Autoimmune Polyglandular Disease Research Articles

LIVER DISEASE IN POLYGLANDULAR AUTOIMMUNE DISEASE TYPE ONE: Clinicopathologic Study of Three Patients and Review of the Literature

We report the findings from liver biopsies of three patients with polyglandular autoimmune disease type 1. The livers in two patients had histologic features of chronic hepatitis that eventuated in bridging fibrosis and arrhosis over a period of several years. Nonspecific lobular and portal tract inflammation was present in the liver biopsy of the third patient. Although these patients did not have liver-specific autoantibodies, the liver disease in polyglandular autoimmune disease type 1 possibly represents an expression of autoimmune hepatitis.

LIVER DISEASE IN POLYGLANDULAR AUTOIMMUNE DISEASE TYPE ONE: Clinicopathologic Study of Three Patients and Review of the Literature

LIVER DISEASE IN POLYGLANDULAR AUTOIMMUNE DISEASE TYPE ONE: Clinicopathologic Study of Three Patients and Review of the Literature

Isolation of cDNA for a Novel Human Protein KNP-I That Is Homologous to theE. coliSCRP-27A Protein from the Autoimmune Polyglandular Disease Type I (APECED) Region of Chromosome 21q22.3

We have isolated cDNA clones for a novel human protein KNP-I from fetal brain and bone marrow cDNA libraries. Northern blot analysis indicated that the KNP-I gene is ubiquitously expressed in various human tissues. Significant homology of the KNP-I protein withEscherichia colianti-sigma cross-reacting protein (SCRP-27A) (44% identity) and zebrafish (Brachydanio rerio)es1 protein (49% identity) suggested that the KNP-I protein may be involved in a basic cellular function. Genomic sequencing revealed that the KNP-I gene consists of seven exons spanning 12 kb. Exon 5 was involved in alternative splicing. The KNP-I gene was mapped between D21S1460 and D21S25 on human chromosome 21q22.3, 26 kb distal to aNotI site of D21S1460. Thus, this novel KNP-I gene could be a candidate gene for autoimmune polyglandular disease type I (APECED) and other disorders mapped to this region.

Type 2 polyglandular autoimmune disease (Schmidt's syndrome).

Data on clinical, genetic, and immunological aspects of sixty patients with type 2 polyglandular autoimmune disease (PGAD) are presented. The literature on this is reviewed and discussed.

A periodic tryptophan protein 2 gene homologue (PWP2H) in the candidate region of progressive myoclonus epilepsy on 21q22.3.

The Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1) has been mapped to human chromosome 21q22.3, and the candidate region has been narrowed to a region of less than 300 kb. We now report the isolation of a novel gene, PWP2H, from this EPM1 candidate region. The putative protein encoded by this gene is a novel member of the beta transducin protein superfamily with high homology to the yeast periodic tryptophan protein 2 (PWP2). PWP2H cDNA was isolated from a 14 week human trisomy 21 fetal brain cDNA library by using a modification of a direct cDNA selection method. PFGE analysis showed that PWP2H is located proximal to D21S25 and distal to TMEM1. Northern analysis of the 3.1-kb PWP2H cDNA revealed that a 3.3-kb major transcript is ubiquitously expressed in human adult tissues. DNA sequence analysis reveals a complete coding region of 2,610 bp as well as 5'- and 3'-UTR. The structure of the putative PWP2H protein contains 6 WD40 repeats, 2 acidic regions and one leucine zipper domain, suggesting that the protein may form specific protein complexes in which the WD40 repeats and the leucine zipper represent protein-protein binding sites. In conclusion, the map location and the homology to a gene family involved in a large variety of biological processes including signal transduction and development make PWP2H an intriguing candidate for EPM1 as well as for APECED (autoimmune polyglandular disease) and HPE1 (holoprosencephaly-1) that also map in this region of chromosome 21.

Liver Disease in Polyglandular Autoimmune Disease Type One: Clinicopathologic Study of Three Patients and Review of the Literature

We report the findings from liver biopsies of three patients with polyglandular autoimmune disease type 1. The livers in two patients had histologic features of chronic hepatitis that eventuated in bridging fibrosis and cirrhosis over a period of several years. Nonspecific lobular and portal tract inflammation was present in the liver biopsy of the third patient. Although these patients did not have liver-specific autoantibodies, the liver disease in polyglandular autoimmune disease type 1 possibly represents an expression of autoimmune hepatitis.

Intestinal lymphangiectasia in a patient with autoimmune polyglandular disease type I and steatorrhea.

