Interferons in antiviral defense and autoimmunity : focus on type 1 diabetes
Author: Hultcrantz, Monica
Date: 2008-01-25
Location: Föreläsningssalen 4V, Alfred Nobels allé 8, Karolinska Universitetssjukhuset, Huddinge
Time: 09.30
Department: Institutionen för medicin, Huddinge Sjukhus / Department of Medicine at Huddinge University Hospital
View/ Open:
thesis.pdf (1.213Mb)
Abstract
Type 1 diabetes (T1D) is a disease characterized by the loss of insulin
producing beta-cells in the pancreatic islets of Langerhans. Interferons
(IFNs), produced by immune cells and infected parenchymal cells, may be
protective or damaging in the pathogenesis of T1D. An intact beta-cell
response to IFNs is critical for beta-cell survival and protection from
diabetes during a Coxsackievirus B (CVB) infection, a virus associated
with T1D in humans. It has also been suggested that IFNs may protect from
natural killer (NK) cell dependent destruction. Importantly, while being
protective during infection with CVB, the pancreatic beta-cell response
to cytokines is crucial for the development of type 1 diabetes (T1D) in
the non-obese diabetic (NOD) mouse. NOD mice overexpressing the
Suppressor of Cytokine Signaling 1 (SOCS-1) specifically in the
beta-cells are protected from spontaneous diabetes. The work in this
thesis focuses on the mechanisms behind the protective and damaging
effects of IFNs in the pathogenesis of T1D. Moreover, it identifies a
possible source of IFNgamma during CVB infection.
This thesis shows that IFNs trigger an antiviral state in mouse and human islets. Both the RNase L and the dsRNA-dependent protein kinase (PKR) pathways are induced by IFNs in mouse islets and play important roles in providing unique and complementary antiviral activities that regulate the outcome of CVB infection. Moreover, this thesis shows that human islet cells also respond to IFNs by expressing signature genes of antiviral defense. It further demonstrates that human islets express three intracellular sensors for viral RNA, the toll like receptor 3 (TLR3) gene, the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene-5 (MDA-5), which contribute to the production of type I IFN in infected cells. These observations suggest that human islet cells have the possibility to detect an invading virus and to produce type I IFNs during an infection. The work presented in this thesis identifies the NK cell as a possible contributor of IFNgamma during CVB infection: it shows that CVB interferes with the expression of NK cell receptor ligands on infected cells and that IFNgamma production, rather than cytotoxicity, marks the early human NK cell response to CVB infection. Finally, this thesis gives new insights into how IFNs, by acting directly on beta-cells, contribute to disease development in the NOD mouse. It demonstrates that the beta-cell, by responding to thepro-inflammatory pancreas milieu, strongly influences the percentage of self-reactive CD8 T-cells in the pancreas.
In conclusion, this thesis supports the notion that cytokine-exposed islet cells affect islet infection and inflammation, highlighting an important role for the beta-cell in the local regulation of the diabetogenic process. By providing a basic understanding for how beta-cells respond to IFNs, and how this relates to their defense against CVB and to the accumulation of pathogenic cells in the pancreas, it may contribute to a future unraveling of the mechanisms underlying beta-cell loss in T1D.
This thesis shows that IFNs trigger an antiviral state in mouse and human islets. Both the RNase L and the dsRNA-dependent protein kinase (PKR) pathways are induced by IFNs in mouse islets and play important roles in providing unique and complementary antiviral activities that regulate the outcome of CVB infection. Moreover, this thesis shows that human islet cells also respond to IFNs by expressing signature genes of antiviral defense. It further demonstrates that human islets express three intracellular sensors for viral RNA, the toll like receptor 3 (TLR3) gene, the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene-5 (MDA-5), which contribute to the production of type I IFN in infected cells. These observations suggest that human islet cells have the possibility to detect an invading virus and to produce type I IFNs during an infection. The work presented in this thesis identifies the NK cell as a possible contributor of IFNgamma during CVB infection: it shows that CVB interferes with the expression of NK cell receptor ligands on infected cells and that IFNgamma production, rather than cytotoxicity, marks the early human NK cell response to CVB infection. Finally, this thesis gives new insights into how IFNs, by acting directly on beta-cells, contribute to disease development in the NOD mouse. It demonstrates that the beta-cell, by responding to thepro-inflammatory pancreas milieu, strongly influences the percentage of self-reactive CD8 T-cells in the pancreas.
In conclusion, this thesis supports the notion that cytokine-exposed islet cells affect islet infection and inflammation, highlighting an important role for the beta-cell in the local regulation of the diabetogenic process. By providing a basic understanding for how beta-cells respond to IFNs, and how this relates to their defense against CVB and to the accumulation of pathogenic cells in the pancreas, it may contribute to a future unraveling of the mechanisms underlying beta-cell loss in T1D.
List of papers:
I. Flodström-Tullberg M, Hultcrantz M, Stotland A, Maday A, Tsai D, Fine C, Williams B, Silverman R, Sarvetnick N (2005). "RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection." J Immunol 174(3): 1171-7.
Pubmed
View record in Web of Science®
II. Hultcrantz M, Hühn MH, Wolf M, Olsson A, Jacobson S, Williams BR, Korsgren O, Flodström-Tullberg M (2007). "Interferons induce an antiviral state in human pancreatic islet cells." Virology 367(1): 92-101.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Hühn M.H, Hultcrantz M, Lind K, Ljunggren H.G, Malmberg K.J, Flodström-Tullberg M (2007). "IFN-gamma production dominates the early human natural killer cell response to coxsackievirus Infection." Cellular Microbiology. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Hultcrantz M, Jacobson S, Santamaria P, Flodström-Tullberg M (2007). "The target cell response to cytokines governs the autoreactive T-cell repertoire in the pancreas." [Manuscript]
I. Flodström-Tullberg M, Hultcrantz M, Stotland A, Maday A, Tsai D, Fine C, Williams B, Silverman R, Sarvetnick N (2005). "RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection." J Immunol 174(3): 1171-7.
Pubmed
View record in Web of Science®
II. Hultcrantz M, Hühn MH, Wolf M, Olsson A, Jacobson S, Williams BR, Korsgren O, Flodström-Tullberg M (2007). "Interferons induce an antiviral state in human pancreatic islet cells." Virology 367(1): 92-101.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Hühn M.H, Hultcrantz M, Lind K, Ljunggren H.G, Malmberg K.J, Flodström-Tullberg M (2007). "IFN-gamma production dominates the early human natural killer cell response to coxsackievirus Infection." Cellular Microbiology. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Hultcrantz M, Jacobson S, Santamaria P, Flodström-Tullberg M (2007). "The target cell response to cytokines governs the autoreactive T-cell repertoire in the pancreas." [Manuscript]
Issue date: 2008-01-04
Rights:
Publication year: 2008
ISBN: 978-91-7357-456-3
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