Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species

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Abstract

Reduced capacity to produce ROS increases the severity of T cell–dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance to the level of that of wild-type mice in a collagen-induced arthritis model but not in a T cell–independent anti-collagen antibody–induced arthritis model. T cell activation was downregulated and skewed toward Th2 in transgenic mice. In vitro, IL-2 production and T cell proliferation were suppressed by macrophage ROS, irrespective of T cell origin. IFN-γ production, however, was independent of macrophage ROS but dependent on T cell origin. These effects were antigen dependent but not restricted to collagen type II. In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis.

Authors

Kyra A. Gelderman, Malin Hultqvist, Angela Pizzolla, Ming Zhao, Kutty Selva Nandakumar, Ragnar Mattsson, Rikard Holmdahl

Mature B cells class switched to IgD are autoreactive in healthy individuals

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Abstract

Determination of the origin and fate of autoreactive B cells is critical to understanding and treating autoimmune diseases. We report that, despite being derived from healthy people, antibodies from B cells that have class switched to IgD via genetic recombination (and thus become class switched to Cδ [Cδ-CS] cells) are highly reactive to self antigens. Over half of the antibodies from Cδ-CS B cells bind autoantigens on human epithelioma cell line 2 (HEp-2) cells or antinuclear antigens, and a quarter bind double-stranded DNA; both groups of antibodies are frequently polyreactive. Intriguingly, some Cδ-CS B cells have accumulated basic residues in the antibody variable regions that mediate anti-DNA reactivity via somatic hypermutation and selection, while other Cδ-CS B cells are naturally autoreactive. Though the total percentage was appreciably less than for Cδ-CS cells, a surprising 31% of IgG memory cell antibodies were somewhat autoreactive, and as expected, about 24% of naive cell antibodies were autoreactive. We interpret these findings to indicate either that autoreactive B cells can be induced to class switch to IgD or that autoreactive B cells that use IgD as the B cell receptor are not effectively deleted. Determination of the mechanism by which the majority of Cδ-CS B cells are autoreactive may be important in understanding peripheral tolerance mechanisms and may provide insight into the enigmatic function of the IgD antibody.

Authors

Kristi Koelsch, Nai-Ying Zheng, Qingzhao Zhang, Andrew Duty, Christina Helms, Melissa D. Mathias, Mathew Jared, Kenneth Smith, J. Donald Capra, Patrick C. Wilson

Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance

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Abstract

We have developed a model of autoimmunity to investigate autoantibody-mediated cross-presentation of self antigen. RIP-mOVA mice, expressing OVA in pancreatic β cells, develop severe autoimmune diabetes when given OT-I cells (OVA-specific CD8+ T cells) and anti-OVA IgG but not when given T cells alone. Anti-OVA IgG is not directly injurious to the islets but rather enhances cross-presentation of apoptotic islet antigen to the OT-I cells, leading to their differentiation into potent effector cells. Antibody-driven effector T cell activation is dependent on the presence of activating Fc receptors for IgG (FcγRs) and cross-priming DCs. As a consequence, diabetes incidence and severity was reduced in mice lacking activating FcγRs. An intact complement pathway was also required for disease development, as C3 deficiency was also partially protective. C3-deficient animals exhibited augmented T cell priming overall, indicating a proinflammatory role for complement activation after the T cell priming phase. Thus, we show that autoreactive antibody can potently enhance the activation of effector T cells in response to cross-presented self antigen, thereby contributing to T cell–mediated autoimmunity.

Authors

Stephanie O. Harbers, Andrea Crocker, Geoffrey Catalano, Vivette D’Agati, Steffen Jung, Dharmesh D. Desai, Raphael Clynes

Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions

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Abstract

Authors

Amrie C. Grammer, Rebecca Slota, Randy Fischer, Hanan Gur, Hermann Girschick, Cheryl Yarboro, Gabor G. Illei, Peter E. Lipsky

Heme oxygenase–1 and carbon monoxide suppress autoimmune neuroinflammation

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Abstract

Heme oxygenase–1 (HO-1, encoded by HMOX1) dampens inflammatory reactions via the catabolism of heme into CO, Fe, and biliverdin. We report that expression of HO-1 dictates the pathologic outcome of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Induction of EAE in Hmox1–/– C57BL/6 mice led to enhanced CNS demyelination, paralysis, and mortality, as compared with Hmox1+/+ mice. Induction of HO-1 by cobalt protoporphyrin IX (CoPPIX) administration after EAE onset reversed paralysis in C57BL/6 and SJL/J mice and disease relapse in SJL/J mice. These effects were not observed using zinc protoporphyrin IX, which does not induce HO-1. CoPPIX protection was abrogated in Hmox1–/– C57BL/6 mice, indicating that CoPPIX acts via HO-1 to suppress EAE progression. The protective effect of HO-1 was associated with inhibition of MHC class II expression by APCs and inhibition of Th and CD8 T cell accumulation, proliferation, and effector function within the CNS. Exogenous CO mimicked these effects, suggesting that CO contributes to the protective action of HO-1. In conclusion, HO-1 or exposure to its end product CO counters autoimmune neuroinflammation and thus might be used therapeutically to treat MS.

