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Model diseases for studies of autoimmunity.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Olle Kämpe)
2015 (Swedish)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The events triggering autoimmune diseases are to large extent unknown and model diseases are an important tool in studies aiming to elucidate molecular mechanisms in autoimmunity. Autoimmune Addison’s disease (AAD) is a rare disease characterized by autoimmune destruction of adrenal glands and most patients with AAD have autoantibodies against the enzyme 21‑hydroxylase in the adrenal cortex. The autoimmune destruction in AAD is however suspected to be initiated by T cells. One of the most important investigations in this thesis was to characterize the T cell response in AAD. It could be concluded the T cells in AAD patients respond to three immunodominant epitopes on the 21-hydroxylase.

In addition, this thesis aims to gain updated data on comorbidities, replacement therapy, autoantibody profiles, and metabolic factors in AAD. A cohort of 660 AAD patients was studied and it was found that AAD patients are prone to develop other autoimmune conditions. AAD is one of three main disease components Autoimmune Polyendocrine Syndrome type 1 (APS-1), a rare disorder caused by mutations in the AutoImmune REgulator gene (AIRE) that can be potentially fatal without timely diagnosis. Screening for autoantibodies against interferon-ω, interferon-α4, and interleukin-22 revealed four new APS-1 patients among the AAD cohort, confirmed by the presence of disease causing mutations in the AIRE gene.

Cancer Associated Retinopathy (CAR) is a paraneoplastic phenomenon arising as a consequence to an autoimmune response triggered by a malignant neoplasm present in the body. This disease is devastating and it is valuable to identify new biomarkers associated with CAR, not least from a tumor diagnostic perspective. In this thesis, a patient with osteosarcoma and CAR was studied and by screening of a proteom array, and the novel CAR autoantigen Aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) was identified.

In conclusion, this thesis covers studies on T cell and B cell responses in AAD. Moreover, it includes an update on clinical and immunological characterisation of AAD patients. Finally, a novel autoantigen in CAR was identified and proposed as a diagnostic marker for the paraneoplastic syndrome.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 44 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1154
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-265276ISBN: 978-91-554-9392-9 (print)OAI: oai:DiVA.org:uu-265276DiVA: diva2:864347
Public defence
2015-12-16, Aula Gunnesalen, Akademiska sjukhuset ingång 10, 751 85, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2015-11-23 Created: 2015-10-26 Last updated: 2016-01-13
List of papers
1. High Frequency of Cytolytic 21-Hydroxylase-Specific CD8(+) T Cells in Autoimmune Addison's Disease Patients
Open this publication in new window or tab >>High Frequency of Cytolytic 21-Hydroxylase-Specific CD8(+) T Cells in Autoimmune Addison's Disease Patients
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2014 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 5, 2118-2126 p.Article in journal (Refereed) Published
Abstract [en]

The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs <= 20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-232996 (URN)10.4049/jimmunol.1400056 (DOI)000341140600014 ()
Available from: 2014-10-13 Created: 2014-09-29 Last updated: 2017-12-05Bibliographically approved
2. Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 (AIPL1) - a Novel Retina-specific Autoantigen in Cancer-Associated Retinopathy
Open this publication in new window or tab >>Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 (AIPL1) - a Novel Retina-specific Autoantigen in Cancer-Associated Retinopathy
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-265263 (URN)
Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13
3. Clinical and immunological characteristics of Autoimmune Addison’s disease in Sweden: a nationwide multicenter analysis of 660 patients
Open this publication in new window or tab >>Clinical and immunological characteristics of Autoimmune Addison’s disease in Sweden: a nationwide multicenter analysis of 660 patients
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-265271 (URN)
Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13Bibliographically approved
4. Identification and characterization of APS-1 patients by autoantibody screening of the Swedish Addison Registry.
Open this publication in new window or tab >>Identification and characterization of APS-1 patients by autoantibody screening of the Swedish Addison Registry.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

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National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-265261 (URN)
Available from: 2015-10-26 Created: 2015-10-26 Last updated: 2016-01-13

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