type gene product. Whenever intronic mutations (i.e. IVS9+6G>A9) are found, these need to be further evaluated for the possibility of producing a ‘splicing effect’. Cervato also reported one patient with chronic hypoparathyroidism, autoimmune thyroiditis and positive for immunological markers such as NALP5 and anti-IFN ω antibodies known to be additional diagnostic markers for APECED (10). This patient carried a novel AIRE mutation in the heterozygous state; the DNA change consisted this time of a substitution of an aspartic acid at position 312 with an asparagine in the AIRE gene region coding for the PHD (D312N in exon 8). The authors comment on the possible evolution of the clinical manifestations of this patient to APS1. Alternatively, this may reinforce the hypothesis of the contribution of heterozygous AIRE mutations to the pathogenesis of autoimmune conditions other than APECED. This could only be unravelled through extended epidemiological investigations in patients and controls, and may provide valuable insights as to whether the combination of genetic and immunological markers may contribute to the development of autoimmunity. REFERENCES1.Fierabracci, A. (2010) Recent insights into the role and molecular mechanims of the autoimmune regulator (AIRE) gene in autoimmunity. Autoimmunity Reviews, doi:10.1016/j.autrev.2010.98.019,2. Cetani, F., Barbesino, G., Corsari, S. et al. (2001) A novel mutation of the autoimmune regulator gene in an italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. Journal of Clinical Endocrinology and Metabolism, 86, 4747-4752.3. Su, M.A., Giang, K., Zủmer, K. et al. (2008) Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in AIRE. The Journal of Clinical Investigation, 118, 1712-1726.4. Chentoufi, A.A. & Polychronakos, C. (2002) Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes, 51, 1383-1390.5. Fan, Y., Rudert, W.A., Grupillo, M. et al. (2009) Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO Journal, 28, 2812-2824.6. Pugliese, A., Zeller, M., Fernandez, A. Jr. et al. (1997) The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for Type 1 diabetes. Nature Genetics, 15, 293-297.7. Vafiadis, P., Bennet, S.T., Todd, J.A. et al. (1997) Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genetics, 15, 289-292.8. Cavadini, P., Vermi, W., Facchetti, F. et al. (2005) AIRE deficiency in thymus of 2 patients with Omenn syndrome. The Journal of Clinical Investigation, 115, 728-732.9. Cervato, S., Morlin, L.; Albergoni, M.P., et al. (2010) AIRE gene mutations and autoantibodies to interferon omega in patients with chronic hypoparathyroidism without APECED. Clinical Endocrinology, 73, 630-636.10. Toth, B., Wolff, A.S.B., Halasz, Z. et al. (2010) Novel sequence variation of AIRE and delection of interferon-ω antibodies in early infancy. Clinical Endocrinology, 72, 641-647.
The role of heterozygous mutations of the autoimmune regulator gene (AIRE) in non-APECED autoimmunity: a comment on recent findings
Fierabracci A
2010-01-01
Abstract
Autoimmune diseases are a heterogeneous group of disorders. Epidemiological studies demonstrate that a complex interaction of genetic and environmental factors underlies their aetiopathogenesis. Autoimmune diseases that result from single gene mutations, although rare, provide a powerful means of studying the potential mechanisms responsible for the development of autoimmunity. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (OMIM 240300) or autoimmune polyendocrine syndrome Type 1 (APS1) is an autosomal recessive disease caused by mutations in the AIRE gene. This disorder has been a powerful model to address the question as to how a tolerant state is achieved or maintained, and to explore how tolerance is lost in the context of autoimmunity (reviewed in 1). AIRE has been proposed to function as a ‘non classical’ transcription factor, strongly implicated in the regulation of organ-specific antigen expression in thymic medullary epithelial cells (MECs), and the imposition of T cell tolerance. Nevertheless, given the complexity of AIRE function in autoimmunity many key questions remain unanswered (1). It has been suggested that genetic variability in the AIRE locus may play an additional role in more common organ-specific autoimmune diseases, such as Type 1 diabetes (T1D) and Hashimoto’s thyroiditis. It has been hypothesised that heterozygous loss-of-function mutations might favour development of certain organ-specific autoimmune disorders by causing inefficient presentation of self-antigens in the thymus and borderline tolerance. Predisposition to develop autoimmunity can also be enhanced by sequence polymorphisms in the coding sequence of AIRE. This heterozygous effect has been reported in mice and humans: a heterozygous AIRE’ variant (G228W) is thought to be responsible for a high prevalence of autoimmune thyroiditis in an Italian kindred (2). Interestingly, a novel G228W-knockin mouse model has been established showing that this variant acts in a dominant-negative manner to cause a unique autoimmune syndrome; this provides evidence that autoimmune predisposition to phenotypes distinct from APECED can be mediated in a dominant-negative fashion by AIRE (3). So far no significant association was found between genetic variation of AIRE and common disorders such as vitiligo and Addison’s disease (1). Recent experimental data regarding the pathogenesis of T1D suggest that the expression of T1D-associated autoantigens in AIRE-expressing cells is needed in order to maintain self-tolerance, in contrast to initial data obtained in epidemiological studies (1). It has also been suggested that graded thymic dysfunction plays a role in insulin deficiency by induction of insulin resistance and an increased number of proinsulin-specific autoreactive T cells in mice (4). Recently, deletion