SummaryInfection with gram-negative and gram-positive bacteria remains a leading cause of death in patients with systemic lupus erythematosis (SLE), even in the absence of immunosuppresive therapy. To elucidate the mechanisms that underly the increased risk of infection observed in patients with systemic autoimmunity, we have investigated host defense against bacterial infection in a murine model of autoimmunity, the MRL/Mp-lpr/lpr (MRL/Ipr) mouse. Our previous study implicated transforming growth factor ~ (TGF-/$) in a novel acquired defect in neutrophil function in MRL/lpr but not congenic MRL/Mp-+/+ (MR.L/n) mice (Gresham, H.D., C.J. Ray, and F.K. O'Sullivan. 1991.j. Immunol. 146:3911.) We hypothesized from these observations that MRL/lpr mice would have defects in host defense against bacterial infection and that they would have constitutively higher local and systemic levels of active TGF-/~ which would be responsible, at least in part, for the defect in host defense. We show in this paper that spontaneous elaboration of active TGF-/$ adversely affects host defense against both gram-negative and gram-positive bacterial infection in MRL/1pr mice. Our data indicate that MRL/lpr mice, as compared with congenic MRL/n mice, exhibit decreased survival in response to bacterial infection, that polymorphonuclear leukocytes (PMN) from MR1/lpr mice fail to migrate to the site of infection during the initial stages of infection, that MR.L/lpr mice have a significantly increased bacterial burden at the site of infection and at other tissue sites, and that this increased bacterial growth occurs at a time (>20 h after infection) when PMN influx is greatly enhanced in MRL/lpr mice. Most intriguingly, the alteration in PMN extravasation during the initial stages of infection and failure to restrict bacterial growth in vivo could be duplicated in MRL/n mice with a parenteral injection of active TGF-/51 at the time of bacterial challenge. Moreover, these alterations in host defense, including survival in response to lethal infection, could be ameliorated in MRL/lpr mice by the parenteral administration of a monoclonal antibody that neutralizes the activity of TGF-fi. These data indicate that elaboration of TGF-fi as a result of autoimmune phenomenon suppresses host defense against bacterial infection and that such a mechanism could be responsible for the increased risk of bacterial infection observed in patients with autoimmune diseases.
Infection remains a leading cause of morbidity and mortality in patients with SLE. To investigate this, previously we assessed the host defense status of autoimmune MRL/lpr mice and found that elaboration of active TGF  suppressed neutrophil function and decreased survival in response to Staphylococcus aureus infection. The purpose of the present work was to elucidate the molecular form and the cellular source of the active TGF  involved. Here, we report for the first time that TGF  1 is found in the active form inside B cells and plasma cells and that it circulates in the plasma complexed with IgG in two murine models of systemic autoimmunity and in some patients with SLE. IgG-bound active TGF  1 is many times more potent than uncomplexed active TGF  1 for suppression of neutrophil function in vitro and host defense against S. aureus infection in vivo. These data indicate that TGF  1 is in the active form inside B cells and plasma cells, that the formation of a complex of IgG and active TGF  1 is greatly accelerated in autoimmunity, and that this complex is extremely potent for suppression of PMN function and host defense against bacterial infection. ( J. Clin. Invest. 1996. 98:2496-2506.)
MRLfl mice spontaneously develop a hindlimb arthropathy, as well as a number of immunologic abnormalities, including circulating rheumatoid factors. Although previous studies have suggested that this arthropathy is primarily an inflammatory process, we performed a comprehensive histomorphologic study which indicated that inflammation is a late manifestation of MRL/I arthritis. The pathologic changes that occur in the joints of these mice can be divided into 3 stages. The first stage develops between the ages of 7 and 13 weeks and consists of synovial cell proliferation in the joint ,recesses. The second stage is characterized by continued proliferation of synovial cells which take on an appearance similar to that of transformed mesenchyma1 cells. The earliest destructive changes occur in the second stage and include marginal erosions, followed soon after by progressive destruction of articular and meniscal cartilage. The final stage is characterized by a diminution of synovial cell proliferation, extensive cartilage destruction, formation of scar tissue and fibrocartilage, and a very moderate infiltration of the synovial stroma by mononuclear and polymorphonuclear inflammatory cells. Throughout the disease progression there is a striking dissociation between inflammatory cell infiltration or exudation and tissue destruction. The histomorphologic similarities between human rheumatoid synovitis and the arthritis of MRL/I mice, as well as the presence of rheumatoid factors, make this mouse strain an excellent model for studying human rheumatoid arthritis.Historically, the joint destruction which occurs in rheumatoid arthritis (RA) has been attributed to complex cellular interactions among acute and chronic inflammatory cells, proliferating synovial lining cells, chondrocytes, macrophages and other monocytic modulatory cells, and to the production of a variety of humoral factors such as proteolytic enzymes and soluble mediators (1-3). However, the elucidation of the precise mechanisms of destruction has been ham-' pered by the lack of an appropriate spontaneous animal model. Until recently, the only available animal models have been based on the induction of inflammatory synovitis by a variety of exogenous agents (4-7). However, the development of the MRLA mouse strain by Murphy and Roths (8) has addressed this problem. These mice, already useful as a model for SLE (9), spontaneously develop inflammatory arthritis o$ the hindlimbs, possess serum IgG and IgM rheumhtoid factors (lO,ll), and develop antibodies to types'I and I1 collagen (12), thus exhibiting the combined morphologic and immunologic similarities to the hu,man disease that experimentally-induced arthritides lack
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