Adrenal Autoantibodies Research Articles

Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies.

Idiopathic Addison's disease is a chronic organ-specific autoimmune disorder with a long subclinical period characterized only by the presence of adrenal autoantibodies (AA) with or without adrenal function failure. The aim of this longitudinal study was to evaluate the behavior of AA using, an indirect fluorescence method, and adrenal function in 20 AA-positive and 50 AA-negative patients screened by an investigation of a large population of organ-specific autoimmune disease patients without clinical Addison's disease. As controls, 100 normal age-matched subjects were tested only once. In the 20 AA-positive and 50 negative patients, AA and adrenal functional tests were evaluated every 4 months for 5 yr. The AA-positive patients were grouped into 5 adrenal functional stages, specifically: stage 0, normal adrenal function; stage 1, high PRA and low (or normal) aldosterone levels alone; stage 2, along with impaired cortisol response to ACTH, stage 3, along with increased ACTH levels; and stage 4, clinically overt Addison's disease. On the basis of the behavior of AA, the 20 positive patients were grouped as follows: group A, 11 patients with AA titer of 1:8 or higher at the first observation and persistently AA positive in subsequent observations, with titers ranging from 1:8 to 1:64; group B, 6 patients with initial AA titers of 1:8 or lower and AA disappearance in subsequent observations; and group C, 3 patients with AA titer of 1:32 or higher, undergoing corticosteroid therapy after the start of the study and showing AA disappearance in subsequent observations. With respect to adrenal function in group A, 2 patients initially in stage 1 and 1 patient initially in stage 2 did not progress to the upper stages, whereas 5 patients initially in stage 0 and 3 initially in stage 1 progressed subsequently to the upper stages, in 2 cases reaching overt clinical Addison's disease (stage 4). On the other hand, all of the patients of group B showed both a spontaneous disappearance of AA and recovery of adrenal function during the study span. Also, the 3 patients of group C showed disappearance of AA after corticosteroid therapy with recovery of adrenal function. None of the 50 patients who were initially AA negative became AA positive subsequently or showed impairment of adrenal function. We reached the following conclusions. 1) AA, even if present initially in some subjects without clinical Addison's disease, can subsequently disappear. 2) Restoration of adrenal function after disappearance of AA indicates that a spontaneous remission of subclinical adrenocortical failure can occur.(ABSTRACT TRUNCATED AT 400 WORDS)

Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies

Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies

Steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison's disease

An adrenal-specific protein reacting with autoantibodies in the sera of patients with adult onset Addison's disease has been purified from human adrenal glands. The protein, mol.wt. 55K, has the biochemical characteristics of steroid 21-hydroxylase and reacts on Western blots with rabbit antibodies to recombinant 21-hydroxylase. Absorption of the native human 55K adrenal protein with human adrenal autoantibodies prevented the subsequent reaction of the 55K protein with rabbit antibodies to 21-hydroxylase in Western blot analysis. In addition, human adrenal autoantibodies reacted with recombinant 21-hydroxylase expressed in yeast. These data indicate that the adrenal specific enzyme steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison's disease.

Autoantibodies during α‐interferon therapy for chronic hepatitis B

The development of autoantibodies and autoimmune reactions has been reported during and after interferon (IFN) therapy. Thirteen different antibodies from the sera of 32 patients with chronic hepatitis B treated with alpha-interferon (alpha-IFN) were tested. Seventeen HBeAg-positive patients received 4.5 megaunits (MU) of recombinant IFN thrice weekly for 4 months, and 15 anti-HBe and HBV-DNA positive patients were treated with 5 MU/m2 of lymphoblastoid IFN thrice weekly for 6 months. Five patients (15%) had antinuclear antibodies (ANA) and one patient (3%) had smooth muscle antibodies before treatment. ANA appeared during IFN treatment in five (18%) of 28 previously negative patients. With discontinuation of treatment, the titer of ANA fell to undetectable levels in all patients. In contrast, none of the patients developed antibodies to endocrine organs, such as thyroid microsomal, thyroglobulin, parietal cells, pancreatic islet cell, and adrenal cortex antibodies or autoantibodies specifically associated with autoimmune liver disease such as liver kidney microsomal antibodies and antimitochondrial antibodies. There was no correlation between autoantibody positivity before therapy or autoantibody occurrence during treatment and response to IFN therapy. None of the patients developed clinical signs of autoimmune disease. These results indicate that these regimens of recombinant and lymphoblastoid IFN therapy of chronic hepatitis B are associated with a low risk of clinically significant autoimmunity.

