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R Mirakian

Publications and source records attributed to R Mirakian.

54 records · Page 3Linked to original sources
PubMed1987

HLA-A,B,C, HLA-D/DR and HLA-D/DQ expression on unfixed liver biopsy sections from patients with chronic liver disease.

The distribution of HLA-A,B,C, HLA-D/DR and HLA-D/DQ molecules was studied by indirect immunofluorescence with an avidin-biotin technique and monoclonal antibodies, in unfixed cryostat sections of liver biopsies from 76 patients with chronic liver diseases of various aetiologies and five normal liver biopsy specimens. In pathological liver, strong cytoplasmic or membrane-like positivity for HLA-A,B,C of hepatocytes was observed in piecemeal necrosis areas in all groups. Cytoplasmic staining was mainly seen in lobular areas in autoimmune, cryptogenic and HBV-related cases with viral replication, while membrane-like positivity was more frequently observed in primary biliary cirrhosis, alcoholic and HBV-related cases without viral replication. A weak cytoplasmic staining for HLA-D/DR was observed in piecemeal necrosis and lobular areas mainly in HBV-related cases with viral replication. While bile duct cells were positive for both HLA-D/DR and HLA-D/DQ, hepatocytes were consistently HLA-D/DQ negative. The increased HLA-A,B,C expression on hepatocytes should allow T cytotoxic cell aggression. Hepatocellular HLA-D/DR expression is definite but weak and probably does not allow direct autoantigen presentation and induction of autoimmunity. Negativity for HLA-D/DQ further supports this hypothesis. Since cytoplasmic staining for Class I and II molecules is greatly lowered by fixing cryostat liver sections, prestaining conditions should be taken into account when comparing different studies.

Bile Ducts↗
PubMed1986

Protracted diarrhoea of infancy: evidence in support of an autoimmune variant.

Circulating autoantibodies to enterocytes were detected by indirect immunofluorescence in 14 out of 25 patients with idiopathic protracted diarrhoea of infancy. Similar specificities were not found in 50 control children with nongastroenterological disorders. The immunofluorescence pattern was more accentuated on the apical border of mature enterocytes. Enterocyte autoantibodies were mainly of IgG class (13/14), but 11 sera were positive for IgM and IgA classes, and five out of 14 positive sera also had the ability to fix complement. Absorption of sera positive for autoantibodies with an IgA coupled immunoabsorbent did not modify the intensity of the staining, indicating that these antibodies were not directed against secretory IgA. High titres and the complement fixing ability of enterocyte autoantibodies indicated a poorer prognosis despite the use of immunosuppressive drugs. Organ specific and non-organ specific autoimmune diseases or corresponding autoantibodies or both were often found in children with enterocyte autoantibodies and their family. These data show the existence of an autoimmune variant of protracted diarrhoea of infancy, despite the rare occurrence of autoimmune diseases in childhood.

Adolescent↗
PubMed1986

Organ-specific autoimmunity: a 1986 overview.

The normally functioning immune system is subject to intricate networks of regulatory mechanisms: it is therefore not surprising to find that autoimmune diseases present a complex pathogenic picture in which the relative contributions of various factors probably determine the precise nature and course of disease. This is particularly evident in the effector mechanisms of organ-specific autoimmunity which are described in this chapter. These ultimately give rise to the disease symptoms, and can be directly cytotoxic, or may either stimulate or block functional activity or growth of the target cells. Their various contributions to human diseases are becoming more firmly established, as in Type I diabetes, or are only now being described, as in the case of EC-Ab in protracted diarrhea of infancy and as evidenced by the growing lists of receptor-stimulating or -blocking antibodies. The nature and precise location of relevant autoantigens is also coming under closer scrutiny. The answers to the question of why these diseases arise in the first place remain more elusive. However, it is again likely that a variety of factors can contribute. The attractive possibility of a role for idiotypic interactions is gaining ground, particularly within the context of antibodies to hormones and their receptors. Another potential mechanism which we believe may be of central importance, particularly in the development of organ-specific destructive autoimmunity, and which we have discussed here in detail, is the aberrant expression of HLA Class II molecules by target cells. Whether this is actually an initiating factor is presently not known, but its potential for promoting pathogenesis both early and late in the process is clear. Furthermore, the complex nature of the regulation of epithelial Class II expression may help to explain the heterogeneity of features and course of disease in different patients with the same underlying pathology. All these advances in our basic understanding of the disease processes should ultimately lead to more effective and specific means of therapeutic intervention.

Animals↗
PubMed1986

HLA-D/DR expression on epithelial cells: the finger on the trigger?