Steatorrhea is seen in 18-24% of patients with autoimmune polyglandular disease (APD) type 1. The etiology and pathophysiology of the steatorrhea in this disease are unknown. We present a patient with APD type 1 and steatorrhea in whom biopsies revealed intestinal lymphangiectasia. This association has not been previously described. Intestinal lymphangiectasia may explain the steatorrhea in some patients with ADP type 1. As blind intestinal biopsies may miss areas of intestinal lymphangiectasia, endoscopically directed intestinal biopsies should be included in the evaluation of steatorrhea in APD type 1.

Intestinal lymphangiectasia in a patient with autoimmune polyglandular disease type I and steatorrhea

Intestinal lymphangiectasia in a patient with autoimmune polyglandular disease type I and steatorrhea

Isolation and characterization of a candidate gene for progressive myoclonus epilepsy on 21q22.3.

The Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1) and autoimmune polyglandular disease type I (APECED) have been mapped to human chromosome 21q22.3 by genetic linkage analysis and/or linkage disequilibrium studies. In order to isolate the genes for these disorders, we have constructed BAC contigs in this region and a 14 week trisomy 21 fetal brain cDNA library. A direct cDNA selection technique, modified to permit the recovery 5' and 3' ends of cDNA, was applied to gene identification using the BAC contigs. We have isolated and characterized a novel gene defined by three overlapping but distinct cDNAs of 5, 3, and 3 kb in size all named EHOC-1 (Epilepsy, HOloprosencephaly Candidate-1). This gene maps less than 45 kb centromeric of D21S25, and spans at least 56 kb of genomic DNA. Northern analysis of the 5 kb cDNA revealed that 8, 7.5 and 5.3 kb transcripts are ubiquitously expressed in adult tissues. DNA sequence analysis of the 5 kb cDNA showed a complete coding sequence of 3570 bp that has multiple putative transmembrane domains and has partial homologies to transmembrane proteins including sodium channel proteins. This gene (EHOC-1) is a good candidate for APECED, and particularly for EPM1 because of the location, size, structure and homologies.

Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison's disease.

Patients with idiopathic Addison's disease have autoantibodies reacting with adrenal cortex. If Addison's disease is associated with other endocrine immune diseases like autoimmune polyglandular diseases (APD) type I and type II, antibodies may recognize all steroid-producing cells. We showed previously that one antigen recognized by APD-I sera is the cytochrome P450c17 hydroxylase. We have now looked for antibodies to P450c17 and to two other key enzymes in the steroid biosynthetic pathway, the P450scc and P450c21, in a series of patients with isolated Addison's disease (8 patients) or with APD-I or APD-II (50 and 9 patients, respectively). The result of antienzyme antibodies were further correlated with the immunofluorescence pattern against adrenal gland, testis, ovary, and placenta, and with the clinical findings presented. In APD-I patients with Addison's disease and in APD-II patients, antibodies to at least one of the P450 enzymes were frequently found (positive findings in 81% and 78%, respectively). Such antibodies were less frequent in APD-I patients without Addison's disease (21%) and in the isolated Addison cases (25%). In APD-I, antibodies recognized as frequently P450c17 and P450scc, specific for all steroid-producing cells as the adrenal specific enzyme P450c21. In contrast, patients with APD-II or with the isolated Addison's disease reacted almost exclusively with P450c21. Immunofluorescence studies showed good correlation with the known fact that the zona glomerulosa of the adrenal cortex is devoid of the P450c17, that the Leydig cells of the testis and the theca interna cells of the ovary express P450c17 and P450scc, and that the placental trophoblasts express only P450scc. The presence of antibodies to P450scc or to at least one of the tested P450 enzymes correlated significantly to gonadal failure in the females but not in the males.

Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison's disease

Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison's disease

An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21.

Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does not show association to specific HLA haplotypes. Unravelling the APECED locus will identify a novel gene outside the HLA loci influencing the outcome of autoimmune diseases. We have assigned the disease locus to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Linkage disequilibrium studies have significantly increased the informativeness of the analyses and helped to locate the critical DNA region for the APECED locus to just 500 kilobases, a much more precise definition than linkage analyses alone could achieve.

