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Nyström, Sofia N.
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Publications (8 of 8) Show all publications
Crisci, E., Ellegård, R., Nyström, S., Rondahl, E., Serrander, L., Bergström, T., . . . Larsson, M. (2016). Complement opsonization promotes HSV-2 infection of human dendritic cells. Journal of Virology, 90(10), 4939-4950
Open this publication in new window or tab >>Complement opsonization promotes HSV-2 infection of human dendritic cells
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2016 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 90, no 10, p. 4939-4950Article in journal (Refereed) Published
Abstract [en]

Herpes virus type 2 (HSV2) is one of the most common sexually transmitted infections globally with a very high prevalence in many countries. During HSV2 infection viral particles become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. In genital mucosa, the primary target cells for HSV2 infection are epithelial cells, but resident immune cells such as dendritic cells (DCs) are also infected. The DCs are the activators of the ensuing immune responses directed against HSV2, and the aim of this study was to examine the effects opsonization of HSV2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV1 or HSV2 specific antibodies more or less abolished the HSV2 infection of DCs.Our results clearly demonstrate the importance of studying HSV2 infection under conditions that ensue in vivo, i.e. when the virions are covered in complement fragments and complement fragments and antibodies, as this will shape the infection and the subsequent immune response and needs to be further elucidated.

IMPORTANCE: During HSV2 infection viral particles should become coated with complement proteins and antibodies, both existent in the genital fluids, which could influence the activation of the immune responses. The dendritic cells are the activators of the immune responses directed against HSV2, and the aim of this study was to examine the effects of complement alone or complement and antibodies, on the HSV2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses.Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV2 pathogenesis.

Place, publisher, year, edition, pages
American society of microbiology, 2016
Keywords
HSV2 infection, dendritic cells, complement, antibodies
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-126480 (URN)10.1128/JVI.00224-16 (DOI)000375126100009 ()26937039 (PubMedID)
Note

Funding agencies: Swedish Research Council [AI52731]; Swedish Physicians Against AIDS Research Foundation; Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; Swedish Society of Medicine; Swedis

Available from: 2016-03-29 Created: 2016-03-29 Last updated: 2018-03-23
Ellegård, R., Crisci, E., Andersson, J., Shankar, E. M., Nyström, S., Hinkula, J. & Larsson, M. (2015). Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1. Journal of Immunology, 195(4), 1698-1704
Open this publication in new window or tab >>Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-1
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2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 4, p. 1698-1704Article in journal (Refereed) Published
Abstract [en]

Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFN gamma and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection.

Place, publisher, year, edition, pages
American Association of Immunologists, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121313 (URN)10.4049/jimmunol.1500618 (DOI)000360013200039 ()26157174 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation [AI52731]; Swedish International Development Cooperation Agency/Swedish Agency for Research Cooperation with Developing Countries-Special Assistant; VINNMER for Vinnova; Linkoping University Hospital Research Fund; central regional agreement on medical training and clinical research (CALF) between Ostergotland County Council and Linkoping University; Swedish Society of Medicine; High Impact Research; University of Malaya [UM.C.625/1/HIR/139]

Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2018-09-28
Eriksson, P., Andersson, C., Cassel, P., Nyström, S. & Ernerudh, J. (2015). Letter: Increase in Th17-associated CCL20 and decrease in Th2-associated CCL22 plasma chemokines in active ANCA-associated vasculitis [Letter to the editor]. Scandinavian Journal of Rheumatology, 44(1), 80-83
Open this publication in new window or tab >>Letter: Increase in Th17-associated CCL20 and decrease in Th2-associated CCL22 plasma chemokines in active ANCA-associated vasculitis
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2015 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 1, p. 80-83Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Informa Healthcare, 2015
National Category
Clinical Medicine Immunology in the medical area Other Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-114016 (URN)10.3109/03009742.2014.952332 (DOI)000347408000013 ()25352172 (PubMedID)
Available from: 2015-02-06 Created: 2015-02-05 Last updated: 2018-01-11
Nyström, S. N. & Westermark, G. T. (2012). AA-Amyloid is cleared by endogenous immunological mechanisms. Amyloid: Journal of Protein Folding Disorders, 19(3), 138-145
Open this publication in new window or tab >>AA-Amyloid is cleared by endogenous immunological mechanisms
2012 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 19, no 3, p. 138-145Article in journal (Refereed) Published
Abstract [en]

