Type II monocytes modulate T cell–mediated central nervous system autoimmune disease

Weber, Martin; Prod’homme, Thomas; Youssef, Sawsan; Dunn, Shannon; Rundle, Cynthia D; Lee, Linda; Patarroyo, Juan C.; Stüve, Olaf; Sobel, Raymond A.; Steinman, Lawrence; Zamvil, Scott S.

doi:10.1038/nm1620

Cited by 425 publications

(494 citation statements)

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“…In vivo counterparts of M2 macrophage polarization have been observed in tissue remodelling during ontogenesis [28], chronic inflammation [29][30][31][32][33][34][35][36][37][38][39][40][41][42], cancer [9,12,16,17], bacterial [43][44][45][46][47][48][49] and parasitic [50][51][52][53] infections. Evidence has also accumulated that polarized macrophages are more than mere spectators of immunopathology [35][36][37][38][39][40][41][50][51][52].…”

Section: Activation and Adaptive Responses Of Macrophagesmentioning

confidence: 99%

“…Evidence has also accumulated that polarized macrophages are more than mere spectators of immunopathology [35][36][37][38][39][40][41][50][51][52].…”

Section: Activation and Adaptive Responses Of Macrophagesmentioning

confidence: 99%

“…For instance, do MDSC retain an immature phenotype in tumour tissues or do they differentiate into tumourassociated macrophages [9][10][11] [9,12,16,17], bacterial [43][44][45][46][47][48][49] and parasitic [50][51][52][53] infections. Evidence has also accumulated that polarized macrophages are more than mere spectators of immunopathology [35][36][37][38][39][40][41][50][51][52].…”

Section: Introductionmentioning

confidence: 99%

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From phagocyte diversity and activation to probiotics: Back to Metchnikoff

Mantovani

2008

Eur J Immunol

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In this issue of the European Journal of Immunology, Siamon Gordon gives a detailed account of Metchnikoff's life and his achievements (Eur. J. Immunol. 2008. 38: 3257-3264). Looking back at the roots of innate immunity stimulates reflections on open issues in the field. Here, I give a personal view of some of these issues, including myeloid-derived suppressor cells, macrophage polarization and adaptive responses of mononuclear phagocytes. Key words: Macrophage activation Á Macrophages Á M1/M2 polarization Á Probiotics See accompanying article by Gordon IntroductionIn his scholarly review [1], Siamon Gordon tracks the roots of innate immunity to Elie Metchnikoff. The essay provides a fascinating insight into Metchnikoff's scientific life and how he tackled fundamental issues in science, some of which remain with us to this day. The perspective offered by a major player in the very same field of phagocytes and innate immunity [2,3] adds flavour and fascination to this article not necessarily present in other accounts [4]. Such a reflection on a central part of modern immunology stimulates consideration of remaining open issues and there follows a personal view of some of these.Phagocyte heterogeneity: From microphage-macrophage dichotomy to myeloid-derived suppressor cellsThe fundamental distinction between polymorphonuclear leukocytes (microphages) and mononuclear phagocytes (macrophages) was a major first step in the dissection of phagocyte heterogeneity and lineage differentiation. The identification of myeloid-derived suppressor cells (MDSC) [5][6][7] raises the questions whether the classic sharp distinction between the myeloid and the monocyte-macrophage differentiation and activation pathways is appropriate. In contrast to long-held views, neutrophils express specific transcriptional programmes in response to environmental signals [8]. MDSC include immature myeloid precursors that can further differentiate, and play a key role in the suppression of adaptive immunity in diverse pathological conditions ranging from cancer to chronic infections [5][6][7]. Are we dealing with a blurring of a classic distinction or with a well-defined third phagocyte population? Using current identification and separation criteria (e.g. Gr1, CD11b, F4/80) MDSC in the blood and lymphoid organs are a mixed population, which includes myeloid cells at different stages of differentiation and mononuclear phagocytes. Thus, the definition of MDSC remains an operational one rather than that of a cell type, a reality that is frequently neglected. The issue of lineage of the actual effectors of MDSC-mediated suppression is even more relevant when their recruitment and activation in non-lymphoid tissues is considered. For instance, do MDSC retain an immature phenotype in tumour tissues or do they differentiate into tumourassociated macrophages [9][10][11] [9,12,16,17], bacterial [43][44][45][46][47][48][49] and parasitic [50][51][52][53] infections. Evidence has also accumulated that polarized macrophages are more than mere spectators of i...