LINKAGE ANALYSES TO ASSIGN THE LOCUS FOR AUTOIMMUNE POLYGLANDULAR DISEASE TYPE I

The autoimmune phenomena associated with many human diseases are still only partially understood. Unravelling the molecular palhogenesis of inherited diseases with a strong autoimmune component in their clinical expression could help to dissect the molecular background of abnormal immune response. One such genetic disorder is autosomal resessive autoimmune polyglandular disease type I (PGD I), also known as autoimmune polyendocrinopathy-candidiasis - ectodermal dystrophy (APECED, MIM 240300). This disease is especially enriched in the genetically isolated population of Finland. Here we have taken advantage of newly developed amplifiable multiallelic microsatellite markers coupled with the microtiter well format of the polymerase chain reaction and linkage analyses to establish the most probable chromosomal location for the APECED locus. The rapid “semiautomated” protocol was here aplied to analyze 100 chromosomally assigned polymorphic loci. The method proved to be an effective and economical tool for gene mapping compared with standard blotting and hybridization and resulted in the preliminary assignment of the APECED locus.

Autoimmune Polyglandular Disease Type I

The pathogenetic background of human autoimmunity is only partially understood. By discovering the defective gene causing the autosomal recessive polyglandular autoimmune disease type I (PGD I, APECED) we hope to provide new insights into autoimmune responses in general. Here we have taken advantage of newly developed amplifiable multiallelic microsatellite markers and performed the analyses using the microtiter well format of the polymerase chain reaction. This rapid semiautomated protocol was applied to analyze 62 assigned highly polymorphic loci. The linkage analyses coupled with the EXCLUDE analysis resulted in an exclusion map of this polyglandular autoimmune disease and in the preliminary assignment of the APECED locus to chromosome 22. The method proved to be an effective and economical tool for gene mapping compared with standard blotting and hybridization.

Frequent occurrence of asplenism and cholelithiasis in patients with autoimmune polyglandular disease type I

purpose: This study assesses the occurrence of asplenism and gallstones in patients with autoimmune polyglandular disease type I (APG I). patients and methods: Nine patients with APG I (ages 14 to 48) were studied at the National Institutes of Health. Each patient received endocrine testing, a careful examination of his or her peripheral blood smear, lymphocyte immunophenotyping, a liver-spleen scan, and either an upper abdominal ultrasound or a computer-assisted tomogram to evaluate the spleen and gallbladder. results: We documented asplenism in four patients and cholelithiasis in four patients, with two patients having both conditions. The patients with asplenism had Howell-Jolly bodies on peripheral blood smears, lack of splenic uptake by liver-spleen scan, and absent spleens by abdominal computed tomographic scan or ultrasound evaluation. The clinical presentation of the patients with cholelithiasis ranged from acute symptoms requiring surgery to asymptomatic gallstones. Lymphocyte immunophenotyping did not reveal consistent changes in either B- or T-cell subpopulations in the patients studied. conclusion: Asplenism and gallstones occur frequently in patients with APG I. In addition to careful examination of the peripheral blood smear for Howell-Jolly bodies to screen for asplenism, we recommend an abdominal ultrasound to detect asplenism and/or gallstones in all patients with APG I. Appropriate immunizations and antibiotic coverage may be helpful in those patients with absent spleens.

Síndrome poliglandular auto-imune num adulto com hepatite crónica activa.

We present a case report with IgA deficiency, pernicious anemia, chronic active hepatitis, insulino-dependent diabetes mellitus and hypogonadism. A diagnosis of Polyglandular Auto-immune Syndrome was done and we discuss the difficulty in including this particular case in any of the types of the Neufeld's classification of Polyglandular Auto-immune Disease.

The expression of autoimmune polyglandular disease type I appears associated with several HLA-A antigens but not with HLA-DR.

We studied HLA-A, -B, -C, and -DR antigens in 45 patients (from among 34 families), aged 10.2-60 yr, with polyglandular autoimmune disease type I (APG I) and in other family members. HLA-A28 was more frequent in the patients (25%) than in unaffected siblings (16%; P less than 0.05) or in normal Finnish subjects (8.8%; P less than 0.005, corrected P less than 0.2). Compared with the normal subjects, HLA-A28 was more frequent in the patients with hypoparathyroidism (31%; P less than 0.001, corrected P less than 0.04), adrenocortical failure (27%; P less than 0.01), insulin-dependent diabetes mellitus (IDDM; 66%; P less than 0.01), keratopathy (53%; P less than 0.001, corrected P less than 0.04), and alopecia (40%; P less than 0.001, corrected P less than 0.04), but not in the patients with ovarian failure (9%; P = NS). HLA-A28 was more frequent in the patients with hypoparathyroidism (31%) than in APG I patients without it (13%; P less than 0.005, corrected P less than 0.2). It was also more frequent in the patients with IDDM (66%) than in those without it (21%; P less than 0.05). HLA-A3 was more frequent in the patients with ovarian failure (82%) than in APG I patients with normal ovarian function (22%; P less than 0.025) and in normal subjects (45.5%; P less than 0.05). HLA-A9 was less frequent in the patients with ovarian failure (0%) than in those with normal ovarian function (55%; P less than 0.005, corrected P less than 0.2), and it was less frequent (P less than 0.025) in the patients with adrenocortical failure than in those with normal adrenal function. No association was found with any single DR antigen, but of 4 DR-typed IDDM patients, 3 were DR3 or DR4 positive (P = NS). The occurrence of adrenocortical failure, but not hypoparathyroidism, was familial and associated with HLA haploidentity among sets of affected siblings.

