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β-Cell Damage in Diabetic Insulitis: Are We Approaching A Diabetologia (1984) 26:241-249 Diabetologia Springer-Verlag 1984 Review articles [I-Cell damage in diabetic insulitis: are we approaching a solution?* Gian Franco Bottazzo Department of Immunology, Middlesex Hospital Medical School, London, UK Several laboratories had previously tried to identify Key words: Type 1 diabetes, insulitis, autoimmunity, islet cell specific ICA in Type 1 (insulin-dependent) diabetic pat- antibody, cell-mediated immunity. ients. However, their efforts proved unsuccessful. His- torically it is of interest to recall that the patients tested in these initial attempts had been diabetic for many years and that the majority of them had no other overt Was it a pure coincidence or a genetically determined endocrine abnormalities [4]. In retrospect it is also trait which led to the original description of islet-cell an- worth noting that the introduction of Ploem's epi-illu- tibodies? Whatever the answer to this intriguing ques- mination system for ultraviolet microscopy, together tion, the fact is that the young researcher who observed with the availability of fresh normal blood group O hu- the reaction under an ultraviolet microscope was born man pancreas from kidney donors, greatly improved in Venice. He was immediately attracted by the green the sensitivity of the immunofluorescence test for ICA. fluorescent shape of the islets of Langerhans, standing Based on the previous negative findings and on the low out brightly against the dark background of the sur- prevalence of ICA in long-standing diabetes, which rounding exocrine pancreatic acini, much as the islands could now be confirmed, both our group and that based of his native city stand out against the dark blue waters in Edinburgh [5] concluded that ICA were found main- of the Venetian Lagoon. In the initiation of this saga, ly in a rare subgroup of diabetic subjects. the 'geographical' genetic influences of Alex Florin- By definition, medical science is a dynamic disci- Christensen, born in Buenos Aires of a Danish/Spanish pline which accepts new findings reluctantly unless they ancestry, and of Deborah Doniach, born in Geneva of are fully substantiated. In the early 1970% the British mixed Russian parentage, remain to be established. Diabetic Association established a register of newly dia- Nevertheless their contributions to it were very real. gnosed diabetic children. This scheme was set up pri- Islet cell antibodies (ICA) were first detected in pat- marily to investigate the epidemiology of the disease ients suffering from 'Schmidt's syndrome', an uncom- throughout the United Kingdom and to study the possi- mon polyendocrine disease centred on adrenocortical ble role of viral infections in its causation [6]. It was insufficiency caused by autoimmune adrenalitis [1]. In- thanks to the availability of a large number of sera col- terestingly enough, the sera of these patients were al- lected from diabetic children within weeks of initial dia- ready known to contain multiple autoantibodies to en- gnosis that Richard Lendrum and his colleagues were, docrine glands, and they were also the first sera which surprisingly, able to demonstrate ICA in this material. later were found to react specifically with prolactin cells The reactions were similar to those found in polyendo- in the human pituitary gland [21. These findings gave a crine cases [7]. The negative results obtained previously clear indication that autoimmune processes can be im- in patients with long-standing disease were soon ex- plicated in lesions affecting the pituitary. Previous ob- plained by the subsequent demonstration that in a large servations on 'lymphocytic hypophysitis' were based proportion of diabetic children ICA tended to disap- entirely upon post mortem material and retrospective pear from the circulation within months, or at least clinical deductions tinged with speculations of possible within the first few years, after onset of symptoms. In autoimmunity [3]. classical 'endocrine autoimmunity', specific humoral and cell-mediated immune phenomena tend to persist for many years, even when the affected gland is largely * Based on the Minkowski Lecture delivered at the 18thAnnual Meet- atrophic. We now know that in polyendocrine diabetes ing of the EASD, Budapest, September 1982 there is a slower destruction of the pancreatic islets with 242 G. F. Bottazzo: t-Cell damagein diabeticinsulitis residual C-peptide secretion persisting for some years. Islet cell surface antibodies (ICSA) are detected on By contrast, in so-called 'juvenile' Type 1 diabetic pat- viable cultured human fetal [20] or adult animal pan- ients, only a minority show persistence of various im- creas [21], and here too separate specificities exist for a mune reactions to islet cells over a period of years. This and/3 cells as shown by Van de Winkel et al. [22]. These small minority also has clinical and serological features authors used a cell-sorter to separate ICSA-positive often described in polyendocrine autoimmunity [8]. cells. In addition