Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation.

Increased production of tumor necrosis factor alpha (TNF) in the bone marrow (BM) in response to both oxidative stress and T cell activation contributes to the bone loss induced by estrogen deficiency, but it is presently unknown whether oxidative stress causes bone loss through T cells. Here we show that ovariectomy causes an accumulation in the BM of reactive oxygen species, which leads to increased production of TNF by activated T cells through up-regulation of the costimulatory molecule CD80 on dendritic cells. Accordingly, bone loss is prevented by treatment of ovariectomized mice with either antioxidants or CTLA4-Ig, an inhibitor of the CD80/CD28 pathway. In summary, reactive oxygen species accumulation in the BM is an upstream consequence of ovariectomy that leads to bone loss by activating T cells through enhanced activity of BM dendritic cells, and these findings suggest that the CD80/CD28 pathway may represent a therapeutic target for postmenopausal bone loss.

IL-7 drives T cell-mediated bone loss following ovariectomy.

Ovariectomy-induced bone loss stems in large measure from a realignment of adaptive immune responses leading to the activation and expansion of tumor necrosis factor (TNF)-producing T cells. The mechanisms driving this T cell expansion are complex but we have recently reported that the pro-osteoclastogenic cytokine interleukin (IL)-7 plays a critical role in this process. The mechanisms of IL-7 action are intricate and poorly defined. We present herein an overview of our current understanding of IL-7 action on bone turnover and the role of IL-7 in ovariectomy-induced bone loss.

Mast cells are required for optimal autoreactive T cell responses in a murine model of multiple sclerosis.

Once considered to be of sole importance in allergy and parasitic infections, the role of mast cells in other pathologic and protective immune responses is becoming increasingly evident. We previously demonstrated that mast cells contribute to the severity of EAE, the rodent model of multiple sclerosis. Here we show that one mode of mast cell action is through effects on the autoreactive T cell response. Early indices of both peripheral CD4 and CD8 T cell activation, including IFN-gamma production and increases in CD44 and CD11a expression, are attenuated in mast cell-deficient (W/Wv) mice after myelin oligodendrocyte glycoprotein(35-55) priming when compared to WT animals. Reduced infiltrates of activated T cells in the central nervous system are also observed. Importantly, selective repletion of the mast cell compartment restores most T cell responses in the lymph nodes and the central nervous system, correlating with reconstitution of severe disease. The adoptive transfer of WT-derived encephalitogenic T cells results in significantly less severe disease in W/Wv recipients, indicating that mast cells also exert potent effects after the initial T cell response is generated. Our data provide the first in vivo evidence that mast cells can significantly influence T cell responses and suggest that mast cells exacerbate disease during both the inductive and effector phases.

MASTering the immune response: mast cells in autoimmunity.

Mast cells are established participants in allergic disease and in protection against extracellular parasites. Recently, it has become apparent that mast cells exert many profound effects on a variety of both innate and adaptive immune responses. Using mast cell-deficient WBB6F1/J-kitW/kitWv (W/Wv) mice, we have demonstrated that mast cells are critical for severe disease in a murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). Reconstitution of the mast cell population in the periphery, but not the CNS, restores EAE severity. Mast cells exert their effects at both the inductive and effector phases of disease. EAE is mediated by autoreactive T cells that enter the CNS and initiate inflammatory responses, leading to demyelination within the spinal cord and brain. Although there are no intrinsic defects in W/Wv-derived T cells, both CD4+ and CD8+ autoreactive T cell responses are attenuated during early disease in W/Wv mice. Thus mast cells are essential for the optimal priming of autoreactive T cells. The entry of encephalitogenic T cells into the CNS is compromised in these mice as well. The effects on early T cell responses are due, in part, to the reduced percentage of activated dendritic cells in the lymph nodes of W/Wv mice after disease induction compared with wild-type mice. The finding that mast cells can alter T cell responses in EAE has much broader implications for understanding the impact of these cells on all T cell-mediated responses.

Mast cells exert effects outside the central nervous system to influence experimental allergic encephalomyelitis disease course.