Adrenal Autoantibodies Bind to Adrenal Subcellular Fractions Enriched in Cytochrome-c Reductase and 5′-Nucleotidase

A quantitative assay for human adrenal autoantibodies has been developed to aid in the detection and isolation of human adrenal antigens. To define the subcellular location(s) of the antigen(s) capable of binding with these antibodies, we have quantitated both antibody binding to various adrenal subcellular fractions and the adrenal autoantibody binding inhibition caused by each subcellular fraction. To further define the subcellular location of the autoantibody binding, each fraction was assayed for organelle-specific marker enzyme activities. Enzyme activities were correlated to adrenal autoantibody binding to each fraction by linear regression. Of the materials tested, both antibody binding and inhibition of binding were most highly correlated with adrenal subcellular fractions enriched with cytochrome-c reductase and 5'-nucleotidase (r = 0.98; P less than 0.05). Thus, our data support the localization of adrenal autoantigen(s) in the microsomes, plasma membrane, or both.

Immunoglobulins of Patients with Idiopathic Addison's Disease Block thein VitroAction of Adrenocorticotropin*

The presence of serum immunoglobulins (Ig) blocking ACTH-induced adrenal DNA synthesis and/or cortisol production was studied in 25 patients with idiopathic Addison's disease. For this purpose guinea pig adrenal segments kept in organ culture were exposed to ACTH and graded concentrations of patient IgG. After a 5-h culture period the cortisol present in the culture fluid was measured by RIA, and DNA synthesis in the adrenal cells was measured using Feulgen densitometry on frozen sections of the cultured adrenal segments. Addition of ACTH alone in concentrations of 0.1-10 pmol/L to the culture system stimulated in vitro cortisol secretion; the maximal stimulation was 63 +/- 35% (+/- SD; n = 5) at a concentration 0.1 pmol/L. ACTH also increased (in concentrations of 1 fmol/L to 1 pmol/L) the percentage of fasciculata cells in S-phase from 0-4% (nonstimulated) to 5-12%. IgG preparations from all but 2 of the 25 patients with idiopathic Addison's disease blocked these in vitro ACTH-induced adrenal responses in a dose-dependent fashion. IgG from 2 patients with tuberculous adrenalitis, 1 patient with secondary adrenal insufficiency, and 7 normal subjects had no blocking activity. Among 5 non-Addisonian autoimmune endocrinopathy patients who had adrenal cytoplasmic autoantibodies, 4 had no ACTH-blocking IgGs. Two of 9 patients with miscellaneous adrenal disorders (Cushing's disease, pigmented adrenal micronodular dysplasia, and adrenal nodules) had ACTH-blocking activity. These results demonstrate the existence of IgGs blocking the in vitro effects of ACTH and suggest their involvement in the pathogenesis of idiopathic Addison's disease.

