Increased CD80(+) B cells in active multiple sclerosis and reversal by interferon beta-1b therapy.

Genç, Kürşad; Donà, Daniele; Reder, Anthony T.

doi:10.1172/jci119455

Cited by 215 publications

(156 citation statements)

References 52 publications

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“…Although some concerns were raised regarding the general validity of this dichotomy of the roles of CD80 and CD86 (39), several reports indicate that the CD80/CD86 costimulatory system is altered in MS patients. Specifically, higher numbers of CD80 ϩ B lymphocytes in the cerebrospinal fluid (40,41) increased serum levels of CD80 ϩ lymphocytes in patients during MS exacerbation (42), and low expression of CD86 on cerebrospinal fluid T cells (41) have been reported in patients with MS. Our data indicate that rolipram down-regulates CD80 expression and up-regulates CD86 expression on monocytes and B and T lymphocytes upon nonspecific activation with PHA or LPS. The likely explanation for this observation is the differential kinetic of induction of these costimulatory molecules on APC; CD80 is expressed later than CD86; therefore, rolipram may be preventing the switch from CD86 to CD80 expression, an issue that merits further study.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Bielekova

Lincoln

McFarland

et al. 2000

The Journal of Immunology

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Phosphodiesterase-4 (PDE4) inhibitors have the potential to modulate immune responses from the Th1 toward the Th2 phenotype and are considered candidate therapies for Th1-mediated autoimmune disorders. However, depending on the model and cell types employed, studies of atopic individuals have come to the opposite conclusion, i.e., that PDE inhibitors may be beneficial in asthma. Using in vitro immunopharmacologic techniques we analyzed the effects of PDE4 and PDE3 inhibitors on human immune cells to address these discrepancies and broaden our understanding of their mechanism of action. Our results indicate that PDE inhibitors have complex inhibitory effects within in vivo achievable concentration ranges on Th1-mediated immunity, whereas Th2-mediated responses are mostly unaffected or enhanced. The Th2 skewing of the developing immune response is explained by the effects of PDE inhibitors on several factors contributing to T cell priming: the cytokine milieu; the type of costimulatory signal, i.e., up-regulation of CD86 and down-regulation of CD80; and the Ag avidity. The combination of PDE4 and PDE3 inhibitors expresses synergistic effects and may broaden the therapeutic window. Finally, we observed a differential sensitivity to PDE inhibition in autoreactive vs foreign Ag-specific T cells and cells derived from multiple sclerosis patients vs those derived from healthy donors. This suggests that PDE inhibition weakens the strength of the T cell stimulus and corrects the underlying disease-associated cytokine skew in T cell-mediated autoimmune disorders. These new findings broaden the understanding of the immunomodulatory actions of PDE inhibitors and underscore their promising drug profile for the treatment of autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Bielekova

Lincoln

McFarland

et al. 2000

The Journal of Immunology

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“…As such, this novel memory B cell subset can mediate the rapid and robust immune responses that together constitute the hallmarks of adaptive immune memory. In this context, reports of increased frequencies of CD80 ϩ B cells in human autoimmune disease (50,51) and observations that autoreactive B cells may function as effective APCs (10,52) raise the possibility that dysregulation of the CD80 ϩ memory B cell subset may contribute to autoimmune pathogenesis. Further studies will be required to elucidate the potential roles of these cells in both health and disease, particularly at a time when novel agents are being developed to target the B7 costimulatory pathway in human clinical trials (24).…”

Section: Discussionmentioning

confidence: 99%

Immunological Memory: Contribution of Memory B Cells Expressing Costimulatory Molecules in the Resting State

Bar‐Or

Oliveira

Anderson

et al. 2001

The Journal of Immunology

126

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Traditionally, emphasis has been placed on the roles of Th cells in generating and amplifying both cellular and humoral memory responses. Little is known about the potential contributions of B cell subsets to immunological memory. Resting memory B cells have generally been regarded as poor APC, attributed in part to the relative paucity of costimulatory molecules identified on their surface. We describe a novel subpopulation of human memory B cells that express CD80 in their resting state, are poised to secrete particularly large amounts of class switched Igs, and can efficiently present Ag to and activate T cells. This functionally distinct B cell subset may represent an important mechanism by which quiescent human B cells can initiate and propagate rapid and vigorous immune memory responses. Finally, these studies extend recent observations in the murine system and highlight the phenotypic and functional diversity that exists within the human B cell memory compartment.

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“…In some experimental systems, CD80 promotes a Th1 cell-mediated inflammatory response, CD86 elicits Th2 humoral response [24,36]. Circulating CD80 1 B cells are increased during MS exacerbations, and the CD80/CD86 ratio on B cells and monocytes is increased during active MS [37]. During IFN-b therapy, the CD80/CD86 ratio approximates control levels.…”

Section: Discussionmentioning

confidence: 99%

Altered phenotype and function of blood dendritic cells in multiple sclerosis are modulated by IFN-βand IL-10

Huang¹,

Stoyanova

Jin

et al. 2001

Clinical and Experimental Immunology

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SUMMARYMultiple sclerosis (MS) is assumed to result from autoaggressive T cell-mediated immune responses, in which T helper type 1 (Th1) cells producing cytokines, e.g. IFN-g and lymphotoxin promote damage of oligodendrocyte-myelin units. Dendritic cells (DCs) as potent antigen presenting cells initiate and orchestrate immune responses. Whether phenotype and function of DCs with respect to Th1 cell promotion are altered in MS, are not known. This study revealed that blood-derived DCs from MS patients expressed low levels of the costimulatory molecule CD86. In addition, production of IFN-g by blood mononuclear cells (MNCs) was strongly enhanced by DCs derived from MS patients. IFNb and IL-10 inhibited the costimulatory capacity of DCs in mixed lymphocyte reaction (MLR) and showed additive effects on suppression of IL-12 production by DCs. Correspondingly, DCs pretreated with IFN-b and IL-10 significantly suppressed IFN-g production by MNCs. IFN-b in vitro also upregulated CD80 and, in particular, CD86 expression on DCs. In vitro, anti-CD80 antibody remarkably increased, while anti-CD86 antibody inhibited DC-induced IL-4 production in MLR. We conclude that DC phenotype and function are altered in MS, implying Th1-biased responses with enhanced capacity to induce Th1 cytokine production. In vitro modification of MS patients' DCs by IFN-b and IL-10 could represent a novel way of immunomodulation and of possible usefulness for future immunotherapy of MS.

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Increased CD80(+) B cells in active multiple sclerosis and reversal by interferon beta-1b therapy.

Cited by 215 publications

References 52 publications

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Therapeutic Potential of Phosphodiesterase-4 and -3 Inhibitors in Th1-Mediated Autoimmune Diseases

Immunological Memory: Contribution of Memory B Cells Expressing Costimulatory Molecules in the Resting State

Altered phenotype and function of blood dendritic cells in multiple sclerosis are modulated by IFN-βand IL-10

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