Type I Interferons: Beneficial in Th1 and Detrimental in Th17 Autoimmunity

Axtell, Robert C.; Raman, Chander; Steinman, Lawrence

doi:10.1007/s12016-011-8296-5

Cited by 79 publications

(65 citation statements)

References 69 publications

(71 reference statements)

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“…Plasmacytoid dendritic cells were the source of type 1 IFN, which was induced by NETosis arising from neutrophil endocytosis of the amyloid fibrils. Production of the type 1 IFN was therapeutic in Th1-induced adoptive transfer EAE, but exacerbated the paralytic signs of Th17-induced disease, consistent with experiments by Axtell et al (3). However, not all amyloidogenic peptides induced equivalent amounts of type 1 IFN.…”

supporting

confidence: 87%

Amyloid fibrils activate B-1a lymphocytes to ameliorate inflammatory brain disease

Kurnellas

Ghosn

Schartner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Amyloid fibrils composed of peptides as short as six amino acids are therapeutic in experimental autoimmune encephalomyelitis (EAE), reducing paralysis and inflammation, while inducing several pathways of immune suppression. Intraperitoneal injection of fibrils selectively activates B-1a lymphocytes and two populations of resident macrophages (MΦs), increasing IL-10 production, and triggering their exodus from the peritoneum. The importance of IL-10–producing B-1a cells in this effective therapy was established in loss-of-function experiments where neither B-cell–deficient (μMT) nor IL10−/− mice with EAE responded to the fibrils. In gain-of-function experiments, B-1a cells, adoptively transferred to μMT mice with EAE, restored their therapeutic efficacy when Amylin 28–33 was administered. Stimulation of adoptively transferred bioluminescent MΦs and B-1a cells by amyloid fibrils resulted in rapid (within 60 min of injection) trafficking of both cell types to draining lymph nodes. Analysis of gene expression indicated that the fibrils activated the CD40/B-cell receptor pathway in B-1a cells and induced a set of immune-suppressive cell-surface proteins, including BTLA, IRF4, and Siglec G. Collectively, these data indicate that the fibrils activate B-1a cells and F4/80+ MΦs, resulting in their migration to the lymph nodes, where IL-10 and cell-surface receptors associated with immune-suppression limit antigen presentation and T-cell activation. These mechanisms culminate in reduction of paralytic signs of EAE.

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supporting

confidence: 87%

Amyloid fibrils activate B-1a lymphocytes to ameliorate inflammatory brain disease

Kurnellas

Ghosn

Schartner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…IL-4, IL-6, IL-17, and glucocorticoid receptor signalling pathways, primarily related to Th2 and Th17 cells rather than Th1 cells. This may suggest that Th cell balances play a critical role in etiology and pathology of MS, and may even be being factors influencing responses to treatments as suggested for example by Axtell et al [81,82]. A list of biomarker candidates in blood is given in Table 4.…”

Section: Blood Biomarker Candidatesmentioning

confidence: 99%

“…In the first scenario the IFN beta works with a great benefit for the patient, in the latter case IFN beta may not improve the disease course or even may be detrimental. Therefore, Th17 cell and Th1 cytokines in combination are proposed to indicate the immunological type of RRMS and, thus, therapy response [80][81][82][83].…”

Section: Blood Biomarker Candidatesmentioning

confidence: 99%

Molecular Biomarkers in Multiple Sclerosis

Paap

Hecker²,

Koczan³

et al. 2013

J Clin Cell Immunol

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Multiple Sclerosis (MS) is a chronic immune-modulated disorder of the central nervous system (CNS) affecting mainly young adults. Due to the complexity and heterogenic etiology of this disease diagnosis, treatment, and estimations concerning the future course of the disease for the individual patient are challenging. To encounter the variability in phenotype, disease progression and response to treatments, various new drugs are in development to complement existing treatment options. Since years intensive efforts are directed to identify biomarkers that are associated with various aspects of MS on different levels of the organizational hierarchy of the human body (e.g. DNA, RNA, proteins, cells).We researched the last ten years of literature to identify those proposed candidates that had been repeatedly published as being associated with MS etiology, clinical manifestation, disease course, and treatment response.Here, we present a categorized overview over molecular biomarkers in MS.However, despite of the large sum of studies and the long list of candidate markers, today only very few biomarkers are of clinical value. This is mostly due to lack of comparability and statistical power in most studies. However, there are recent advances in the field of applicable molecular biomarkers in MS: For example measurement of anti-AQP4 levels allows differentiation between neuromyelitis optica (NMO) and MS.

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“…These discrepancies may be attributed to several reasons, such as the production of neutralizing antibodies (NAbs) [26] and/or the elevated levels of endogenous IFN-β and its gene products prior to initiation of treatment [27]. Nonetheless, IFN-βefficacy seems to be altered by the profile of encephalitogenic T helper cells; IFN-β alleviates symptoms in conditions with Th1 bias, whereas it promotes pathology in Th17 mediated disease [28,29]. Finally, it was recently suggested that high levels of serum IL-17F above a threshold prior to IFN-β treatment may also be responsible for the non-responsiveness of MS patients [29,30].…”

Section: 2ifn-β: As First-line Intervention For Msmentioning

confidence: 99%