Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado 80262
Address all correspondence and requests for reprints to: George S. Eisenbarth, M.D., Ph.D., Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box B140, Denver, Colorado 80262. E-mail: George.Eisenbarth{at}uchsc.edu.
Autoimmune polyendocrine syndrome type I (APS-I; Ref. 1) is an autosomal recessive syndrome characterized by multiple endocrine and nonendocrine autoimmune diseases accompanied by dystrophy of ectodermal tissue such as enamel hypoplasia and keratoconjunctivitis (2). Patients with APS-I also exhibit a chronic candida infection presumably because of a T-cell defect, but they do not have any other clinical evidence of T-cell immunodeficiency. Here, we discuss the main feature of APS-I and review some of the autoantibodies linked to the autoimmunity associated with this disease. We also describe the cells composing the diffuse endocrine system in the different areas of the gastrointestinal (GI) tract. Finally, we discuss GI dysfunction in APS-I in relation to the study by Sköldberg et al. (3) in this issue of the Journal. The most common endocrine manifestations of APS-I include hypoparathyroidism (2, 4) and Addisons disease (2, 4), but hypogonadism (5), hypothyroidism (6), and type IA (immune-mediated) diabetes can also occur (7).
Most patients with APS-I have a mutation in the AIRE autoimmune regulator gene (8), the recently hypothesized function of which is to enhance thymic expression of peripheral antigens leading to tolerance (9). The causative role of this gene in APS-I is confirmed by a gene knockout mouse model (10) that has a phenotype characterized by multiple autoimmune diseases. Despite the fact that the defect leading to APS-I is inherited in an autosomal recessive manner, the clinical features of the disease are heterogeneous. In general, in this and other polyendocrine autoimmune syndromes, there is a hierarchy in the frequency of different endocrine diseases, reflecting how frequent these diseases are in the general population. A notable exception to this is the frequent occurrence in APS-I of autoimmune hypoparathyroidism, which is rare in the general population.
The clinical manifestations, which occur in individual cases of APS-I, may be determined by additional genes, conferring either susceptibility or protection for specific endocrine disease. An obvious example of such a gene is the HLA DQB1*0602 allele, which protects from the immune-mediated form of diabetes (type 1A) occurring sporadically (11), in association with a neurological disease termed "stiff person syndrome" (12), and for patients with APS-I. A major clinical problem arising from the heterogeneity of APS-I and other polyendocrine syndromes is the necessity to follow affected individuals over time for development of other endocrine diseases. One major feature of endocrine autoimmunity is that it is often accompanied with and preceded by the development of autoantibodies directed to antigens expressed by endocrine cells that are, or in some cases will be, the target of the autoimmune attack. For many endocrine autoimmune diseases, T cells are pathogenetic whereas autoantibody formation is a consequence of cell destruction. However, despite recent advances such as the introduction of tetramer technology (12A ), autoreactive T-cell assays are not sufficiently reliable and reproducible to be offered as clinical tests (13). In contrast, in many instances, the measurement of autoantibodies directed to relevant endocrine and nonendocrine cell autoantigens can now be used to diagnose and, for certain disorders, predict autoimmune disease (14). In type 1A diabetes, fluid phase RIAs to the islet autoantigens GAD, IA-2, and insulin are characterized by high sensitivity and specificity (15).
Therefore, providing that one knows the relevant antigen(s) for a given autoimmune disease, it is potentially feasible to develop highly specific and sensitive fluid phase radioassays. The presence of autoantibodies directed to a single autoantigen often has a low positive predictive value in the general population with its a priori low risk for endocrine autoimmunity. However, in high-risk groups, such as relatives of patients with type 1A diabetes or individuals with a polyendocrine syndrome, autoantibodies to specific antigens are more predictive of specific endocrine diseases. In APS-I, autoantibodies to the islet autoantigen GAD65 are associated with a decreased insulin secretory capacity (16). In addition to GAD65, other autoantigens have been identified in APS. Generally, in APS-I patients, there is a good correlation between the presence of organ-specific autoantibodies and the presence of the endocrine disease targeting that particular organ, although, for instance, even for APS-I patients the presence of multiple anti-islet autoantibodies gives a higher positive predictive value. Among the APS-I-associated diseases for which autoantigens have been characterized are Addisons disease (17), chronic active hepatitis (2), vitiligo (18), type 1A diabetes (15), and hypogonadism (5). In some instances, the autoantigens identified in endocrine disease occurring in the context of APS-I are the same antigens identified in the sporadic form of the disease. For instance, this is the case for autoantibodies reacting with the adrenal enzyme 21-hydroxylase (seen in both sporadic Addisons disease and in Addisons disease associated with APS-I; Ref. 17). In contrast, antibodies directed to the side chain cleavage enzyme (SCC) are predominantly present only in APS-I associated Addisons disease compared with the sporadic form of this condition (19). The autoantibodies directed to GAD in APS-I react with different epitopes compared with the usual autoantibodies found in type IA diabetes (16).
