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.

IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation.

T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-gamma is a major product of activated T helper cells that can function as a pro- or antiresorptive cytokine, but the reason why IFN-gamma has variable effects in bone is unknown. Here we show that IFN-gamma blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-alpha.

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.

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).

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.

An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency.

The bone wasting induced by estrogen deficiency is, in part, a consequence of increased T cell production of the osteoclastogenic cytokine TNF-alpha. This phenomenon is due to an expansion of T cells, but the responsible mechanism is unknown. We now show that ovariectomy (ovx) disregulates T lymphopoiesis and induces bone loss by stimulating, through a rise in IL-7 levels, both thymic-dependent differentiation of bone marrow-derived progenitors and thymic-independent, peripheral expansion of mature T cells.

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.

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.

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.

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.