Potential Pathogenic Roles for AECAs

The spectrum of autoantibodies present in patients with autoimmune diseases provides diagnostic utility and must also in principle provide information about the mechanisms underlying the disease process. In several instances, it is also certain that these autoantibodies play a causal role in pathogenesis (e.g., myasthenia gravis, autoimmune thyroid disease). A pathogenic role for AECAs is less certain, and it may well be that in some diseases AECAs arise as the consequence of vascular damage, which exposes epitopes not usually visible to the immune system, and thus they are simply markers of the extent of vascular pathology. However, there is good evidence that other autoantibodies in systemic vasculitic diseases are pathogenic—notably anti-neutrophil cytoplasmic antibodies (ANCAs)—and increasing evidence that AECAs have effects that are consistent with a role in pathogenesis in the diseases where they are detected.

A pathogenic role for AECAs was first demonstrated in patients with Kawasaki disease, an acute childhood autoimmune vasculitis almost certainly triggered by infection. If not recognized and promptly treated, these children suffer from blood vessel damage that can lead to fatal aneurysm formation. In the mid-1980s Leung and colleagues discovered that sera from patients during the active phase of Kawasaki disease contained Ig that in the presence of complement were selectively cytotoxic to cultured endothelial cells that had been pretreated with proinflammatory cytokines. There is now extensive knowledge of the wide range of changes in endothelial cell functions induced by cytokines such as interleukin-1 (IL-1), tumor necrosis factor, and interferon-g during the acute inflammatory response, notably including the upregulation of a series of cell surface molecules involved in leukocyte adhesion. Thus it is likely that the AECAs in Kawasaki disease (where the patients have raised circulating levels of these cytokines) recognize one or more newly expressed endothelial cell surface antigens and contribute directly to the vascular damage. More recent work, using a cell binding assay rather than a cell killing assay, supported this hypothesis by showing that sera from patients with Kawasaki disease contain AECAs that bind to unstimulated endothelial cells in culture, but AECA binding is significantly increased after treatment of the endothelial cells with proinflammatory cytokines.

AECAs detected in other systemic autoimmune vas-culitic diseases or in scleroderma are not usually cytotoxic to cultured endothelium, whether in the presence of complement or in that of leukocytes. As in Kawasaki disease, however, AECAs from patients with Wegener's granulomatosis bind more strongly to cytokine-pretreated endothelial cells. In addition, there is increasing experimental evidence that these AECAs may be pathogenic, by themselves altering endothelial cell phenotype in a proinflammatory or pro-thrombotic manner similar to the effects caused by defined proinflammatory cytokines. Early indications included the demonstration that Ig from SLE patients can either directly induce or enhance the ability of tumor necrosis factor to induce the expression of the procoagulant tissue factor on endothelial cells in culture. More recently, a series of studies has demonstrated that pretreatment of cultured endothe-lial cells with AECAs from patients with SLE, systemic vasculitis, or scleroderma causes the subsequent upregula-tion of leukocyte adhesion molecules including E-selectin and VCAM on the endothelial cell surface, comparable to the effects of pretreating with IL-1 or bacterial endotoxin (see Figure 1). Indeed, Carvalho and coworkers were able to show that the majority of this effect was due to the induction by AECAs of endogenous IL-1 synthesis in the endothelial cells, which then acts in an autocrine or paracrine fashion to induce adhesion molecule expression.

As noted previously, the target antigens recognized by AECAs are not well described. However, in SLE one of the signature autoantibodies in a subset of patients recognizes

Igg Subsets Human Serum

0 100 250 500 1000

Figure 1 Pretreatment of cultured human umbilical vein endothelial cells with IgG from AECA-positive sera, but not from AECA-negative or normal sera, dose-dependently induces leukocyte adhesion. Endothelial cells were preincubated with IgG for 6 hours. After rinsing, U937 cells were added and adhesion was measured after 30 minutes. Results are expressed as a percentage of added cells that adhered and show means ± SEM from four to six observations. (■) IgG from AECA-positive scleroderma serum; (•) IgG from AECA-negative scleroderma serum; (O) IgG from another AECA-negative scleroderma serum; (□) IgG from normal serum. Reproduced with permission from Carvalho et al. (1996). J. Clin. Invest. 97, 111-119.

b2-glycoprotein-I. These autoantibodies are associated with increased prothrombotic risk. Since they can bind to endothelial cell surface b2-glycoprotein-I, they are likely to contribute to the procoagulant effects of AECAs in SLE noted earlier, and purified anti-b2-glycoprotein-I antibodies have, like other AECAs, been found to enhance adhesion molecule expression on endothelium.