The findings we have described here show a clear association between epithelial HLA-D/DR expression and autoimmunity. Furthermore, the ability of class II+ thyrocytes to present both exogenous antigens and autoantigens indicates an active role for these HLA-D/DR molecules in autoimmune pathogenesis. IFN-gamma is capable of inducing HLA-D/DR expression by thyroid epithelium, but a number of observations suggest the involvement of other inducers as well. Overall, we conclude that epithelial class II expression very probably plays a key role in the propagation and also in possibly the initiation of autoimmune attack. This is in accord with the proposal of a more general relationship between inappropriate or excessive class II expression and pathogenesis.

Antigen-Presenting Cells↗
PubMed1986

Lymphocytic hypophysitis with isolated corticotropin deficiency.

In a 32-year-old woman, acquired, isolated corticotropin deficiency resulted from postpartum lymphocytic hypophysitis. The literature suggests that lymphocytic hypophysitis may cause acquired deficiencies of anterior, and possibly posterior, pituitary hormones. Immunologic evaluation of our patient failed to uncover anticorticotroph antibodies. Prompt recognition of this potentially fatal condition is important because of the availability of effective treatment.

Adrenocorticotropic Hormone↗
PubMed1986

Characterization of monoclonal antibodies directed towards the microsomal/microvillar thyroid autoantigen recognized by Hashimoto autoantibodies.

Monoclonal antibodies reacting with thyroid microsomes have been described. In this report, we present evidence that some of these monoclonal antibodies (MoAb) MAH C3 and perhaps MAH C6 are directed towards the thyroid microsomal antigen towards which microsomal autoantibodies from Hashimoto patients are directed. Immunofluorescence on cryostat sections with MAH C3 and MAH C6 on thyroid gland gave cytoplasmic staining patterns that were comparable to those obtained with autoantibodies. By western blotting, reactivity of MAH C3 was shown to be directed towards a 105,000 mol. wt component, comparable to that recognized by autoantibodies by immunoprecipitation. Double immunofluorescence with MAH C3 and autoantibodies on cultured, viable thyroid monolayers revealed a large number of comparable binding sites; in contrast, binding sites for asioloagalactothyroglobulin were different of binding of MAH C3 by the autoantibodies suggesting that the epitopes recognized were different. This was confirmed with the use of a rat thyroid cell line FRTL-5 and fluorescence activated cell sorter analysis which showed binding to the rat microsomal component with autoantibodies but negligible binding with MAH C3 and MAH C6. It therefore appears that the monoclonal antibodies recognize species specific determinants while the autoantibodies recognize species cross reactive determinants. These monoclonal antibodies will be useful for purification and immunochemical analysis of this autoantigen in human thyroid disease.

Animals↗
PubMed1985

Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhoea.

Two male infants with severe protracted diarrhoea presenting at 4 months (patient 1) and 10 weeks (patient 2) of age are reported. In both patients jejunal biopsy showed subtotal villous atrophy. Both had specific complement-fixing autoantibodies reacting by immunofluorescence with human duodenal, jejunal, and colonic epithelium. Patient 1 also had hypothyroidism and type 1 diabetes mellitus with thyroid and islet cell autoantibodies. His gut antibodies were of IgG class, reached a titre of 1:512, and remained positive throughout his illness. He died at 16 months of age. Patient 2 had gut antibodies of IgM class, which reached a titre of 1:128 and disappeared at the time of spontaneous recovery of the diarrhoea. The findings suggest that an autoimmune process was the basis for the enteropathy in these patients. We recommend that autoantibody tests should be performed in infants with unexplained protracted diarrhoea.

Antibody Specificity↗
PubMed1984

Aberrant expression of HLA-DR antigens on bileduct epithelium in primary biliary cirrhosis: relevance to pathogenesis.

Direct immunofluorescence with an avidinbiotin system was used to investigate the expression of MHC molecules HLA-DR and HLA-A,B,C on bileducts in cryostat sections from 10 primary biliary cirrhosis (PBC) patients. Needle biopsy specimens from 55 patients with various chronic liver disorders, surgical biopsy specimens from 2 patients with recurrent secondary cholangitis, and 4 normal livers were used as controls. Normal bileducts did not express DR whereas in 8/10 PBC biopsy specimens there were varying degrees of cytoplasmic DR staining in septal or interlobular bileduct epithelium. In the early histological stages of PBC the aberrant DR expression was multifocal, but in late-stage specimens whatever ducts remained were all positive. This pattern resembles that in focal thyroiditis and suggests that DR expression is an early manifestation of autoimmune cholangitis. In 6/61 control biopsies only weak staining was detected in occasional small interlobular ducts. The class I HLA-A,B,C expression normally seen on biliary epithelium was increased in 8/10 PBC cases and in 19/61 non-PBC biopsies. Perhaps the aberrant expression of HLA-DR antigens on bileduct epithelium in PBC enables these cells to present "self antigens" to sensitised T-lymphocytes and to promote autorecognition, possibly in response to several environmental triggers; the increased HLA-A,B,C, expression may be a means of amplifying T-cell cytotoxic responses.