of insulin in the mouse thymus resulted in development of diabetes, which indicates the importance of self-antigen expression in AIRE-expressing cells (5). Variability in the function of the insulin gene (INS) promoter, conferred by the VNTR polymorphism, produces a failure to induce or to maintain self-tolerance to insulin because of reduced INS expression within the thymus and lymphoid tissues (6,7). Variability of expression due to polymorphisms is probably reinforced by the complex actions of AIRE in modulating autoantigen expression (1). In support of this hypothesis, deficiency of AIRE expression is also observed in severe immunodeficiencies characterised by abnormal T cell development, such as Omenn syndrome (8); as a consequence, the few residual T cell clones that develop may escape negative selection and therefore expand in the periphery, causing massive autoimmune reactions.Two recently published papers (9, 10) reported novel heterozygous AIRE mutations in patients affected by organ-specific autoimmune disorders. Cervato et al (9) described a novel heterozygous c.1411C>T mutation in exon 12, causing substitution of arginine at position 471 by cysteine (R471C). This mutation lies in one of the zinc fingers of the AIRE plant homeodomain (PHD), which is known to be involved in chromatin-mediated regulation of transcription (1). The mutation was described in a patient with chronic hypoparathyroidism, transient diabetes insipidus, chronic thyroiditis and evidence of circulating parietal cell antibodies (PCA) (9). The novel heterozygous IVS9+6G>A DNA change was described by Toth et al (10) in a patient with Sjőgren syndrome, autoimmune thyroiditis and psoriasis (5). These single heterozygous DNA changes were also detected in a few controls and therefore considered ‘not disease causing’. Nevertheless it has to be emphasised that, in the same paper, the compound herozygous state IVS9+6G>A /c.1411C>T was found in an additional patient with multi-organ autoimmune disease including adrenal failure and autoimmune thyroiditis (Type 2 polyendocrinopathy or Schmidt syndrome) (10). This fact also emphasises the importance of looking at AIRE DNA changes, mutations and polymorphisms that, when present as compound heterozygote changes, could be responsible for organ-specific autoimmune manifestations other than APECED. In this regard, we cannot exclude that some patients with single heterozygous AIRE changes may harbour a second AIRE mutation in the non-coding region, thus making their apparent phenotype in the ‘heterozygous’ state a false impression. Investigations based on biological systems are needed to verify the effect of mutated AIRE proteins compared to wild type proteins. Functional experimental evidence is required to prove whether missense dominant negative AIRE mutations, well-documented at the molecular level, can indeed generate an altered protein that interacts with the remaining wild-type gene product. Whenever intronic mutations (i.e. IVS9+6G>A9) are found, these need to be further evaluated for the possibility of producing a ‘splicing effect’. Cervato also reported one patient with chronic hypoparathyroidism, autoimmune thyroiditis and positive for immunological markers such as NALP5 and anti-IFN ω antibodies known to be additional diagnostic markers for APECED (10). This patient carried a novel AIRE mutation in the heterozygous state; the DNA change consisted this time of a substitution of an aspartic acid at position 312 with an asparagine in the AIRE gene region coding for the PHD (D312N in exon 8). The authors comment on the possible evolution of the clinical manifestations of this patient to APS1. Alternatively, this may reinforce the hypothesis of the contribution of heterozygous AIRE mutations to the pathogenesis of autoimmune conditions other than APECED. This could only be unravelled through extended epidemiological investigations in patients and controls, and may provide valuable insights as to whether the combination of genetic and immunological markers may contribute to the development of autoimmunity. REFERENCES1.Fierabracci, A. (2010) Recent insights into the role and molecular mechanims of the autoimmune regulator (AIRE) gene in autoimmunity. Autoimmunity Reviews, doi:10.1016/j.autrev.2010.98.019,2. Cetani, F., Barbesino, G., Corsari, S. et al. (2001) A novel mutation of the autoimmune regulator gene in an italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. Journal of Clinical Endocrinology and Metabolism, 86, 4747-4752.3. Su, M.A., Giang, K., Zủmer, K. et al. (2008) Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in AIRE. The Journal of Clinical Investigation, 118, 1712-1726.4. Chentoufi, A.A. & Polychronakos, C. (2002) Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes, 51, 1383-1390.5. Fan, Y., Rudert, W.A., Grupillo, M. et al. (2009) Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO Journal, 28, 2812-2824.6. Pugliese, A., Zeller, M., Fernandez, A. Jr. et al. (1997) The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for Type 1 diabetes. Nature Genetics, 15, 293-297.7. Vafiadis, P., Bennet, S.T., Todd, J.A. et al. (1997) Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genetics, 15, 289-292.8. Cavadini, P., Vermi, W., Facchetti, F. et al. (2005) AIRE deficiency in thymus of 2 patients with Omenn syndrome. The Journal of Clinical Investigation, 115, 728-732.9. Cervato, S., Morlin, L.; Albergoni, M.P., et al. (2010) AIRE gene mutations and autoantibodies to interferon omega in patients with chronic hypoparathyroidism without APECED. Clinical Endocrinology, 73, 630-636.10. Toth, B., Wolff, A.S.B., Halasz, Z. et al. (2010) Novel sequence variation of AIRE and delection of interferon-ω antibodies in early infancy. Clinical Endocrinology, 72, 641-647.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