Reactive amyloidosis is a complication to longstanding inflammatory diseases.Protein amyloid A (AA), an N-terminal fragment of the acute phase protein serumamyloid A, undergoes conformational changes and is deposited as amyloid in tissue.AA-amyloidosis is reversible and reduction of amyloid mass has been reported as theinflammation ceases. Not much is known about the endogenous factors thatcontribute to amyloid resolution. Herein, we describe the dynamics of amyloiddegradation in experimental murine AA-amyloidosis and show that amyloiddegradation depends on macrophages and antibody formation. AA-amyloidosis wasinduced in mice and resolution of amyloid was monitored over time by histologicaltechniques. Internalized amyloid was present in macrophages that appeared at siteof deposition. At 9 months, when virtually all amyloid was cleared, amyloidosis wasre-induced in one group of animals by a single silver nitrate injection. This causedeposition of excessive amounts of amyloid, and indicate that even thoughundetectable the amyloid reseed in the body and can there act as amyloid enhancingfactor. Antibodies directed against protein AA were detected in animals duringamyloid clearance by ELISA-technique. Passive immunization with an amyloidspecific monoclonal antibody, produced by a B-cell clone recovered from an animalwith advanced AA-amyloidosis, diminish amyloid deposits in murine AA-amyloidosis.Immunoglobulins co-localize with amyloid deposits and can contribute to amyloiddegradation by Fc-receptor mediated phagocytosis.

Keywords
Amyloid A (AA), Amyloid β(Aβ), Amyloid light chain (AL), Alzheimer’s disease (AD), amyloid enhancing factor (AEF), serum amyloid A (SAA), tumour necrosis factor (TNF)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20807 (URN)10.3109/13506129.2012.711391 (DOI)000307635600004 ()
Note

funding agencies|Swedish Research Council|2010-55x-20326-04-3|Swedish Rheumatology Association||

Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2017-12-13Bibliographically approved
Nyström, S. N. (2009). Deposition and Resolution of AA Amyloid. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Deposition and Resolution of AA Amyloid
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloidosis is a group of protein misfolding diseases characterized by extracellulardeposition of fibrillar protein aggregates. Today more than 25 different human amyloidogenicproteins have been identified, causing a variety of pathological conditions that includeAlzheimer’s disease, type 2 diabetes and prion diseases. Amyloid A (AA) amyloidosis is acomplication to long standing inflammatory disorders and amyloid is formed from N-terminalfragments of the acute phase protein serum amyloid A. AA amyloidosis developsspontaneously in many mice strains in response to inflammatory stimulation. Amyloidformation is nucleation dependent and develops after a lag phase of months. If an extract fromamyloid loaded tissue is administered to the animal, the lag phase is shortened to days. Thetissue extract is referred to as amyloid enhancing factor, AEF.

In paper I we demonstrate that the active component of AEF is the amyloid fibril itself. We doalso show that AEF retains its activity over a long period of time and is active in very low(femtomolar) doses. AEF activity can be transmitted in a serial manner, also by oraladministration. Thus, AEF shares several characteristics with the infectious prion protein. Wetherefore suggest that AEF induces protein conformational changes in a prion like manner andthat experimental AA amyloidosis is a transmissible disease.

In paper II we showed that peripheral blood monocytes recovered from mice with AAamyloidosis carry AEF activity but plasma does not. AA amyloid was detected in occasionalmonocytes. It is possible that these fibrils serve as seeds or nuclei for conformational changesand subsequent amyloid deposition in the recipient animal.

In paper III mechanisms of amyloid clearance in experimental AA amyloidosis were studied.During amyloid clearance antibodies directed against AA were detected. Immunoglobulinsdid also co-localize with AA deposits. Amyloid fibrils were detected intracellular inmacrophages. These findings suggest that immune mechanisms contribute to AA amyloidclearance in mice and that macrophages are key players in the process. Immunoglobulins mayserve as opsonins facilitating phagocytosis of amyloid.

It is believed that the early stages of amyloidogenesis are common in all forms of amyloiddiseases and that the amyloid formation process is cytotoxic. There are few studies onbiological effects of AA deposition in post mitotic tissue such as the heart. In paper IV weinvestigate the effects of cardiac AA amyloid deposition. Our results indicate that cardiac AAdeposition is associated with increased autophagic activity.

In conclusion this thesis provides new insights to the dynamics of the turnover of AA amyloidand the mechanisms involved. Our results clearly show that the innate capacity of amyloidclearance is efficient.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. p. 69
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1105
Keywords
AA-amyloid, autophagy, resolution
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-20292 (URN)978-91-7393-684-2 (ISBN)
Public defence
2009-03-20, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:15 (English)
Opponent
Supervisors
Available from: 2009-09-21 Created: 2009-09-02 Last updated: 2018-01-13Bibliographically approved
Sponarová, J., Nyström, S. & Westermark, G. T. (2008). AA-amyloidosis can be transferred by peripheral blood monocytes. PloS one, 3(10), e3308
Open this publication in new window or tab >>AA-amyloidosis can be transferred by peripheral blood monocytes
2008 (English)In: PloS one, ISSN 1932-6203, Vol. 3, no 10, p. e3308-Article in journal (Refereed) Published
Abstract [en]

Spongiform encephalopathies have been reported to be transmitted by blood transfusion even prior to the clinical onset. Experimental AA-amyloidosis shows similarities with prion disease and amyloid-containing organ-extracts can prime a recipient for the disease. In this systemic form of amyloidosis N-terminal fragments of the acute-phase reactant apolipoprotein serum amyloid A are the main amyloid protein. Initial amyloid deposits appear in the perifollicular region of the spleen, followed by deposits in the liver. We used the established murine model and induced AA-amyloidosis in NMRI mice by intravenous injections of purified amyloid fibrils ('amyloid enhancing factor') combined with inflammatory challenge (silver nitrate subcutaneously). Blood plasma and peripheral blood monocytes were isolated, sonicated and re-injected into new recipients followed by an inflammatory challenge during a three week period. When the animals were sacrificed presence of amyloid was analyzed in spleen sections after Congo red staining. Our result shows that some of the peripheral blood monocytes, isolated from animals with detectable amyloid, contained amyloid-seed that primed for AA-amyloid. The seeding material seems to have been phagocytosed by the cells since the AA-precursor (SAA1) was found not be expressed by the monocytes. Plasma recovered from mice with AA amyloidosis lacked seeding capacity. Amyloid enhancing activity can reside in monocytes recovered from mice with AA-amyloidosis and in a prion-like way trigger amyloid formation in conjunction with an inflammatory disorder. Human AA-amyloidosis resembles the murine form and every individual is expected to be exposed to conditions that initiate production of the acute-phase reactant. The monocyte-transfer mechanism should be eligible for the human disease and we point out blood transfusion as a putative route for transfer of amyloidosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20806 (URN)10.1371/journal.pone.0003308 (DOI)18830411 (PubMedID)
Note
Original Publication: Jana Sponarová, Sofia Nyström and Gunilla T Westermark, AA-amyloidosis can be transferred by peripheral blood monocytes, 2008, PloS one, (3), 10, e3308. http://dx.doi.org/10.1371/journal.pone.0003308 Licensee: PLoS Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2009-10-30Bibliographically approved
Lundmark, K., Westermark, G. T., Nyström, S., Murphy, C. L., Solomon, A. & Westermark, P. (2002). Transmissibility of systemic amyloidosis by a prion-like mechanism. Proceedings of the National Academy of Sciences of the United States of America, 99(10), 6979-6984
Open this publication in new window or tab >>Transmissibility of systemic amyloidosis by a prion-like mechanism
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2002 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, no 10, p. 6979-6984Article in journal (Refereed) Published
Abstract [en]

The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this “amyloid enhancing factor” (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20805 (URN)10.1073/pnas.092205999 (DOI)12011456 (PubMedID)
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2017-12-13Bibliographically approved
Nyström, S. N. & Westermark, G. T.Cardiac Amyloid in Experimental AA Amyloidosis is Associated with IncreasedAutophagic Activity.
Open this publication in new window or tab >>Cardiac Amyloid in Experimental AA Amyloidosis is Associated with IncreasedAutophagic Activity
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Cardiac involvement in reactive amyloidosis is a severe complication that leads to reducedsurvival. We induced reactive amyloidosis in mice by induction of chronic inflammation andfound that cardiac involvement develops later than spleen and liver deposits. TEM studiesrevealed intracellular amyloid deposits, but endogenous production of SAA1, SAA2 or SAA3by the cardiomyocytes was not supported by mRNA analysis. Therefore, the intracellulardeposits of protein AA must derive from SAA produced at another location. Autophagosomeswere present in close association with intracellular amyloid and the autophagy marker LC3was increased 20 times in cardiac tissue with moderate amounts of amyloid. Increase in LC3was not paralleled by an increase in LAMP-2. The ER-stress marker Bip was unchanged ininflamed heart tissue and in amyloid-containing heart. Even though procaspase-12 increasedin heart after silver nitrate injections and in heart with AA-amyloid, no active caspase-12could be detected. We suggest that autophagosomes are involved in amyloid clearance, buttheir accumulation indicate that the formation of autophagolysosomes is hampered.

Keywords
AA-amyloid, cardiomyocytes, autophagy, Amyloid enhancing factor (AEF)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20808 (URN)
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2010-01-14Bibliographically approved
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