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Section: Activation and Adaptive Responses Of Macrophagesmentioning

confidence: 99%

“…Evidence has also accumulated that polarized macrophages are more than mere spectators of immunopathology [35][36][37][38][39][40][41][50][51][52].…”

Section: Activation and Adaptive Responses Of Macrophagesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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From phagocyte diversity and activation to probiotics: Back to Metchnikoff

Mantovani

2008

Eur J Immunol

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“…Treatment with GA is associated with a decreased production of TNF-a and IL-12p70 by monocyte-derived DCs, reduced CD40 expression and reduced pro-inflammatory activity in pDCs. [78][79][80][81] GA has also been shown to induce type II anti-inflammatory monocytes that share some functional and phenotypic characteristics with anti-inflammatory DCs and have an important role in the therapeutic effects of GA in MS. 82 Thus it is possible that similar molecular mechanisms operate in the induction of antiinflammatory DCs and type II monocytes by GA.…”

Section: Effect Of Ms Disease-modifying Therapies On Dcsmentioning

confidence: 99%

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

2014

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Dendritic cells (DCs) are professional antigen-presenting cells that control the generation of adaptive immunity. Consequently, DCs have a central role in the induction of protective immunity to pathogens and also in the pathogenic immune response responsible for the development and progression of autoimmune disorders. Thus the study of the molecular pathways that control DC development and function is likely to result in new strategies for the therapeutic manipulation of the immune response. In this review, we discuss the role and therapeutic value of DCs in autoimmune diseases, with a special focus on multiple sclerosis. Cell Death and Differentiation (2015) 22, 215-224; doi:10.1038/cdd.2014; published online 29 August 2014 FactsDendritic cells (DCs) control central and peripheral tolerance through their effects on effector and regulatory T cells. Specific signaling pathways regulate the ability of different DC populations to promote effector and regulatory T-cell responses. Abnormalities in DC numbers, recruitment and function contribute to the pathology of multiple sclerosis (MS) and can be partially overcome by the use of disease-modifying therapies and the targeting of specific molecular pathways. Nanotechnology provides new tools for the modulation of DC activity in vivo and the therapeutic induction of antigenspecific tolerance in immune-mediated disorders. Open QuestionsAlthough DC populations that promote the development of forkhead box P3-positive (FoxP3 þ ) regulatory T cells (Tregs) have been identified, it is not yet clear whether these populations constitute separate tolerogenic DC lineages or represent alternative activation or maturation states of other DC populations. What are the different molecular pathways that control the DC's ability to prime effector or tolerogenic T-cell responses?There is an unmet clinical need for the development of methods for the efficient and consistent generation of tolerogenic DCs in vitro and in vivo that can be implemented in large-scale clinical setups.Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that control the activation and polarization of T cells into specific lineages and, consequently, the generation of antigen-specific antibody and T-cell responses. 1 In the context of an infectious challenge, the induction of pathogenspecific immune responses provides protective immunity to fight the infection. However, in the context of autoimmune diseases DCs regulate the balance between pathogenic and regulatory immune mechanisms, controlling disease onset and progression. Thus, DCs have a central role in the control of the adaptive immune response to pathogens and selftissues and therefore constitute potential targets for the therapeutic modulation of the immune response. In this review, we discus the role of DCs in autoimmune diseases, with a special emphasis on their role in the modulation of central nervous system (CNS) inflammation in MS. Received 12.6.14; accepted 23.6.14; Edited by H-U Simon; published online 29.8.14 Abbreviations: A...

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“…Currently, there are no approved therapies aimed at modulating these adaptive immune responses in MS, though there is evidence from pre-clinical work in the mouse that one of the current approved therapies for MS, glatiramer, may influence adaptive immunity indirectly via modulation of type 2 monocytes. 3 Instead of targeting adaptive immunity, current therapies for MS are directed at modulating, often actually deleting, very broad swathes of the immune system. When a large chunk of the immune system is deleted or "blocked", though benefits may be apparent, the risks are stark.…”

Section: Introductionmentioning

confidence: 99%

Antigen-Specific Therapy of Multiple Sclerosis: The Long-Sought Magic Bullet

Steinman

2007

Neurotherapeutics

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Summary:The adaptive immune response in multiple sclerosis (MS) targets various myelin proteins and even some inducible heat shock proteins. A few attempts have been made to tolerize relapsing-remitting patients with MS to either fulllength myelin basic protein or to a key peptide epitope between residues 83-99. These trials have demonstrated that this approach may potentially provide benefit to patients with relapsing-remitting MS. However, manipulation of responses to myelin proteins can have deleterious effects. The immune response to myelin components is positioned at a key tipping point in the pathophysiology of the disease. Clarification of the key target antigens in MS, and better understanding of practical methods to attain tolerance to a wide variety of myelin and neuronal molecules will provide the basis for the ultimately successful antigen specific therapy.

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Type II monocytes modulate T cell–mediated central nervous system autoimmune disease

Cited by 425 publications

References 50 publications

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

Antigen-Specific Therapy of Multiple Sclerosis: The Long-Sought Magic Bullet

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