Epidemiology of insulin-dependent diabetes mellitus in Canterbury, New Zealand

A prospective study of incidence and prevalence of insulin-dependent diabetes mellitus in persons under 20 years was conducted over a 4-year period (1 February 1982-1 February 1986) for the Canterbury Hospital Board (total population 342,000) area in New Zealand. A central register for the area was established at the beginning of the study period. Degree of ascertainment was close to 100%. Average annual incidence was 11.7 persons per 100,000 (females: 10.6 per 100,000; males: 12.7 per 100,000) with no significant sex difference or temporal trends. Incidence peaks were seen for both sexes in the pubertal ages (females: 11 years; males: 13 years), with minor peaks occurring for both sexes in the pre-school ages. Age of onset was significantly younger in females than males. A seasonal variation in incidence was seen for males, with peaks in late autumn and mid-winter. 5.7% of the new diabetics had a first-degree relative with insulin-dependent diabetes mellitus. Islet cell cytoplasmic antibodies were detected in 68% of new diabetics and in 0% of age- and sex-matched healthy controls. Thyroid, gastric and adrenal auto-antibodies were seen more frequently in diabetics than in controls, but this difference was not significant. Prevalence of insulin-dependent diabetes on 1 February 1982 was 1.00 per 1000 and 1.05 per 1000 on 1 February 1986. The insulin-dependent diabetes mellitus incidence characteristics noted for the Canterbury Hospital Board area are similar to those reported for European and North American populations.

128 INHERITED SUSCEPTIBILITY TO AUTOIMMUNE ADDLSON'S DISEASE IS LINKED TO HLA-DR3 AND DR4

Inherited susceptibility to Addison's disease has been linked to the leukocyte antigen (HLA)-B8 allele, and by inference because of linkage disequilibrium between B8 and DR3, this susceptibility should be primarily to that of the DR3 antigen. Twenty four patients who had presented with overt Addison's disease, and another 28 patients who had been found to have adrenocortical autoantibodies, were HLA typed. Six of the Addisonian patients and 22 of the adrenal autoantibody positive patients had co-existing insulin dependent diabetes (IDD). In relation to HLA typing data from 253 Caucasian controls, Addison's disease was significantly associated with DR3 (X2 6.0 ; p = 0.014), DR4 (X2 7.4; p = 0.007) and DR3/DR4 heterozygosity (X2 25.4; p 0.0001). Of the 6 Addison's patients who lacked DR3 and DR4 alleles in their HLA phenotype, 3 had type I autoimmune polyglandular syndrome.

Pancreatic alpha cell autoantibodies and glucagon response to arginine.

The frequency and significance of cytoplasmic pancreatic alpha cell autoantibodies (ACA) were investigated in 2102 healthy controls, 879 patients with insulin-dependent diabetes mellitus (IDDM) who were negative for islet cell autoantibodies (ICA), and 1567 relatives of IDDM patients. ACA were found in approximately 1 in 200 people of all ages and were not significantly associated with IDDM, the IDDM-associated HLA phenotypes DR3 and DR4, or thyrogastric or adrenal autoantibodies. Of 11 ACA-positive patients studied by arginine stimulation tests, none had frank glucagon deficiency. Thus, ACA do not appear to be associated with defective alpha cell function or with IDDM.

COMPLEMENT-FIXING ADRENAL AUTOANTIBODIES AS A MARKER FOR PREDICTING ONSET OF IDIOPATHIC ADDISON'S DISEASE

In a prospective investigation of the role of adrenal autoantibodies (AA) in predicting the onset of idiopathic Addison's disease, 9 initially non-addisonian AA-positive autoimmune subjects were followed for 42 months. In 4 of these subjects Addison's disease developed within 1-31 months. A fifth had reduced adrenocortical reserve at the start and at the end of the investigation. An AA capable of fixing the membrane attack complex of complement [(C5-C9) F-AA] was detected before onset of the disease in the sera of the 4 patients in whom Addison's disease developed. (C5-C9) F-AA may be involved in the pathogenesis of idiopathic Addison's disease and may be regarded as a marker for individuals in whom idiopathic adrenal insufficiency is likely to develop.

