Foreword

This series of reviews capture some of the excitement and mystery of antiphospholipid antibodies (aPL) that have intrigued investigators for more than a quarter century. The subject of autoantibodies has fascinated investigators long before aPL were broadly recognised. Perhaps, the most intriguing questions are how, when and why they originate and whether they are merely footprints of the disorder or if they play a prime role in the pathogenesis of the disease. In some ‘organ specific autoimmune disorders’ such as Graves disease or Hashimoto’s thyroiditis, there is reasonable evidence suggesting that autoantibodies may either stimulate or destroy thyroid cells, respectively. In rheumatic heart disease, there is circumstantial evidence that autoantibodies induced by an infectious agent – β-haemolytic streptococcus – may cross-react with heart tissue causing valvular damage. Evidence for autoantibodies playing a role in disease pathogenesis in other autoimmune diseases such as systemic lupus erythematosus, Sjogren’s syndrome or rheumatoid arthritis is probably weaker, and the deposition of immune complexes has been blamed for most of the pathogenicity. One of the most important aspects of studying aPL is that they offer unique and important clues about the role of autoantibodies in disease manifestation. The fact that some of these autoantibodies can inhibit clotting when present in plasma reflects a functional effect not as easily demonstrable for almost any other autoantibody. The really intriguing bit is that these unusual autoantibodies are paradoxically associated with thrombosis rather than bleeding, as one might expect for an autoantibody that demonstrably inhibits clotting in a test tube. The fact that aPL are directly related to thrombosis and recurrent pregnancy loss is amply demonstrated in many animal studies. Human aPL introduced passively into mice or aPL actively induced by a variety of immunogens have been shown to enhance thrombus formation and to promote pregnancy loss. Only few other autoantibodies where such pathogenic effects are as manifest have been reported. This series of publications represent a comprehensive exploration of how aPL might cause the clotting tendency with which they are associated. Modulation of endothelial or platelet function, induction of tissue factor, inhibition of protein C activation or inhibition of fibrinolysis have all been subjects of intense interest as mechanisms responsible for thrombosis. Inhibition of the effect of Annexin A5 or modulation of complement activation has received much recent attention in terms of explaining foetal loss. Not addressed in this series is the question of what induces aPL, an area that has fascinated the investigators. Proteins such as β2-glycoprotein I, human polyclonal aPL, viral proteins and peptide sequences common to these proteins have all been shown to induce aPL in mice. Those viral peptides that can induce these antibodies give credence to the theory that infective agents may play a causative role in some autoimmune disorders. What induces autoantibodies and, once induced, what role they play in disease manifestations are indeed some of the most intriguing questions in medicine today. Understanding the origins and role of aPL may yield valuable answers to both those questions. It is in this context that the articles contained in this special issue of Lupus are important and one hopes that they can excite the interest of future generations of researchers.