Finally, it is worth pointing out that AECAs unrelated to differences between graft and host major histocompatibility (MHC) antigens have been implicated in both acute and chronic graft rejection. As in autoimmune vasculitic diseases, the target antigens recognized by AECAs seem to be variable between patients and are poorly identified. Careful research, particularly by Pober and colleagues, has shown that endothelial cells, unlike other tissue cells, are effective at presenting antigens to and stimulating resting memory T cells, though unlike professional antigen-presenting cells such as dendritic cells they do not promote the full differentiation of T cells into cytokine-secreting effector cells. Thus, although resident dendritic cells are undoubtedly important in the process of rejection, graft endothelial cells are also likely to be involved.

AECAs will improve our understanding of the pathogenesis of autoimmune vasculitic diseases, will shed further light on their contribution to organ rejection, and may indicate novel avenues for therapy.


AECAs (anti-endothelial cell antibodies): Autoantibodies frequently detected in patients with small or large blood vessel diseases. Bind to endothelium but have poorly characterized antigenic specificity.

ANCAs (anti-neutrophil cytoplasmic antibodies): Autoantibodies to defined neutrophil secretory granule proteins, with proven pathogenic role in small-vessel vasculitic diseases.

Cytokines: Secreted proteins with receptor-mediated pro- or antiinflammatory effects on target cells.

Vasculitis: Inflammatory disease characterized by leukocyte infiltration of the walls of small or large blood vessels and consequent vascular damage.


Armitage, J. D., Homer-Vanniasinkam, S., and Lindsey, N. J. (2004). The role of endothelial cell reactive antibodies in peripheral vascular disease. Autoimmun. Rev. 3, 39-44. Covers in more detail several of the topics in this article.

Carvalho, D., Savage, C. O., Black, C. M., and Pearson, J. D. (1996). IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J. Clin. Invest. 97, 111-119.

Davidson, A., and Diamond, B. (2001). Autoimmune diseases. N. Engl. J. Med. 345, 340-350. Excellent general overview of the topic.

Frampton, G., Moriya, S., Pearson, J. D., Isenberg, D. A., Ward, F. J., Smith, T. A., Panayiotou, A., Staines, N. A., and Murphy, J. J. (2000). Identification of candidate endothelial cell autoantigens in systemic lupus erythematosus using a molecular cloning strategy: A role for ribo-somal P protein P0 as an endothelial cell autoantigen. Rheumatology 39, 1114-1120.

Leung, D. Y. M., Collins, T., Lapierre, L. A., Geha, R. S., and Pober, J. S. (1986). Immunoglobulin M antibodies present in the acute phase of Kawasaki syndrome lyse cultured vascular endothelial cells stimulated by gamma interferon. J. Clin. Invest. 77, 1428-1435.

Pober, J. S., Kluger, M. S., and Schechner, J. S. (2001). Human endothelial cell presentation of antigen and the homing of memory/effector T cells to skin. Ann. N. Y. Acad. Sci. 941, 12-25. Additionally reviews background evidence for endothelial cell presentation of antigen to and activation of T cells.

Rose, M. L. (1998). Endothelial cells as antigen-presenting cells: Role in human transplant rejection. Cell. Mol. Life Sci. 54, 965-978.

Rosenbaum, J. R., Pottinger, B. E., Woo, P., Black, C. M., Loizou, S., Byron, M. A., and Pearson, J. D. (1988). Measurement and characterization of circulating anti-endothelial IgG in connective tissue diseases. Clin. Exp. Immunol. 72, 450-456.

Savage, C. O. (2002). The evolving pathogenesis of systemic vasculitis. Clin. Med. 2, 458-464. Reviews the pathogenic role of ANCAs in vas-culitis and also emphasizes the role of endothelial cell activation.


AECAs contribute to the pathogenesis of vascular damage in autoimmune microvascular diseases, though the mechanisms involved and the target antigens recognized by AECAs are in general poorly defined. Future research on

Capsule Biography

Jeremy Pearson is Professor of Vascular Biology at King's College London and Sarah Riley is his graduate student. Dr. Pearson's primary research interests are in endothelial cell pathophysiology, notably intracel-lular signaling and secretory responses to inflammatory mediators, and interactions with leukocytes.

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