Previous studies using mast cell-deficient mice (W/W(v)) revealed that mast cells influence disease onset and severity of experimental allergic/autoimmune encephalomyelitis (EAE), the murine model for multiple sclerosis. The mast cell populations of these mice can be restored by transferring bone marrow-derived mast cells (BMMCs). Studies using the W/W(v) reconstitution model have lead to major advances in our understanding of mast cell roles in vivo. However, despite its common use, details regarding the sites and kinetics of mast cell repopulation have remained largely uncharacterized. In this study, we examined the kinetics and tissue distribution of green fluorescent protein(+) BMMCs in reconstituted W/W(v) mice to identify sites of mast cell influence in EAE. Reconstitution of naive animals with BMMCs does not restore mast cell populations to all organs, notably the brain, spinal cord, lymph nodes, and heart. Despite the absence of mast cells in the CNS, reconstituted mice exhibit an EAE disease course equivalent to that induced in wild-type mice. Mast cells are found adjacent to T cell-rich areas of the spleen and can migrate to the draining lymph node after disease induction. These data reveal that mast cells can act outside the CNS to influence EAE, perhaps by affecting the function of autoreactive lymphocytes.

Cutting edge: both activating and inhibitory Fc receptors expressed on mast cells regulate experimental allergic encephalomyelitis disease severity.

Mast cell-deficient mice (W/W(v)) exhibit significantly reduced severity of experimental allergic encephalomyelitis (EAE), a murine model of multiple sclerosis. In this study, the contribution of FcR-mediated mast cell activation to disease was examined. W/W(v) mice were reconstituted i.v. with bone marrow-derived mast cells (BMMCs) from wild-type mice or those lacking functional FcRs. Eight weeks later, EAE was induced by immunization with the myelin oligodendrocyte glycoprotein 35-55 peptide. Disease scores were analyzed in reconstituted mice and compared with age-matched W/W(v) mice and wild-type littermates. Mice reconstituted with FcRgamma(-/-) BMMCs or FcgammaRIII(-/-) BMMCs exhibited less severe clinical symptoms similar to W/W(v) controls, while reconstitution with FcRIIB(-/-) BMMCs resulted in disease significantly more severe than wild-type controls. Notably, mice reconstituted with FcgammaRIII(-/-) BMMC exhibit a relapsing-remitting course of disease. These data demonstrate that both activating and inhibitory FcRs expressed on mast cells influence the course of EAE.

The role of mast cells in allergy and autoimmunity.

Two potential outcomes of dysregulated immunity are allergy and autoimmunity. Both are characterized by localized inflammation that leads to the injury and/or destruction of target tissues. Until recently, it was generally accepted that the mechanisms that govern these disease processes are quite disparate; however, new discoveries suggest that the mast cell may underlie much of the pathology in both these disease syndromes. Amongst these discoveries is the observation that mast cell-deficient mice exhibit significantly reduced disease severity compared to wild-type littermates in a murine model of multiple sclerosis (MS) and drugs that block mast cell function can improve clinical symptoms in this model. In addition, gene microarray analysis has revealed that the expression of several mast cell-specific genes is increased in the central nervous system plaques of MS patients. Although well established as effector cells in allergic inflammation, the location of mast cells and the wealth of inflammatory mediators they express make it likely that they have profound effects on many other autoimmune processes.

Mechanisms underlying mast cell influence on EAE disease course.

It is well established that CD4(+) T cells are of central importance in mediating the autoimmune destruction associated with the neurological demyelinating disease Multiple sclerosis (MS) and the rodent model of MS, EAE (experimental allergic encephalomyelitis). However, other cells also play a critical role in the inflammatory events that lead to the varying degrees of myelin and axonal damage observed in this disease syndrome. In this review, we present evidence that mast cells, best studied in the context of allergic disease, contribute to EAE disease pathology. Using mast cell-deficient mice, we demonstrate that mast cells are necessary for the full manifestation of MOG-induced EAE disease and show that cross-linking of Fc receptors is one mechanism of mast cell activation in disease. In addition, we provide evidence that mast cells exert influences outside the CNS, perhaps through the effects on the generation of the anti-MOG T cell response.