Authors

Ângelo A. Chora, Paulo Fontoura, Andreia Cunha, Teresa F. Pais, Sílvia Cardoso, Peggy P. Ho, Lowen Y. Lee, Raymond A. Sobel, Lawrence Steinman, Miguel P. Soares

Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis

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Abstract

Loss of Treg function appears to be a critical factor in the pathogenesis of human autoimmune diseases. Attention has focused on defects of CD4+CD25high Tregs, and techniques have been developed to determine their function. In contrast, the role of Tr1 regulatory T cells, which secrete the antiinflammatory cytokine IL-10, in autoimmune disease has not been well assessed. CD46 is a newly defined costimulatory molecule for T cell activation, and CD46-costimulated human T cells induce a Tr1 Treg phenotype with considerable amounts of IL-10 secretion. Here, we examined the role of Tr1 cells in patients with multiple sclerosis (MS) by stimulating CD4+ T cells with anti-CD3 and -CD46 mAbs and measuring IL-10 secretion. There were striking defects in the induction of Tr1 cells with CD46 costimulation as measured by IL-10 but not IFN-γ secretion in patients with MS compared with healthy subjects. This loss of Tr1 cell–associated IL-10 secretion was specific to CD46 and not CD28 costimulation and was associated with an altered regulation of the CD46-Cy2 isoform that differentially regulates T cell function in a CD46-transgenic murine model. These data demonstrate a second major Treg defect in human autoimmune disease associated with the CD46 pathway.

Authors

Anne L. Astier, Gregory Meiffren, Samuel Freeman, David A. Hafler

Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis

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Abstract

Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit–expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-α release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-α production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.

Authors

Ricardo T. Paniagua, Orr Sharpe, Peggy P. Ho, Steven M. Chan, Anna Chang, John P. Higgins, Beren H. Tomooka, Fiona M. Thomas, Jason J. Song, Stuart B. Goodman, David M. Lee, Mark C. Genovese, Paul J. Utz, Lawrence Steinman, William H. Robinson

FcγRIII engagement provides activating signals to NKT cells in antibody-induced joint inflammation

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Abstract

NKT cells promote antibody-induced arthritis, but the mechanism by which NKT cells are activated in this model remains unclear. It has been proposed that Fcγ receptor (FcγR) contributes to NKT cell activation in antibody-induced arthritis. To address this issue, we explored the functions of FcγR on NKT cells in antibody-induced arthritis. RT-PCR and flow cytometric analysis demonstrated that NKT cells constitutively express surface FcγRIII but not FcγRI, -II, or -IV. FcγRIII engagement by aggregated IgG on NKT cells enhanced CD25 and CD69 expression, whereas FcγR–/– mouse NKT cells did not enhance activation. FcγRIII engagement on NKT cells enhanced the production of IL-4, IL-10, IL-13, and IFN-γ, whereas FcγR-deficient NKT cells did not alter the production of these cytokines after aggregated IgG treatment. However, FcγR-deficient NKT cells were functionally intact in terms of TCR-induced activation. Moreover, adoptive transfer of FcγR-deficient NKT cells could not restore inflammation or TGF-β production in the joint tissues of CD1d–/– mice, whereas adoptive transfer of wild-type NKT cells induced arthritis and reduced TGF-β production in joint tissues. We conclude that FcγRIII engagement by IgG in joint tissues provides activating signals to NKT cells in antibody-induced arthritis.

Authors

Hye Young Kim, Sanghee Kim, Doo Hyun Chung

Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation

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Abstract

We describe a double-transgenic mouse strain (opticospinal EAE [OSE] mouse) that spontaneously develops an EAE-like neurological syndrome closely resembling a human variant of multiple sclerosis, Devic disease (also called neuromyelitis optica). Like in Devic disease, the inflammatory, demyelinating lesions were located in the optic nerve and spinal cord, sparing brain and cerebellum, and the murine lesions showed histological similarity with their human correlates. OSE mice have recombination-competent immune cells expressing a TCR-αβ specific for myelin oligodendrocyte glycoprotein (MOG) aa 35–55 peptide in the context of I-Ab along with an Ig J region replaced by the recombined heavy chain of a monoclonal antibody binding to a conformational epitope on MOG. OSE mouse B cells bound even high dilutions of recombinant MOG, but not MOG peptide, and processed and presented it to autologous T cells. In addition, in OSE mice, but not in single-transgenic parental mice, anti-MOG antibodies were switched from IgM to IgG1.

Authors

Gurumoorthy Krishnamoorthy, Hans Lassmann, Hartmut Wekerle, Andreas Holz

Myelin oligodendrocyte glycoprotein–specific T and B cells cooperate to induce a Devic-like disease in mice

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Abstract

Multiple sclerosis (MS) is a clinically and pathologically heterogeneous inflammatory/demyelinating disease of the CNS. In the MS variant Devic disease, lesions are predominantly found in the optic nerves and spinal cord but not the brain. The immunological bases of the different forms of MS are unknown. We previously generated myelin oligodendrocyte glycoprotein–specific (MOG-specific) TCR transgenic mice (TCRMOG mice; also referred to as 2D2 mice) and reported that a large proportion of these mice develop spontaneous isolated optic neuritis. We have now crossed the TCRMOG mice with MOG-specific Ig heavy-chain knock-in mice (IgHMOG mice; also referred to as Th mice), in which one-third of the B cells are specific for MOG. In these mice, MOG-specific B cells are very efficient in presenting MOG to the transgenic T cells and undergo class switching to IgG1 in the presence of the transgenic T cells. Sixty percent of TCRMOG×IgHMOG mice spontaneously developed a severe form of experimental autoimmune encephalomyelitis (EAE). Histological examination of the CNS revealed a selective distribution of meningeal and parenchymal inflammatory lesions in the spinal cord and optic nerves. Thus, CNS antigen–specific T and B cells cooperate to induce a distinct clinicopathologic EAE pattern that closely replicates human Devic disease.

Authors

Estelle Bettelli, Dominique Baeten, Anneli Jäger, Raymond A. Sobel, Vijay K. Kuchroo