Adrenal and Steroidal Cell Antibodies in Patients with Autoimmune Polyglandular Disease Type I and Risk of Adrenocortical and Ovarian Failure*

Thirty-one patients with autoimmune polyglandular disease type I who initially had no adrenocortical and/or ovarian failure were followed for 1.2-12.1 yr (mean, 8.3) by determinations of adrenal (AA) and steroidal cell antibodies (SCA) and functional tests. Adrenocortical failure developed in 13 and ovarian failure in 11 patients. SCA or AA preceded adrenocortical failure in 12 of the 13 patients and were found in 2 of 9 patients (so far) who still have normal adrenal function (P = 0.001). SCA preceded ovarian failure in all 11 patients and were found in 6 of 11 patients who still have normal ovarian function (P = 0.02). The sensitivities/specificities/predictive values were 0.77/0.78/0.90 in all patients for SCA predicting adrenocortical failure, and 0.92/0.89/0.92 for adrenal-binding antibody (which includes all AA and most SCA) in predicting adrenocortical failure. The sensitivities/specificities/predictive values in females who initially had normal adrenocortical and ovarian function were 1.0/0.56/0.50 for SCA in predicting ovarian failure, 0.86/0.83/0.86 for SCA in predicting adrenocortical failure, and 1.0/1.0/1.0 for adrenal-binding antibody in predicting adrenocortical failure. Thus, the appearance of AA or SCA in a male patient without adrenocortical failure or a female patient without adrenocortical or ovarian failure signals a high risk of their development.

The effects of long-term normalization of sodium balance on linear growth in disorders with aldosterone deficiency.

The effect of normalization of sodium balance was evaluated in children with aldosterone deficiency of several etiologies. In salt-losing congenital adrenal hyperplasia (CAH), treatment with a mineralocorticoid in doses that normalized plasma renin activity (PRA) induced a marked increase in linear growth. Serum 17-hydroxyprogesterone (17-OHP) and androgens fell further when adequate sodium balance was achieved, allowing in some cases a reduction in glucocorticoid replacement dose. Together with PRA measurement they were the most sensitive indicators of adequate mineralocorticoid and glucocorticoid replacement therapy. In 2 teenage children with aldosterone deficiency due to Addison's and autoimmune polyglandular disease similar improvement in growth as well as onset of puberty occurred when sodium balance was normalized by increased mineralocorticoid therapy. These studies show that adequate sodium balance is essential for normal growth and pubertal development.

Progressive adrenal failure in polyglandular autoimmune disease

We describe here the clinical course of a boy who developed isolated failure of the zona glomerulosa as part of polyglandular autoimmune disease(PAD)and in whom function of the zona fasciculata remains intact.Initially the patient presented with hypoparathy-roidism and mucocutaneous candidiasis.ACTH tests at age 8 and 11 yrs resulted in a normal response of both mineralo- and glucocorticoids.The constellation of hyponatremia, hyperkalemia and growth failure at age 14 yrs prompted a reevaluation. A repeat ACTH test, assessing individual contributions of zona fasciculata and glomerulosa, showed normal plasma cortisol, DOC and B responses and a normal urinary response of 18 OH DOC and TH DOC.Urinary 18 OH B and urinary as well as plasma aldosterone were undetectable. Plasma renin activity(PRA)was markedly elevated.The ACTH response of adrenal androgens,presumably metabolic products of the zona reticularis was also deficient.Antiadrenal antibodies against all three layers of the adrenal cortex were positive. Mineralo-corticoid therapy resulted not only in normalization of electrolytes and PRA but also in catch up growth.The course of this patient suggests that in addition to monitoring the electrolyte status, periodic tests for both mineralo- and glucocorticoid synthesis should be performed in children with PAD because progressive adrenal insufficiency may go unrecognized.