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Aire deficient mice develop hematopoetic irregularities and marginal zone B cell lymphoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. (Autoimmuna sjukdomar (Kämpe))
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2006 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 108, no 6, 1941-1948 p.Article in journal (Refereed) Published
Abstract [en]

Autoimmune polyendocrine syndrome type I (APS I) is an inherited recessive disorder with a progressive immunological destruction of many tissues including the adrenal cortex, the parathyroid glands, and the gonads. APS I is caused by mutations in the AIRE gene (autoimmune regulator), expressed in cells of the thymus and spleen, suggesting a role in central and peripheral tolerance. Aire(-/-) mice replicate the autoimmune features of APS I patients with the presence of multiple autoantibodies and lymphocytic infiltrates in various tissues, but young mice appear clinically healthy. We here report the investigation of 15- to 24-month-old Aire(-/-) mice. We did not observe any endocrinological abnormalities, nor did sera from these mice recognize known APS I autoantigens. Interestingly, however, there was a high frequency of marginal zone B-cell lymphoma in Aire(-/-) mice and liver infiltrates of B cells, suggesting chronic antigen exposure and exaggerated activation. Furthermore, increased numbers of monocytes in blood were identified as well as augmented numbers of metallophilic macrophages in the spleen. We propose that Aire, in addition to its function in the thymus, also has a peripheral regulatory role by controlling the development of antigen-presenting cells (APCs) and marginal zone B-cell activation.

Place, publisher, year, edition, pages
2006. Vol. 108, no 6, 1941-1948 p.
National Category
Hematology
Identifiers
URN: urn:nbn:se:uu:diva-95063DOI: 10.1182/blood-2006-04-019679ISI: 000240394800031PubMedID: 16709926OAI: oai:DiVA.org:uu-95063DiVA: diva2:169129
Available from: 2006-11-10 Created: 2006-11-10 Last updated: 2011-06-17Bibliographically approved
In thesis
1. Autoimmune Regulator Deficient Mice, an Animal Model of Autoimmune Polyendocrine Syndrome Type I
Open this publication in new window or tab >>Autoimmune Regulator Deficient Mice, an Animal Model of Autoimmune Polyendocrine Syndrome Type I
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [sv]

Autoimmune diseases develop when the immune system fails to distinguish self from non-self or when the immune system is hypersensitive to endogenous or exogenous danger signals, or when a tissue erroneously sends a danger signal to the immune system. The education of the immune system to distinguish self from non-self is mainly carried out in the thymus and gives rise to central tolerance, whereas the ability to sense a danger or a healthy tissue constitutes peripheral tolerance. In these studies we have investigated the peripheral tolerance mechanisms controlled by the autoimmune regulator (Aire) gene in Aire deficient mice, an animal model of the monogenic disease autoimmune polyendocrine syndrome type I (APS I).

Aire-/- mice displayed increased numbers of myeloid-derived antigen-presenting cells (APCs) in the spleen, lymph nodes and peritoneum as well as more blood monocytes and metallophilic macrophages in the spleen. Monocytes were also increased in the blood of APS I patients. Monocyte precursors displayed an accelerated development in the bone marrow of Aire-/- mice, and Aire-/- APCs had an altered phenotype that caused an increased immune response in several different contexts. Aire-/- splenic and lymph node dendritic cells had an increased ability to activate naive T cells, partly as a result of an upregulated expression of the costimulatory molecule VCAM-1. In Aire-/- mice increased activity of the metallophilic macrophages in the splenic marginal zone seems to be responsible both for the activated phenotype of marginal zone B cells and for the frequent development of marginal zone lymphoma with aging. In a TCR transgenic model Aire deficiency caused an increased superantigen-mediated TCR revision in the spleen, perhaps as a result of the altered phenotype of APCs in the spleen. Finally, Aire was shown to influence autoimmune disease development by a macrophage-dependent mechanism in diabetes induced with multiple low dose streptozotocin injections.

These results indicate that Aire has an important function in peripheral tolerance by controlling the phenotype of myeloid-derived APCs and thereby regulating the activation of T and B lymphocytes.

Abstract [en]

Autoimmune diseases develop when the immune system fails to distinguish self from non-self or when the immune system is hypersensitive to endogenous or exogenous danger signals, or when a tissue erroneously sends a danger signal to the immune system. The education of the immune system to distinguish self from non-self is mainly carried out in the thymus and gives rise to central tolerance, whereas the ability to sense a danger or a healthy tissue constitutes peripheral tolerance. In these studies we have investigated the peripheral tolerance mechanisms controlled by the autoimmune regulator (Aire) gene in Aire deficient mice, an animal model of the monogenic disease autoimmune polyendocrine syndrome type I (APS I).

Aire-/- mice displayed increased numbers of myeloid-derived antigen-presenting cells (APCs) in the spleen, lymph nodes and peritoneum as well as more blood monocytes and metallophilic macrophages in the spleen. Monocytes were also increased in the blood of APS I patients. Monocyte precursors displayed an accelerated development in the bone marrow of Aire-/- mice, and Aire-/- APCs had an altered phenotype that caused an increased immune response in several different contexts. Aire-/- splenic and lymph node dendritic cells had an increased ability to activate naive T cells, partly as a result of an upregulated expression of the costimulatory molecule VCAM-1. In Aire-/- mice increased activity of the metallophilic macrophages in the splenic marginal zone seems to be responsible both for the activated phenotype of marginal zone B cells and for the frequent development of marginal zone lymphoma with aging. In a TCR transgenic model Aire deficiency caused an increased superantigen-mediated TCR revision in the spleen, perhaps as a result of the altered phenotype of APCs in the spleen. Finally, Aire was shown to influence autoimmune disease development by a macrophage-dependent mechanism in diabetes induced with multiple low dose streptozotocin injections.

These results indicate that Aire has an important function in peripheral tolerance by controlling the phenotype of myeloid-derived APCs and thereby regulating the activation of T and B lymphocytes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 193
Keyword
Molecular medicine, autoimmune regulator, autoimmune polyendocrine syndrome type I, peripheral tolerance, antigen presenting cells, autoimmunity, danger signal, knockout mice, Molekylärmedicin
Identifiers
urn:nbn:se:uu:diva-7218 (URN)91-554-6701-6 (ISBN)
Public defence
2006-12-01, Enghoffsalen, Akademiska sjukhuset Ing. 50, Uppsala, 09:15
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Supervisors
Available from: 2006-11-10 Created: 2006-11-10Bibliographically approved

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Hässler, SigneLarsson, DisaHerrmann, BjörnPeltonen, LeenaKämpe, OlleWinqvist, Ola

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