Islet cell autoantibodies: a case of a premature obituary

Samuel Clemmons, more commonly recognized as the author Mark Twain, is widely known to have quipped after reading his own obituary, ‘‘. the report of my death was an exaggeration’’. We believe the notion underlying this quote is one that is especially well fitting for the current and, moreover, unfortunate perception regarding one form of autoantibody associated with type 1 diabetes, that being the islet cell cytoplasmic autoantibody (ICA). Since their initial description in the early 1970s, ICAs have widely been accepted as the gold standard for confirming the diagnosis of type 1 diabetes. Furthermore, their presence in non-diabetic relatives of type 1 diabetic probands as well as in those from the general population has also served to identify subjects with a significantly elevated risk for the development of the disorder. These autoantibodies are identified in serum samples by indirect immunofluorescence testing using blood group O human pancreas as a substrate. ICAs are polyclonal autoantibodies that react with all cells of the islet (i.e., a, b, d, and pancreatic polypeptide cells). Early efforts to define the molecule(s) to which ICA reacts within islets suggested antigens that were glycosphingolipid in nature. Additional attempts over the years seeking to identify the self-antigens to which type 1 diabetes-associated autoantibodies react, including those of ICA, have resulted in the identification of over two dozen putative targets. While that list is long, over time, only four autoantibodies have proven themselves popular as diagnostic or predictive markers of the disease: ICAs, insulin autoantibodies (IAAs), glutamic acid decarboxylase autoantibodies (GADAs), and autoantibodies to a transmembrane protein of the protein tyrosine phosphatase family known as insulinomaassociated-2 autoantibodies (IA-2As or ICA512As). The identification of the latter three biochemical autoantibodies has been one of the more promising success stories in modern type 1 diabetes research, as knowledge of the biochemical nature for the autoantigens to which these autoantibodies react has afforded many practical and logistical benefits. Indeed, high throughput assays (most often radioimmunoassays yet in rare instances, ELISA assays) have been developed for GADA, IA-2A, and IAA, an advance that portended improved quality assurance, reproducibility, automation, and standardization. As a result, many laboratories over the past few years have either completely done away with or, in the more conservative of stances, are slowly transitioning away from determination of ICA. At one level, the rationale for such a change makes sense; the ICA assay is certainly labor-intensive, nonautomated, requires donor human pancreas (a major limitation in and of itself) and necessitates a very high level of quality assurance and quality control to produce accurate and precise results. Many research efforts utilizing biochemical autoantibodies (rather than ICA) have been conducted, the collective body of which safely indicates that the presence of biochemical autoantibodies, especially when multiple in number within an individual, confers increased risk for development of type 1 diabetes. For example, in the Seattle (USA) Family Study, an effort which included screening of first-degree relatives of type 1 diabetes probands, GADA predicted a 50% 5-year risk for the development of type 1 diabetes (1). In a similar family study in Munich (Germany), GADA-positive relatives demonstrated a 56% 5-year risk for developing type 1 diabetes vs. a 24% risk in GADA-negative relatives (2). Nevertheless, Schmidli et al. (3) showed that GADAs in the absence of ICAs and IAAs were uncommon in first-degree relatives progressing to disease, and the presence of GADA did not increase the risk in ICA negative relatives. In the same Germany family study, IA-2A-positive relatives had a 64% 5-year risk for type 1 diabetes vs. a 13% risk in IA-2A-negative relatives. However, the manuscript by Peitropaolo in this issue (4) places into question the rationale underlying what appears to be, from our viewpoint, the gradual extinction of ICA testing. What evidence does this group present that is so novel to draw a stop to this process? The first issue involves antigens that comprise ICA reactivity. For the last decade, it has been generally accepted that both lipid and protein autoantigens are Pediatric Diabetes 2005: 6: 181–183 # 2005 The Authors Journal compilation # 2005 Blackwell Munksgaard All rights reserved