Jeremy D Pearson and Sarah E Riley

Cardiovascular Division, King's College London, Guy's Campus, London, United Kingdom

Patients with a variety of diseases involving damage to small and large blood vessels, unlike healthy controls, have circulating antibodies that bind to endothelial cells. These autoantibodies constitute a marker of the extent of disease activity and increasingly have been implicated as contributing to the pathogenesis of several of these diseases.

Autoimmune Diseases and Autoantibodies

Autoimmune diseases are those in which clinical problems are due to dysregulation of the patient's immune system in the absence of ongoing infection, and they are characterized by the presence of autoantibodies, that is, antibodies that react with self-antigens. Autoimmune diseases arise in susceptible individuals due to variations in the ability of T and/or B lymphocytes to be activated or to undergo apoptosis—this variation presumably usually being genetically determined, and often involving inappropriate expression of cytokines—coupled with exposure to an environmental trigger, often unknown in individual cases but including microbial antigens and drugs.

Two processes are considered to be important in the generation of autoantibodies: molecular mimicry and epitope spreading. The former implies that the initial antibody formation is directed at epitopes of foreign antigens that are sufficiently similar to epitopes of self-antigens that they cross-react with them. The latter is well documented, though not fully understood, and describes how the repertoire of epitopes recognized increases with time to encompass a wider variety of self-antigens, probably due to B cell processing of the initial antigenic complexes leading to presentation of previously cryptic peptides to T cells. The identified self-antigens recognized in autoimmune diseases are commonly intracellular, often intranuclear, proteins, perhaps exposed during apoptosis. In the systemic autoimmune diseases the pattern of autoantibodies found is highly characteristic of each disease and often allows subsetting with prognostic implications. Both autoreactive T cells and autoantibodies can damage tissues, though the extent to which autoantibodies are markers of disease extent rather than pathogenic remains debatable.

Anti-endothelial Cell Autoantibodies (AECAs)

Over the past 20 years it has become apparent that AECAs are present in a significant proportion of patients with a wide variety of autoimmune diseases that include a vascular pathology. In addition, AECAs have been detected in patients with advanced atherosclerosis, and antibodies that target donor endothelium have been implicated in the process of chronic rejection of transplanted tissues and organs. One of the first suggestions that AECAs are involved in microvascular pathology was made by Shingu and Hurd in 1981, who reported that immunoglobulins (Ig) from the sera of some patients with the autoimmune disease systemic lupus erythematosus (SLE), but not Ig from healthy controls, bound selectively to cultured endothelial cells. The patients whose Ig bound to endothelium were those who had clinical evidence of inflammatory damage to blood vessels (vasculitis), indicating a possible causal relationship.

Since then, AECAs, mainly IgG or IgM, have been detected in patients with many different diseases where damage to blood vessels is occurring, ranging from primary systemic vasculitic diseases (such as Wegener's granulo-matosis and microscopic polyangiitis) and connective tissue diseases (notably systemic sclerosis, also known as sclero-derma) to thrombotic disorders (such as hemolytic uremic syndrome and anti-phospholipid syndrome) and multiple sclerosis. AECAs are usually detected by their ability to bind to cultured human endothelial cells, and although estimates vary it seems likely that between a third and two thirds of patients with a systemic vasculitic disease, SLE, or scleroderma have detectable AECAs.

As noted earlier, patients with systemic autoimmune diseases have autoantibodies to a wide variety of target proteins, with particular signature autoantibodies defining clinical subsets of the diseases and often being valuable in prognosis. AECAs are in general distinct from these signature autoantibodies. The endothelial cell specificity of AECAs is less rigorously defined; it is clear that AECAs do not recognize target antigens on blood cells, but it is less certain that they cannot additionally recognize antigens present in some other cell types or in the extracellular matrix. However, since they are found in the context of vascular damage, it is reasonable to assume that AECAs either contribute to causing the damage or at the least arise as a consequence of the damage and thus serve as markers of the extent of vascular pathology.

The main difficulty with research in this field has been the lack of characterization of the target antigens recognized by AECAs. In part, this stems from the fact that AECAs are clearly heterogeneous between different diseases and between individuals with a particular disease, and exhibit multiple specificities within individuals. Several investigators have tried to identify target proteins by immunoblotting with purified AECAs, and they have usually found multiple bands on gels and have not molecularly identified any band unequivocally. When IgG AECAs from a series of patients with SLE were used to compete with radiolabeled AECAs from one individual for binding to endothelial cells, some did block and others did not, indicating that binding specificities for the AECAs from different patients are only partially shared. More recent attempts to define the target antigens have used methods such as phage display libraries of endothelial proteins, with some success. For example, Frampton and colleagues showed in 2000 that AECAs from patients with active SLE included Ig that recognized an endothelial cell-selective antigen (plasminogen activator inhibitor type 1).

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