Autoimmunity in type I (insulin-dependent) diabetes mellitus in North India

Pancreatic islet cell, thyroid, gastric parietal cell, and adrenal autoantibodies were studied in 110 young insulin-dependent diabetics (type I; IDDM), 12 non-insulin-dependent diabetics (NIDDM), 26 patients with pancreatic diabetes, and 123 age- and sex-matched healthy controls. All the patients were aged 30 years or under at the onset of diabetes. Islet cell antibody was found in 31% of the patients with IDDM, but in only one patient with NIDDM, one patient with pancreatic diabetes, and one healthy control subject. Thyroid, parietal cell, and/or adrenal antibodies were present in 26% of the IDDM patients, 17% of the NIDDM patients, 12% of the patients with pancreatic diabetes, and 19% of the control subjects. There was no association between the presence of islet cell antibody and other organ-specific autoantibodies and any particular HLA phenotype. Data from the North Indian study have been compared with those from other populations of the world, similarities and differences have been brought out, and their significance has been discussed. The relative contribution of the autoimmune component in the etiopathogenesis of different forms of diabetes mellitus varies among the different populations of the world, accounting to some extent for the observed differences in incidence and clinical profiles.

Purulent pericarditis in children: an analysis of 28 cases.

<h3>BACKGROUND/AIMS</h3> Interferon alpha (IFN-α) therapy for chronic hepatitis C may trigger induction of autoimmunity against several organs. Immune reactions against distinct adrenocortical protein antigens involved in adrenal autoimmune disease have not been reported to date. Therefore, we investigated the development of highly sensitive and specific adrenal autoantibodies in patients with chronic hepatitis C in response to IFN-α treatment. In addition, we studied induction of pancreatic islet and thyroid autoantibodies. <h3>PATIENTS/METHODS</h3> Sera of 75 patients (42 males, 33 females; mean age 47 (13) years) were analysed before, during, and after IFN-α therapy (9–18×10⁶ IE/week; mean duration 8.3 (3.5) months). Autoantibodies (Abs) to adrenal 21-hydroxylase (21OH-Abs), and to islet glutamic acid decarboxylase (GAD65-Abs) and protein tyrosine phosphatase (IA2-Abs) were determined by a radiobinding assay using³⁵S labelled protein generated by an in vitro translation system. Thyroid antibodies were measured by a commercially available ELISA. <h3>RESULTS</h3> Thirteen of 75 patients were initially positive for some of the autoantibodies. During or after IFN-α therapy, 3/62 initially negative patients (4.8%) developed 21OH-Abs. GAD65-Abs or IA2-Abs appeared in 5/62 and 1/62 patients, respectively (9.7% in total). In 12/62 patients (19.4%), thyroid specific antibodies appeared. In none of the 21OH-Ab positive subjects was adrenal dysfunction observed, and no patient with islet autoantibodies developed diabetes mellitus or impaired glucose tolerance. <h3>CONCLUSIONS</h3> IFN-α induces 21OH-Abs in some cases, while islet and thyroid specific autoantibodies are more frequently found. However, our results indicate for the first time that the adrenal cortex also has to be considered as a potential target of IFN-α related autoimmunity.

Addison's disease and diabetes mellitus

A 15-year-old boy developed diabetes mellitus 33 months after the onset of Addison's disease. His 10-year-old brother died of Addison's disease. Maternal family members had diabetes mellitus and thyroiditis. Thyroid and adrenal autoantibodies were present in the sera of the patient, his mother, and a maternal aunt. Antibody to β-cells of the pancreas was not present in the serum of the patient before insulin therapy was instituted. Immunologic factors were strongly implicated to explain the coexistance of Addison's disease and diabetes mellitus in this patient.

AUTOANTIBODIES IN PATIENTS WITH VITILIGO

Patients with vitiligo show a tendency to increased autoantibody formation. Those patients with adrenal autoantibodies may be clinically at risk for the development of adrenal insufficiency. Vitiligo may be regarded as a member of the family of autoimmune disorders.

CUSHING'S SYNDROME WITH ADRENAL MEDULLARY INSUFFICIENCY AND ADRENAL AUTOANTIBODIES

CUSHING'S SYNDROME WITH ADRENAL MEDULLARY INSUFFICIENCY AND ADRENAL AUTOANTIBODIES