to the reactions specific for a,/3, and These early results sustained the credibility of the con- cells, they identified a small number of sera containing cept that Type I diabetes was a heterogeneous groul~ of surface reactive antibodies to 'pancreatic polypeptide' disorders and that several causes must be implicated in (PP) cells. Antibodies to these cells have not been de- the initiation of the/3 cell damage [9]. tected so far on cryostat sections, probably because it is 1974 and 1975 were exciting years in diabetes re- necessary to employ the dorsal portion of the head of search and the work accomplished in several laborato- the pancreas known to be rich in PP cells (the PP lobe ries laid the foundations for the subsequent expansion described by Orci [23]). By analogy with the surface ex- of this chapter in human pathology [10, 11]. pression of other organ-specific 'microsomal' systems, such as the thyroid, gastric, or adrenal, in which the cy- toplasmic autoantigens are also expressed on the cell surface [24], it is probable that some 'selective' CF-ICA Humoral immunity in diabetes represent the cytoplasmic portion of those ICSA that react with/3 cells and are therefore cytotoxic to cultured ICA are organ-specific for endocrine pancreas, they animal islets, or interfere with glucose-stimulated insu- cross-react with other species, and they are invariably of lin secretion in these cultures [25]. However, islet-cell IgG class. Several antigens, including some that are pre- surface staining is obtained in about 30% of diabetic sent only in/3 cells, are now envisaged in what is basical- sera that give negative results on sections [26]. This ly a polyclonal autoimmune response with subclass res- strongly suggests the involvement of an additional anti- trictions [12]. The antibodies may be complement fixing gen that is expressed entirely on the plasma membrane (CF-ICA) and this is a separate variant [13]. The more of/3 cells. These data support the existence of multiple common ICA are not able to fix complement (ICA- antibodies specific to different islet antigens, and it is IgG). As the islet-cell antigens have not yet been isolat- only when the antigens are isolated and characterized ed and are at present only partially characterized [14], that we will be in a position to study their effects sepa- cytoplasmic ICA are still normally detected by standard rately. The 'monoclonal revolution' has already pro- indirect immunofluorescence. Unfixed group O human duced hybrid clones that permit the analysis of human pancreas is still the substrate of choice [15]. Fixed pan- polyclonal antibody mixtures in 'receptor' diseases, creas substrates give controversial readings, especially such as myasthenia gravis and thyrotoxicosis. in complement-fixation immunofluorescence tests with anti-C3 conjugates used to detect CF-ICA [16]. In the screening test, ICA-IgG reacts with all four Humoral immunity in predisposed individuals endocrine cells of the islet [17]. This 'shared' autoanti- gen is not represented on the cell surface and therefore Because Type 1 diabetes often starts as an abrupt illness, cannot be in direct contact with sensitized lymphocytes it was a surprise to discover, by regular testing of 'unaf- in the living gland. Since circulating antibodies exert fected' relatives of diabetic children, that autoimmune cytotoxic effects through complement-dependent phenomena exist for years in some siblings who are mechanisms, extensive parallel tests for ICA-IgG and HLA-identical or haplo-identical with the proband CF-ICA have been undertaken. In all diabetic groups (and thus have probably inherited the diabetogenic tested, only half the ICA fixed complement [13]. genes), and possess CF-ICA during the latency period Most interestingly, CF-ICA also constituted about [27]. These siblings proved to be the most vulnerable for half the total ICA-IgG reactivity in healthy, genetically future diabetes. predisposed, first-degree relatives of diabetic probands. In the Barts/Windsor/Middlesex Family study, 13 Non-diabetic 'autoimmune endocrine' patients gave of approximately 700 relatives had persistent CF-ICA similar results. In both groups some individuals with and seven of these became diabetic over a follow-up pe- persistent CF-ICA later became diabetic. This led to the riod of 5.5 years. A recent analysis of the family data conclusion that CF-ICA reactions obtained on pancre- showed interesting new features [28]. Five unaffected atic sections include the [~-cell-specific autoantibodies siblings who had CF-ICA for 11-44 months became that are the most relevant markers for ongoing insulitis. negative. A further four siblings had these antibodies in- We now know that some CF-ICA selectively stain/3 termittently for 55-61 months of observation, while one cells [18]. We also found some sera containing comple- unaffected brother has shown this reactivity for over ment-fixing variants specific for glucagon or somatos- 56 months without developing evidence of glucose in- tatin cells. These single-cell antibodies were known to tolerance.
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