Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase

Shi, Fu‐Dong; Flodström, Malin; Kim, Soon Ha; Pakala, Shyam; Cleary, Mary Malo; Ljunggren, Hans‐Gustaf; Sarvetnick, Nora

doi:10.4049/jimmunol.167.5.3000

Cited by 34 publications

(21 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…iNOS induction by activated T cells and subsequent suppression of T cell expansion are thought to be mechanisms responsible for immunosuppression by NO in vivo [2,5,[12][13][14][15]. Simultaneously with NO production, O 2 Ϫ production by NADPH oxidase increased as well.…”

Section: Discussionmentioning

confidence: 99%

“…Mice deficient in inducible NO synthase (iNOS) develop exacerbated experimental immunopathologies, including myasthenia gravis [5], arthritis [6], myocarditis [7], and experimental autoimmune encephalomyelitis (EAE) [8 -10], as well as increased T cell responses during parasitic infections [11]. NO induction during T cell activation inhibits subsequent T cell expansion and has been implicated as the mechanism of NO-mediated immunosuppression in vivo [2,5,[12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion

Dietlin

Hofman

Lund

et al. 2007

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Similar to the regulation of vasodilation, the balance between NO and superoxide (O2-) regulates expansion of activated T cells in mice. Reduction of suppressive NO levels by O2- is essential for T cell expansion and development of autoimmunity. In mice primed with heat-killed Mycobacterium, a splenocyte population positive for Gr-1 (Ly-6G/C) is the exclusive source of both immunoregulatory free radicals. Distinct Gr-1+ cell subpopulations were separated according to Ly-6G expression. In culture with activated T cells, predominantly monocytic Ly-6G- Gr-1+ cells produced T cell-inhibitory NO but no O2-. However, mostly granulocytic Ly-6G+ cells produced O2- simultaneously but had no measurable effect on proliferation. Recombination of the two purified Gr-1+ subpopulations restored controlled regulation of T cell proliferation through NO and O2- interaction. Coculture of p47phox-/- and inducible NO synthase-/- Gr-1+ cells confirmed this intercellular interaction. These data suggest that bacterial products induce development of distinct Gr-1+ myeloid lineages, which upon stimulation by activated T cells, interact via their respective free radical products to modulate T cell expansion.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion

Dietlin

Hofman

Lund

et al. 2007

Journal of Leukocyte Biology

View full text Add to dashboard Cite

show abstract

“…Several studies with iNOS-deficient mice and autoimmune models have implicated NO in the control of autoreactive T cells and prevention of the development of autoimmunity. [64][65][66][67][68][69][70] The effect of NO on DC migration and cytokine production reported here might contribute to the observed protective effects of NO in autoimmune disorders.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide and cGMP protein kinase (cGK) regulate dendritic-cell migration toward the lymph-node–directing chemokine CCL19

