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The cerebrospinal fluid cytokine signature of multiple sclerosis: a homogenous response that does not conform to the Th1/Th2/Th17 convention
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.ORCID-id: 0000-0002-7045-1806
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS) that could be used as an outcome measure in clinical trials. To this end, cerebrospinal fluid from a cohort of patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Cerebrospinal fluid from a separate confirmatory cohort was used to validate cytokines pertinent to SPMS. Increased levels of CCL22, CXCL10 and sCD40L characterized RRMS patients with presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of RRMS patients irrespectively of presence of gadolinium-enhancing lesions. IL-15 and IL-27 were increased in SPMS patients, but non-significantly in the confirmation cohort. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.

Nyckelord [en]
cerebrospinal fluid, cytokines, magnetic resonance imaging, multiple sclerosis
Nationell ämneskategori
Neurologi
Forskningsämne
Neurologi
Identifikatorer
URN: urn:nbn:se:uu:diva-223241OAI: oai:DiVA.org:uu-223241DiVA, id: diva2:712895
Tillgänglig från: 2014-04-16 Skapad: 2014-04-16 Senast uppdaterad: 2014-06-30
Ingår i avhandling
1. Curing Multiple Sclerosis: How to do it and how to prove it
Öppna denna publikation i ny flik eller fönster >>Curing Multiple Sclerosis: How to do it and how to prove it
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for multiple sclerosis (MS) with now more than 600 documented cases in the medical literature. Long-term remission can be achieved with this therapy, but when is it justified to claim that a patient is cured from MS? In attempt to answer this question, the outcome of the Swedish patients is described, mechanisms behind the therapeutic effect are discussed and new tools for demonstration of absence of disease have been developed.

In Swedish patients treated with HSCT for aggressive MS, disease free survival was 68 % at five years, and no patient progressed after three years of stable disease. Presence of gadolinium enhancing lesions prior to HSCT was associated with a favorable outcome (disease free survival 79 % vs 46 %, p=0.028). There was no mortality and no patient required intensive care.

The immune system of twelve of these patients was investigated further. In most respects HSCT-treated patients were similar to healthy controls, demonstrating normalization. In the presence of a potential antigen, leukocytes from HSCT-treated patients ceased producing pro-inflammatory IL-17 and increased production of the inhibitory cytokine TGF-β1 suggesting restoration of tolerance.

Cytokine levels and biomarkers of tissue damage were investigated in cerebrospinal fluid from a cohort of MS patients. The levels were related to clinical and imaging findings. A cytokine signature of patients with relapsing-remitting MS could be identified, characterized by increased levels of CCL22, CXCL10, sCD40L, CXCL1 and CCL5 as well as down-regulation of CCL2. Further, we could demonstrate that active inflammation in relapsing-remitting MS is a tissue damaging process, with increased levels of myelin basic protein and neurofilament light. Importantly, relapsing-remitting MS patients in remission displayed no tissue damage. In secondary progressive MS, moderate tissue damage was present without signs of active inflammation.

From a clinical vantage point, it seems that we confidently can claim cure of relapsing-remitting MS patients after five years absence of disease activity. The new tools for evaluation of disease can strengthen this assertion and may enable earlier prediction of outcome.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 74
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1005
Nyckelord
biomarkers, cerebrospinal fluid, cytokines, hematopoietic stem cell transplantation, immunology, magnetic resonance imaging, multiple sclerosis, neuroimmunology, neurology
Nationell ämneskategori
Neurologi Immunologi inom det medicinska området
Forskningsämne
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-221888 (URN)978-91-554-8964-9 (ISBN)
Disputation
2014-06-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-05-23 Skapad: 2014-04-07 Senast uppdaterad: 2018-01-11

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Burman, Joachim

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