Defective Fas ligand-mediated apoptosis predisposes to development of a chronic erosive arthritis subsequent toMycoplasma pulmonis infection

Abstract

Objective To determine whether defective T cell apoptosis is associated with the development of a chronic arthritis subsequent to mycoplasma infection, and to determine whether deletion of T cells can prevent the development of this arthritis. Methods B6 wild‐type (B6‐+/+), B6‐lpr/lpr, and B6‐gld/gld mice were infected with Mycoplasma pulmonis. The severity of lymphocytic infiltration and joint damage was evaluated, and the degree of recovery of viable mycoplasma from the spleen and joints was determined. Antigen‐presenting cells derived from Fas mutant lpr mice (lpr‐APC) were transfected ex vivo with an adenovirus (Ad) vector to yield lpr‐APC expressing high levels of Fas ligand (lpr‐APC‐AdFasL), which in turn were transferred intraperitoneally into M pulmonis–infected B6‐gld/gld mice. The development of arthritis subsequent to M pulmonis infection and the induction of apoptosis of cells within the synovial tissue and lymph nodes of lpr‐APC‐AdFasL–treated B6‐gld/gld mice were determined. Results Infection of B6‐lpr/lpr and B6‐gld/gld mice with M pulmonis resulted in an acute‐phase inflammation of the synovium that later developed into a chronic erosive arthritis. Similar infection of B6‐+/+ mice resulted only in an acute joint inflammatory response that resolved. Chronic arthritis in B6‐gld/gld mice and B6‐lpr/lpr was not due to persistent infection, since there were no differences in the rates of clearance of M pulmonis from the joints of B6‐gld/gld or B6‐lpr/lpr mice compared with B6‐+/+ mice. Treatment of infected B6‐gld/gld mice with lpr‐APC‐AdFasL resulted in a significantly decreased incidence of chronic arthritis that was associated with a decrease in lymph node T cells, but not with apoptosis of synovial T cells or fibroblasts. Conclusion Defective Fas/FasL‐mediated apoptosis of T cells is an important factor that rendered arthritis‐resistant B6 mice susceptible to the development of a chronic erosive arthritis subsequent to mycoplasma infection. In vivo lpr‐APC‐AdFasL cell–gene therapy is a safe and effective method for inhibiting the development of this arthritis.

CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis

“…This results in specific induction and elimination of the T cells in the spleen (Figure 6) of the mouse, which prevents their migration into the joint. This is consistent with our previous results using a macrophage-derived APC-FasL cell gene therapy to prevent the development of arthritis in other murine arthritis models (16,31). The present strategy is superior to our previous version, however, since DCs are more resistant to apoptosis than macrophages (54).…”

“…We have previously described techniques for modifying APCs so that they express specific Ag's along with FasL and have demonstrated that these modified APCs deleted only those T cells that recognize the specific Ag without causing general immunosuppression (29,30). We previously demonstrated that treatment of mycoplasmas-infected B6-generalized lymphoproliferative disease (gld/gld) mice with adenovirus (Ad) FasLtransfected (AdFasL-transfected) APCs derived from Fas-deficient lpr mice (lpr-APC-AdFasL) resulted in a significantly decreased incidence of chronic arthritis (31). We also have shown previously that normal APCs can be…”

Inhibition of the catalytic function of activation-induced cytidine deaminase promotes apoptosis of germinal center B cells in BXD2 mice

“…Joints (knee, elbow, ankle, and wrist) tissue and sections using the method we previously described (29). Joints were scored by a blinded observer for chronic arthritis damage based on the criteria we described previously (29).…”

Les complications ostéoarticulaires des déficits immunitaires primitifs

“…Dans ces arthrites chroniques, il existe probablement d'autres facteurs immunitaires mal connus qui prédisposent à la chronicité [42]. Récemment, il a été démontré qu'une anomalie de l'apoptose des lymphocytes T peut favoriser l'apparition d'une arthrite chronique dans un modèle murin d'arthrite à mycoplasme [43]. En effet, les souris B6 infectées par Mycoplasma pulmonis ne développent qu'une arthrite transitoire spontanément résolutive [44].…”

“…En réalité, l'effet de ce superantigène n'a été démontré que pour Mycoplasma arthritidis chez la souris [40]. En fait, il est possible que l'activation lymphocytaire soit amplifiée par une dérégulation de l'apoptose comme cela a été démontré dans le modèle d'arthrite expéri-mentale (souris B6/lpr-lpr et B6/gld-gld) décrit pré-cédemment [43] ou par d'autres anomalies de l'immunité cellulaire observées dans certains DIP humoraux (DICV, déficits avec hyperIgM par anomalie du CD40 Ligand), mais cela n'a pas été démontré. -Les mycoplasmes ont la capacité de pénétrer et de persister dans les cellules de l'hôte, en particulier dans les cellules mononucléées et les cellules fibroblastiques [52].…”