Jolene Clarke

Identification of an autoantibody to vascular endothelial cell-specific antigens in patients with systemic vasculitis

PURPOSE Although immunologic mechanisms have been postulated in the pathogenesis of vasculitis, an autoimmune process directed against specific autologous vascular wall antigens has not been previously documented. We examined the role of an immunologic response to vascular endothelial cell (VEC) antigens in patients with vasculitis, because of the observed immunogenicity of VECs in renal and cardiac allograft recipients. PATIENTS AND METHODS The study patients included 21 with systemic vasculitis and four with hypersensitivity vasculitis. A healthy, normal control group consisted of 51 young subjects and 61 older subjects. Thirty-two patients with connective tissue diseases were also evaluated. The presence of autoantibody to autologous monocytes and other cell types was determined with previously described standard crossmatch techniques. Patient sera exhibiting autoantibody to autologous monocytes were screened against a panel of allogeneic cells. The cell panel consisted of concordant T and B lymphocytes, monocytes, and VECs from 16 umbilical cord donors. Sera from four patients were analyzed for specificity to the vascular endothelium of frozen sections of vessels. RESULTS An autoantibody to VEC antigens was detected in 18 of the 21 patients (86%) with confirmed systemic vasculitis, not of the hypersensitivity type. This autoantibody was highly cytotoxic, complement-fixing, and specific for antigens on the surface of the VEC. Findings on allogeneic VEC panel analysis support the existence of multiple allotypes in the VEC antigen system. In three patients, fluctuations in the titer of the autoantibody generally correlated with clinical symptoms. In the four patients screened for the specificity of the autoantibody to anatomically different cadaveric blood vessels, specific anatomic patterns of reactivity were observed. Autoantibody to VEC antigens was not found in young controls and was documented in low frequency in older controls and in patients with connective tissue diseases. The autoantibody was seen in one of four patients (25%) with hypersensitivity vasculitis. CONCLUSION Our results indicate that an autoantibody to VEC antigens may be involved in the pathogenesis of systemic vasculitis or may be a diagnostic marker for the disease process.

The Vascular Endothelial Cell Antigen System

Vascular endothelial cells (VEC) are clearly immunogenic and express antigens unique to vascular endothelial cells. The observation that peripheral blood monocytes also express this VEC antigen system made prospective testing feasible. Preformed antibody to the VEC/monocyte antigen system of the donor usually leads to graft rejection in HLA-identical combinations, but antibody directed against donor monocytes exclusively (monocyte-specific antigens) appears to be benign. Clearly the VEC antigen system is an important immunogen in HLA-identical living-related donor combinations—and, in addition, this antigen system may be equally important in the non-HLA-identical combinations. The identification of antibody directed against the VEC/monocyte antigens of the donor is frequently masked by the concurrent developmetn of anti-HLA antibody. Preliminary family segregation studies support the concept of genetic linkage between the VEC/monocyte antigen system and the major histocompatibility complex. A group of 153 consecutive, prospective monocyte crossmatches performed have yielded approximately a 7% incidence of positive monocyte crossmatches, with traditional crossmatches being negative. This frequency of patients sensitized to the VEC/monocyte antigens of the donor could conceivably account for up to 70% of the observed early graft loss in living-related donors. We think a positive monocyte crossmatch to the donor in the presence of positive reactivity to concordant VEC and monocytes remains a contraindication to transplantation.

Identification of the antibody to vascular endothelial cells in patients undergoing cardiac transplantation

Acute cardiac dysfunction occurred in four cardiac allograft recipients with negative donor-specific lymphocyte crossmatches. In two recipients the transplanted heart was removed and the patients were maintained on bypass for several hours until a second cardiac allograft was available. In these patients the second transplanted heart also underwent acute dysfunction. The lymphocyte crossmatch was again negative in both second transplants. Two of the four recipients had no detectable antibody to a panel of lymphocytes. Examination of the hearts demonstrated histologic findings consistent with hyperacute rejection. Direct immunofluorescence performed on the transplanted hearts revealed the presence of immunoglobulin and complement deposited on the vascular endothelium. Pathology data was available on 3 of the 4 patients who experienced acute cardiac dysfunction. Pretransplant sera from these four recipients were screened for the presence of antivascular endothelial cell (VEC) antibody. The sera from all four recipients were found to contain antibody against an endothelial cell panel. In addition, donor-specific aorta and vena cava were available from one of the heart donors. The recipient was found to have donor-specific antibody to VEC. Thus, antibody directed against VEC specific antigens appears to be related to hyperacute rejection of heart allografts.

The significance of a donor-specific vessel crossmatch in renal transplantation.

Very early graft rejection is usually attributed to pretransplant sensitization to HLA antigens represented on the lymphocyte. However, it is possible that such rejection episodes are secondary to antibody to a transplant-relevant system that is not represented on the lymphocyte but is represented within the allograft. This study suggests that sensitization to antigens on the VEC is detrimental to allograft success and can occur in the absence of sensitization to HLA antigens on the T or B cell or monocyte. When antibody to donor VEC is not present pretransplant, almost all patients (95%) will have a very benign posttransplant clinical course. When anti VEC antibody is present, early graft rejection or severe rejection episodes occur with a very high frequency (80%) in the nondiabetic patient. These observations, therefore, suggest that the pretransplant presence of antibody to VEC is detrimental to graft survival, and that such antibody can develop in the absence of anti HLA antibody. While the presence of such antibody is not an absolute contraindication to transplantation it does appear to represent a significant risk factor for immunological graft loss.