Adult↗
PubMed1983

Autoantibodies to gut hormone secreting cells as markers of peptide deficiency.

Autoantibodies reacting with endocrine cells in the gastrointestinal mucosa were found by indirect immunofluorescence in 22 out of 268 sera (8.2%) obtained from patients with coeliac disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, and from subjects without bowel disease. A double immunofluorescence technique showed that the autoantibodies reacted with cells secreting gastric inhibitory polypeptide (glucose dependent insulinotropic polypeptide, GIP), secretin, somatostatin or enteroglucagon. Most sera contained antibodies against more than one cell type. Neither the presence of a particular antibody nor the pattern of antibody combinations appeared to be specific for any diagnostic category. The mean plasma GIP concentrations, however, both fasting and two hours after a test meal, were significantly lower in subjects with GIP cell autoantibodies. Thus gut hormone cell autoantibodies may be markers of impaired hormone secretion.

Adolescent↗
PubMed1982

Autoimmunity to anterior pituitary cells and the pathogenesis of insulin-dependent diabetes mellitus.

An immunofluorescence study using unfixed cryostat sections of human pituitary glands was carried out on sera from patients with type-Ia (juvenile-onset) diabetes (61 recent onset, 48 longstanding). 63 of their selected high-risk first-degree relatives and 117 patients with type-Ib ("polyendocrine") diabetes were tested for comparison. Healthy controls included 48 sera from laboratory staff and students. Pituitary-cell antibodies were found in none of the controls, in 2% of patients with longstanding diabetes, in 16.6% of patients with diabetes of recent onset, and in 36.6% of genetically predisposed relatives with islet-cell antibodies in their sera (of whom 7 became diabetic during a 3-year follow-up period, 4 of them reacting with pituitary cells for 1-3 years before the onset of diabetes). Thus pituitary antibodies tended to disappear after onset of symptoms. Many of the sera reacted with multiple anterior-pituitary cell types. These findings suggest a wider involvement of the endocrine-organ system in the pathogenesis of insulin-dependent diabetes and are in accordance with clinical observations showing excess growth in prepubertal boys at onset of diabetic symptoms and with the results of experiments on virus-induced diabetes in mice. The connection of these pituitary antibodies with autoimmune lymphocytic hypophysitis is at present unknown.

Adolescent↗
PubMed1980

Autoantibodies to duodenal gastric-inhibitory-peptide (GIP) cells and to secretin (S) cells in patients with coeliac disease, tropical sprue and maturity-onset diabetes.

The presence of autoantibodies detected by immunofluorescence to single endocrine cells, of human duodenum is described in three groups of patients and two control groups. Of 173 coeliac cases, four had GIP cell antibodies, one had secretin cell antibodies and twenty-one reacted with both cell types. Of twelve tropical sprue sera, four reacted with the same two cells. Among fifty elderly diabetics treated with hypoglycaemic drugs, seven sera gave a positive cytoplasmic IFL on duodenal substrate. Four were identified as GIP cells by use of the appropriate hormone antiserum and three reactions were against cells distinct from those stained by anti-GIP, -secretin, -somatostatin, -glucagon and -gastrin. Additional gut hormone antisera will have to be tested to identify these APUD cells. Thirty blood donors and seventy-three sera from autoimmune endocrine patients gave entirely negative results on unfixed cryostat sections of duodenal mucosa. Although impaired GIP and secretin responses have been reported in coeliac disease, and abnormal GIP values were found in Type II diabetes, there is as yet no data to correlate these metabolic dificiencies with the presence of endocrine cell antibodies in the serum. These studies are in progress.

Adult↗
PubMedDate not supplied

Unresponsive enteropathy associated with circulating enterocyte autoantibodies in a boy with common variable hypogammaglobulinemia and type I diabetes.

A 13-year-old boy with common variable hypogammaglobulinemia and type I diabetes developed a severe enteropathy that proved to be unresponsive to any treatment, including total parenteral nutrition. No evidence of known etiologies of malabsorption and/or secretory diarrhea was found in this subject. A high titer of complement-fixing enterocyte autoantibody was persistently found in the patient's serum. These features suggest that the enteropathy of this primarily immunodeficient subject had an autoimmune origin. A cycle of cyclophosphamide failed to show any amelioration of the diarrhea or a significant decrease in the autoantibody titer.

Adolescent↗