Circulating immune complexes in diabetes.

Abstract

Over the last few years more sensitive, reproducible and in some instances more specific techniques for the detection of circulating immune complexes (AgAb) have been developed [1-4]. Using these newer techniques immunological aspects of various diseases have been reappraised, and the presence of AgAb in diabetes has also been investigated. The interest in immune phenomena in diabetes has been increasing progressively. In the 1960s several studies, originating from the immunological implications of heterologous insulin administration, suggested that immune mechanisms could be of importance in the aetiology of diabetic microangiopathy. Morphological similarities with other immunological disorders were described [5-7], immune components were found in microangiopathic vessels [8-11], and diabeticlike lesions were experimentally induced by immune mechanisms especially in the renal glomeruli [12-14]. In the 1970s works by different authors provided a completely new outlook on the pathogenesis of insulin dependent diabetes. Clinical studies had shown a suggestive relationship between insulindependent diabetes and other organ specific autoimmune diseases [15, 16]. It was then reported that in insulin-dependent diabetes [17-18] there was a modification in the cell-mediated immune response [19-21], an association with particular HLA antigens [22-24], and finally the presence of autoantibodies against islet cells was demonstrated [25-27]. In 1977 Irvine et al. using a single sensitive method [28] reported an increase in circulating immune complexes (AgAb) in some insulin-dependent diabetics at the time of diagnosis as well as in treated diabetics. Since then other investigators have confirmed an increase in AgAb in many diabetics, and have shown a correlation between the presence of AgAb and various diabetic conditions [29-39]. Before proceeding further it is necessary to delineate precisely what can be measured by the AgAb methods. The solid phase CIq binding test, the Raji cell radioimmune assay and the conglutinin binding assay are some of the most sensitive techniques presently available [4, 40]. These methods are antigen non specific and may be influenced by immunoglobulin aggregates but not by DNA, bacterial endotoxins and heat induced aggregates. The CIq method detects mainly complexes in antigen excess through the Fc portion of immunoglobulin aggregates, whilst the other two methods reveal complexes near the equivalence point, mostly through the third component of the complement. The complexes detected by all these methods are potentially harmful since they may activate the complement system or react with those cells bearing receptors for complexed immunoglobulins or the complex bound complement (namely lymphocytes and macrophages). The antigens involved in the complex formation may be either part of a cell membrane and secondarily shed into the circulation as a complex or non-cellbound antigens. In the latter situation complexes may be formed either in the circulation, with subsequent localisation in vessel walls or perivascular tissues, or locally in certain organs or tissues. As the methods presently available do not distinguish between complexes related to specific disease processes and those found in other more common conditions, e.g. viral infections, it is not surprising that circulating AgAb are also found in some apparently healthy subjects. Thus in evaluating the presence of AgAb in a particular disease it is important to compare the results with those found in a large normal population and to select an appropriate limit of positivity [41]. Differences in these basic points may explain some of the discrepancies between the various reported data. In 1978 the increase in circulating AgAb in newly diagnosed insulin-dependent diabetics was confirmed in a large series of patients compared with agematched healthy controls using two different and sensitive methods [35]. In most of the patients AgAb