One of the clinical features associated with APS type 1A is gastroenteric dysfunction consisting of malabsorption, constipation. or diarrhea. This has been considered to be a nonendocrine manifestation of APS-I. However, new evidence indicates that an autoimmune attack against the cells of the GI-associated diffuse endocrine system may be responsible for a subset of GI dysfunction in APS.
Endocrine cells are present throughout the GI tract. In the gastric antrum, there are three main types of endocrine cellsG cells producing gastrin (50% of the whole endocrine population in the antrum), enterochromaffin (EC) cells producing serotonin, and D cells producing somatostatin (15%; Ref. 20). In the gastric fundus, the majority of endocrine cells secrete histamine and are termed EC-like (ECL) cells (21). The gastric endocrine cells discharge their granules directly into the lamina propria from where intestinal hormones can enter the blood stream or exert a paracrine effect on the other gastric cells. In the small bowel, endocrine cells are more abundant in the crypts than in the villous epithelium and occur as single cells or discontinuous groupings. Multiple endocrine cell types are present in the small bowel with differing distribution in different regions. The proximal segment of the small bowel contains cells producing cholecystokinin, secretin, gastric inhibitory polypeptide, and motilin (enteroglucagon, substance P, and neurotensin-storing cells are seen more often in the ileum; Ref. 20). Numerous types of endocrine cells are also contained in the colonic crypts. These cells display an opposite polarity compared with goblet cells with granule containing cytoplasm below the nucleus. The different type of colonic endocrine cells includes cells producing peptide YY, glicentin, serotonin, somatostatin, and many other hormones (23, 24).
Figure 1 summarizes the main cell types present in the GI tract. Autoantibodies directed to the neurotransmitter tryptophan hydroxylase have been described in APS-I-associated GI dysfunction (25). This is also associated with destruction of serotonin-producing EC cells.
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In a previous study by Hogenauer et al. (22), GI dysfunction in APS-I patients was associated with loss of colecystokinin-producing cells in the proximal portion of the small intestine. It is possible, therefore, that the autoimmune reaction to intestinal cells in APS is not limited to EC and ECL cells. In this patient the severe malabsorption caused by a deficiency of cholecystokinin was reversible. When this patient had severe malabsorption, postprandial serum cholecystokinin concentrations were not detectable and duodenal biopsy specimens did not contain cholecystokinin cells. However, during episodes of clinical remission of the malabsorption, cholecystokinin concentrations increased normally in response to food and cholecystokinin cells could be identified in the biopsy. This may imply that autoimmunity to GI-associated endocrine cells has a fluctuating pattern resulting in periodical waves of cell destruction. In the case described, clinical improvement probably resulted from the regenerative capacity that intestinal endocrine cells shared with all intestinal crypt-derived cells.
It is likely that additional autoantibody radioassays will be developed for other organ-specific autoimmune diseases in the context of polyendocrine syndromes. In particular, it is possible that GI dysfunction-related antibodies to additional subsets of endocrine GI cells will be identified. This will allow identification of subsets of patients at particular risk for a given autoimmune disease and provide diagnostic information in individuals with unexplained GI dysfunction. Furthermore, the identification of disease-specific antigens may further elucidate the pathogenesis of the disease and lead to interventional strategies aimed at preventing individual disorders.
Footnotes
Abbreviations: APS-I, Autoimmune polyendocrine syndrome type I; EC, enterochromaffin; ECL, EC-like; GI, gastrointestinal; HDC, histidine decarboxylase.
Received February 14, 2003.
Accepted February 19, 2003.
References
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