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      Pernicious Anemia in an Adult with Trisomy 21


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          Pernicious anemia is an autoimmune disease caused by the malabsorption of vitamin B12. It usually appears in the elderly. People with trisomy 21 are susceptible to autoimmune diseases. This susceptibility is thought to be due to altered expression of the AIRE gene, which is located in the 21q22.3 region. Although pernicious anemia is not common in people with trisomy 21, AIRE is pointed out as a susceptibility gene of pernicious anemia in a genome-wide association study. Here, we report a man with trisomy 21, who suffered from the pernicious anemia. When he was in his 30 s, he visited our hospital because of diarrhea and poor oral intake. He showed thrombocytopenic purpura-like features, and was diagnosed as pernicious anemia. After supplementation of vitamin B12, he recovered from the illness. The reason for his early onset may be because of trisomy 21. Altered expression of AIRE might trigger the disease.

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          AIRE-mutations and autoimmune disease.

          The gene causing the severe organ-specific autoimmune disease autoimmune polyendocrine syndrome type-1 (APS-1) was identified in 1997 and named autoimmune regulator (AIRE). AIRE plays a key role in shaping central immunological tolerance by facilitating negative selection of T cells in the thymus, building the thymic microarchitecture, and inducing a specific subset of regulatory T cells. So far, about 100 mutations have been identified. Recent advances suggest that certain mutations located in the SAND and PHD1 domains exert a dominant negative effect on wild type AIRE resulting in milder seemingly common forms of autoimmune diseases, including pernicious anemia, vitiligo and autoimmune thyroid disease. These findings indicate that AIRE also contribute to autoimmunity in more common organ-specific autoimmune disorders.
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            Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens.

            Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals. Copyright © 2014 by The American Association of Immunologists, Inc.
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              Decreased AIRE expression and global thymic hypofunction in Down syndrome.

              The Down syndrome (DS) immune phenotype is characterized by thymus hypotrophy, higher propensity to organ-specific autoimmune disorders, and higher susceptibility to infections, among other features. Considering that AIRE (autoimmune regulator) is located on 21q22.3, we analyzed protein and gene expression in surgically removed thymuses from 14 DS patients with congenital heart defects, who were compared with 42 age-matched controls with heart anomaly as an isolated malformation. Immunohistochemistry revealed 70.48 ± 49.59 AIRE-positive cells/mm(2) in DS versus 154.70 ± 61.16 AIRE-positive cells/mm(2) in controls (p < 0.0001), and quantitative PCR as well as DNA microarray data confirmed those results. The number of FOXP3-positive cells/mm(2) was equivalent in both groups. Thymus transcriptome analysis showed 407 genes significantly hypoexpressed in DS, most of which were related, according to network transcriptional analysis (FunNet), to cell division and to immunity. Immune response-related genes included those involved in 1) Ag processing and presentation (HLA-DQB1, HLA-DRB3, CD1A, CD1B, CD1C, ERAP) and 2) thymic T cell differentiation (IL2RG, RAG2, CD3D, CD3E, PRDX2, CDK6) and selection (SH2D1A, CD74). It is noteworthy that relevant AIRE-partner genes, such as TOP2A, LAMNB1, and NUP93, were found hypoexpressed in DNA microarrays and quantitative real-time PCR analyses. These findings on global thymic hypofunction in DS revealed molecular mechanisms underlying DS immune phenotype and strongly suggest that DS immune abnormalities are present since early development, rather than being a consequence of precocious aging, as widely hypothesized. Thus, DS should be considered as a non-monogenic primary immunodeficiency.

                Author and article information

                Case Reports Immunol
                Case Reports Immunol
                Case Reports in Immunology
                26 August 2023
                : 2023
                : 2747756
                1Department of Pediatrics, Obihiro Kosei Hospital, Nishi 6-jo Minami 8-1, Obihiro, Hokkaido 080-0016, Japan
                2Okurayama-gakuin, 20-2 Miharashi-cho, Otaru, Hokkaido 047-0263, Japan
                3Department of Hematology, Obihiro Kosei Hospital, Nishi 6-jo Minami 8-1, Obihiro, Hokkaido 080-0016, Japan
                Author notes

                Academic Editor: Ahmad Mansour

                Author information
                Copyright © 2023 Kentaro Kamada et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 27 June 2023
                : 9 July 2023
                : 17 August 2023
                Case Report


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