Spontaneous elaboration of transforming growth factor beta suppresses host defense against bacterial infection in autoimmune MRL/lpr mice.

Abstract

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.

B7+ Iris Pigment Epithelium Induce CD8+ T Regulatory Cells; Both Suppress CTLA-4+ T Cells

“…TGF␤ is a pleiotropic cytokine/growth factor and its capacity to suppress aspects of immunity is only one dimension of its activities (11)(12)(13). In the absence of TGF␤, mice develop a massive, multifocal inflammatory disease, suggesting a major role for this factor in regulation of both adaptive and innate immunity (26).…”

“…TGF␤ is an immunomodulatory cytokine (11)(12)(13) that has been found to be constitutively present in ocular fluids (3,14) and to be associated with regulatory T cells of different types (15)(16)(17)(18)(19)(20)(21)(22)(23). Suspecting that TGF␤ might be involved in the process by which IPE generate Tregs, we have recently reported that as the CTLA-4 ϩ CD8 ϩ T cells cultured with IPE become B7-expressing IPE Tregs, they secrete enhanced amounts of both latent and active TGF␤ (5).…”

Fas ligand (gld)- and Fas (lpr)-deficient mice do not show alterations in the extravasation or apoptosis of inflammatory neutrophils

“…This alteration in the kinetics of the neutrophil response probably is not a primary effect of deficient FasL-Fas interactions, particularly because inflammatory neutrophils from B6/gld and B6/lpr mice show no difference in their ability to undergo apoptosis in vitro; instead, the altered kinetics is likely to represent a secondary effect of the sequelae of immune alterations that follow the development of autoimmunity in these mice. Studies by Gresham and colleagues [60,61] demonstrate that elevated levels of TGF-␤ produce alterations in neutrophil extravasation to the inflamed peritoneal cavity in MRL/Mp-lpr/lpr mice, when compared to MRL/Mp-ϩ/ϩ mice, which suggests that factors associated with autoimmunity can alter neutrophil responses. The mice used in the current study were on average old enough to be showing signs of autoimmune disease and although no obvious differences were noted between younger and older B6/gld and B6/lpr mice in the kinetics and magnitude of neutrophil extravasation to the TG-inflamed peritoneum, the effects of age and severity of the autoimmune syndrome were not examined directly.…”

Survival of Staphylococcus aureus Inside Neutrophils Contributes to Infection

“…In this study, the total ablation of PMN resulted in decreased survival of the mice and increased bacteremia, suggesting that some numbers of PMN are necessary to provide protection against this pathogen. However, in our studies of TGF-␤-mediated defects in PMN function and host defense against S. aureus infection in autoimmune mice, we noted that decreased survival of the mice correlated with excessive numbers of PMN and an increased bacterial burden at the site of infection (9,10). These data raised the question as to whether the increased numbers of PMN actually contributed to the increased number of organisms.…”