Expression of Aire and the Early Wave of Apoptosis in Spermatogenesis

Department of Microbiology and Immunology, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2008; 180(3):1338-43. DOI: 10.4049/jimmunol.180.3.1338
Source: PubMed


Expression of the autoimmune regulator (Aire) protein in mice and humans is thought to be restricted to the medullary epithelial and monocyte-dendritic cells of the thymus. There it mediates expression and presentation of a large variety of proteins, including those that are peripheral organ-specific and are not expressed by other thymocytes. In this way, self-reactive T lymphocytes that would attack peripheral cells producing these proteins are confronted with the self-Ags and, as a consequence, are deleted. In this study, we show that Aire mRNA is also expressed in the testis--another tissue with promiscuous gene expression. Aire protein, however, is expressed only sporadically in spermatogonia and spermatocytes. Transcription of genes that are under Aire control in the thymus is unaffected by Aire in the testis. However, in mice with a disrupted Aire gene, the scheduled apoptotic wave of germ cells, which is necessary for normal mature spermatogenesis, is reduced, and sporadic apoptosis in adults is increased. Because Rag-1 deficiency does not abolish the effect, the adaptive immune system is not involved. We suggest that there is a link between the scheduled and sporadic apoptotic processes and propose that scheduled apoptosis provides a counterselection mechanism that keeps the germline stable.

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    • "In another study, RT-PCR and IHC were used to demonstrate Aire transcription and translation in spermatogonia and early spermatocytes, where Aire would play a role in the program of early, scheduled apoptosis indispensable to the maintenance of germline stability [43]. "
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    ABSTRACT: The autoimmune polyendocrine syndrome type 1 (APS-1) is a monogenic disease due to pathogenic variants occurring in the autoimmune regulator (AIRE) gene. Its related protein, AIRE, activates the transcription of genes encoding for tissue-specific antigens (TsAgs) in a subset of medullary thymic epithelial cells: the presentation of TsAgs to the maturating thymocytes induces the apoptosis of the autoreactive clones and constitutes the main form of central tolerance. Dysregulation of thymic AIRE expression in genetically transmitted and acquired diseases other than APS-1 may contribute to further forms of autoimmunity. As AIRE and its murine homolog are also expressed in the secondary lymphoid organs, the extent and relevance of AIRE participation in the mechanisms of peripheral tolerance need to be thoroughly defined.
    Full-text · Article · Oct 2012 · Clinical and Developmental Immunology
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    • "Destruction of the spleen in APECED has been related to an autoimmune attack against the spleen (Perheentupa, 2002, 2006; Betterle and Zanchetta, 2003; Husebye et al., 2009) although the exact mechanism remains obscure. Again, the mechanisms proposed by Schaller et al. (2008) and by Matsumoto (2011) are of interest, as AIRE expression has also been described in lymphoid tissue and skin. A speculative hypothesis to the evolution of splenic atrophy could thus be disturbance of differentiation, due to lack of AIRE expression. "
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    ABSTRACT: In APECED, the key abnormality is in the T cell defect that may lead to tissue destruction chiefly in endocrine organs. Besides, APECED is characterized by high-titer antibodies against a wide variety of cytokines that could partly be responsible for the clinical symptoms during APECED, mainly chronic mucocutaneous candidiasis, and linked to antibodies against Th17 cells effector molecules, IL-17 and IL-22. On the other hand, the same antibodies, together with antibodies against type I interferons may prevent the patients from other immunological diseases, such as psoriasis and systemic lupus erythematous. The same effector Th17 cells, present in the lymphocytic infiltrate of target organs of APECED, could be responsible for the tissue destruction. Here again, the antibodies against the corresponding effector molecules, anti-IL-17 and anti-IL-22 could be protective. The occurrence of several effector mechanisms (CD4(+) Th17 cell and CD8(+) CTL and the effector cytokines IL-17 and IL-22), and simultaneous existence of regulatory mechanisms (CD4(+) Treg and antibodies neutralizing the effect of the effector cytokines) may explain the polymorphism of APECED. Almost all the patients develop the characteristic manifestations of the complex, but temporal course and severity of the symptoms vary considerably, even among siblings. The autoantibody profile does not correlate with the clinical picture. One could speculate that a secondary homeostatic balance between the harmful effector mechanisms, and the favorable regulatory mechanisms, finally define both the extent and severity of the clinical condition in the AIRE defective individuals. The proposed hypothesis that in APECED, in addition to strong tissue destructive mechanisms, a controlling regulatory mechanism does exist, allow us to conclude that APECED could be treated, and even cured, with immunological manipulation.
    Full-text · Article · Aug 2012 · Frontiers in Immunology
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    • "The localization of AIRE protein was predominantly nuclear in immature testis, though the functional relevance of this observation is currently unclear. In adult testis sections, we could locate AIRE protein on spermatogonia and primary spermatocytes, which is consistent with the findings of Schaller et al. (2008), whereas AIRE protein on secondary spermatocytes and spermatozoa in various stages of development is novel. Confocal laser microscopy also revealed heavy localization of AIRE in the principal acrosomal segment (indicated with arrows in Fig. 5), which lost the pattern after the acrosome reaction. "
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    ABSTRACT: The autoimmune regulator gene Aire shows predominant expression in thymus and other immunologically relevant tissues, and is assigned the major function of programming autoreactive T-cell deletion. However, the expression of this gene in tissues outside the immune system raises a question about its possible function beyond the T-cell deletion dogma. We detected Aire in mouse testis, and the expression of AIRE protein was remarkably high in postmeiotic germ cells. Sequencing results indicate that testis expressed Aire variant 1a. AIRE could be detected in spermatozoa, with heavy localization on the principal acrosomal domains. Mouse oocytes stained negatively for AIRE before fertilization, but stained positively for AIRE 30 min after fertilization. In the zygote, the levels of AIRE correlated negatively with cyclin B2 levels. Goat testicular lysates spiked with recombinant human AIRE exhibited augmented cyclin B2 degradation in the presence of protease inhibitors, which was inhibited by MG-132, indicating the operation of proteasomal pathways. Thus, this study identifies a correlation between the presence of AIRE and proteasomal breakdown of cyclin B2, which leads us to speculate that cyclin B2 could be a target of AIRE's E3-ubiquitin ligase activity.
    Full-text · Article · Aug 2011 · Biochemistry and Cell Biology
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