Giordano

Magaletti

Clark

2006

Blood

View full text Add to dashboard Cite

Dendritic-cell (DC) migration to secondary lymphoid organs is crucial for the initiation of adaptive immune responses. Although LPS up-regulates CCR7 on DCs, a second signal is required to enable them to migrate toward the chemokine CCL19 (MIP-3␤). We found that the nitric oxide (NO) donor NOR4 provides a signal allowing LPS-stimulated DCs to migrate toward CCL19. NO affects DC migration through both the initial activation of the cGMP/cGMP kinase (cGMP/cGK) pathway and a long-term effect that reduced cGK activity via negative feedback. Indeed, migration of DCs toward CCL19, unlike migration toward CXCL12 (SDF-1␣), required inhibition of cGK. LPS increased both cGK expression and cGK activity as measured by phosphorylation of the key cGK target vasodilator-stimulated phosphoprotein (VASP). Because cGK phosphorylation of VASP can disrupt focal adhesions and inhibit cell migration, LPSinduced VASP phosphorylation may prevent DCs from migrating without a second signal. Long-term NOR4 treatment inhibited the increase in cGK-dependent VASP phosphorylation, releasing this brake so that DCs can migrate. NO has been implicated in the regulation of autoimmunity through its effect on T cells. Our results suggest that NO regulation of DC migration and cytokine production may contribute to the protective effects of NO in autoimmune disorders. IntroductionDendritic cells (DCs) activate naive T cells in peripheral lymphoid tissues and play a pivotal role in initiating and instructing adaptive immune responses. 1,2 At the site of infection where they take up antigens, DCs also contribute to innate immunity: They recognize and respond to common pathogen-associated molecular patterns (PAMPs) by releasing proinflammatory products that regulate other inflammatory cells. 3 In a later phase, recognition of PAMPs triggers a complex maturation program that results in the increase in DC antigen-presenting ability and responsiveness to chemokines like CCL19/MIP-3␤, which promote DC migration from peripheral tissues to secondary lymphoid organs. 4,5 The outcome of an immune response depends not only on the pathogen that activates DCs but also on various inflammationassociated factors that modulate DC maturation and determine whether DCs polarize T-cell development into T helper 1 (Th1)-, Th2-, or regulatory T-cell subsets. 6 Prostaglandin E2 (PGE2) and other inflammatory products that act through the cAMP/cAMP kinase (cAMP/cAK) signaling pathway can affect DC maturation and drive them toward a Th2-inducing program. [7][8][9] These agents also regulate DC chemokine and chemokines receptor expression; they down-regulate receptors for inflammatory chemokines like CCR5 while increasing CCR7 or CXCR4 receptors for CCL19/ MIP-3␤ and CXCL12/SDF-1␣, respectively. [10][11][12] Interestingly, inflammatory agents are required for mature DCs to be able to migrate toward certain chemokines. Even after monocyte-derived immature DCs (iDCs) are induced to mature and up-regulate CCR7, they remain unresponsive to CCL19 and do not migrate unless they are e...

show abstract

“…Transfer of myasthenogenic lymphocytes from humans with MG or from EAMG mice results in clinical EAMG [28,29]. We isolated CD4 + cells from control mice and CCL2 -/-for transfer into RAG1 -/-deficient mice (which are devoid of intrinsic T and B cells) [30].…”

Section: Autoreactive Th17 Cells Drive Igg2b Antibody Response In Vivomentioning

confidence: 99%

CCL2 recruitment of IL‐6‐producing CD11b⁺ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

et al. 2008

View full text Add to dashboard Cite

The development and function of Th17 cells are influenced in part by the cytokines TGF-b, IL-23 and IL-6, but the mechanisms that govern recruitment and activity of Th17 cells during initiation of autoimmunity remain poorly defined. We show here that the development of autoreactive Th17 cells in secondary lymphoid organs in experimental autoimmune myasthenia gravis -an animal model of human myasthenia gravis -is modulated by IL-6-producing CD11b + cells via the CC chemokine ligand 2 (CCL2). Notably, acetylcholine receptor (AChR)-reactive Th17 cells provide help for the B cells to produce anti-AChR antibodies, which are responsible for the impairment of the neuromuscular transmission that contributes to the clinical manifestations of autoimmunity, as indicated by a lack of disease induction in IL-17-deficient mice. Thus, Th17 cells can promote humoral autoimmunity via a novel mechanism that involves CCL2.

show abstract

Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase

Cited by 34 publications

References 35 publications

Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion

Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion

Nitric oxide and cGMP protein kinase (cGK) regulate dendritic-cell migration toward the lymph-node–directing chemokine CCL19

CCL2 recruitment of IL‐6‐producing CD11b⁺ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

Contact Info

Product

Resources

About

Control of the Autoimmune Response by Type 2 Nitric Oxide Synthase

Cited by 34 publications

References 35 publications

Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion

Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion

Nitric oxide and cGMP protein kinase (cGK) regulate dendritic-cell migration toward the lymph-node–directing chemokine CCL19

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

Contact Info

Product

Resources

About

CCL2 recruitment of IL‐6‐producing CD11b⁺ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity