Report on 'Medical and surgical management of rhinitis' course.
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Anti-Inflammatory Agents↗
Biomedical subjects
R Mirakian
Publications and source records attributed to R Mirakian.
Endomysial antibody screening in children.
It has been suggested that endomysial antibodies are specific markers for coeliac disease. In a 13-month study, we examined the usefulness of screening for these antibodies in the diagnosis of coeliac disease in children. Twenty-one of 223 (9.4%) serum samples [or 17 of 192 (9%) children undergoing investigation for GI disorders] were found to be positive for serum IgA class endomysial antibodies. These included eight strong positives, eight positives, and five weak positives. One-hundred-thirty-four children had small bowel biopsies performed. Endomysial antibodies were found in all children with severe villous atrophy on a gluten-containing diet who were diagnosed as having coeliac disease. Three children with positive and four with weak-positive results did not have coeliac disease. One had partial villous atrophy consistent with the diagnosis of cow-milk-sensitive enteropathy and the others had a normal small bowel mucosa. This study confirms a strong association between endomysial antibodies and coeliac disease; however, not all cases with positive antibodies had the disease. At the present time, small bowel biopsy remains essential for the diagnosis of coeliac disease.
Adolescent↗
Intercellular adhesion molecule-1 (ICAM-1) in Graves' disease: contrast between in vivo and in vitro results.
We have reassessed the possible role of the adhesion molecule ICAM-1 in the pathogenesis of thyroid autoimmunity. In order to do that, we have investigated its expression in eight Graves' thyroids both in vivo (i.e. on cryostat sections and on cell suspensions), and in vitro (i.e. on cells cultured in monolayers for 3 days), and the results were compared with those obtained with similar preparations from four normal glands. On cryostat sections, the expression of ICAM-1, and for comparison that of HLA Class I and Class II molecules, was studied by immunofluorescence (IFL), but the former were also assessed by a distinct immunohistochemical technique. ICAM-1 was not detected in thyrocytes in vivo of both normal and Graves' glands, but solely in endothelial cells and antigen-presenting cells (APC). This selective reaction was confirmed by a four-layer technique using specific markers which identify endothelial cells and thyrocytes. HLA Class II molecules were confirmed to be inappropriately expressed in thyrocytes of Graves' glands, but there was no co-expression of these products and ICAM-1 in the same cells. In contrast, ICAM-1 appeared de novo in a proportion of Graves' and normal thyrocytes soon after the attachment and spreading of these cells in monolayer cultures (36-48 h). Graves' thyrocytes showed a quantitatively higher degree of expression compared with that detected on normal thyroid cells (40-70% versus 12-20%). Under these experimental conditions, the four-layer staining with thyroid microsomal antibodies confirmed that thyrocytes were indeed the positive cells which expressed ICAM-1. Blocking experiments with cultured thyrocytes from two Graves' glands and MoAbs to tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) did not prevent the occurrence of ICAM-1 expression. As a result of our study, we failed to demonstrate that Graves' thyrocytes express ICAM-1 in vivo. The unexpected case of inducing ICAM-1 on thyroid cells under certain in vitro conditions remains intriguing. The phenomenon could be the simple consequence of a mechanical effect rather than exerted by specific biological processes. Further investigations are, therefore, needed to establish whether ICAM-1 is really involved in the pathogenesis of Graves' disease.
Antigen-Presenting Cells↗
Adhesion molecule expression in Graves' thyroid glands; potential relevance of granule membrane protein (GMP-140) and intercellular adhesion molecule-1 (ICAM-1) in the homing and antigen presentation processes.
To assess the potential role of adhesion molecules in the pathogenesis of Graves' disease, we examined the expression of several of these adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1) and granule membrane protein-140 (GMP-140), in sections of Graves' thyroid glands and control thyroids, using immunohistochemical techniques. Up-regulated expression of GMP-140 was frequently observed on endothelial cells (EC) of post-capilliary venules in all Graves' thyroids examined, compared with an occasional weak staining on EC control glands. Some capillary EC around thyroid follicles (perifollicular EC) were strongly positive for GMP-140 in the Graves' thyroids in contrast to a negative staining on the same structures in the control glands. In addition, there was a correlation between the reactivity and frequency of GMP-140 expression on EC and the severity of mononuclear cell (MNC) infiltration in the Graves' thyroids. The expression of ICAM-1 was up-regulated on perifollicular EC and EC of small venules in some thyroids of both Graves' and control groups. Conversely, no significant expression was observed on any type of EC for both endothelial-leucocyte adhesion molecule-1 (ELAM-1) and VCAM-1. However, dendritic-like cells, present within lymphocytic infiltrates, were positive for VCAM-1 in most of the Graves' thyroids examined, especially in those with a severe lymphocytic infiltration. Thyrocytes were constantly negative for the expression of all four adhesion molecules investigated. These data suggest that GMP-140, as well as ICAM-1, could play an important role in the initiation of MNC infiltration in Graves' disease. ELAM-1 and VCAM-1 appear not to be relevant for the migration of MNC from the blood vessels into the target gland, although VCAM-1 expression on dendritic-like cells might play an additively tissue-selective role in autoantigen presentation and subsequent elicitation of autoimmune phenomena.
Cell Adhesion Molecules↗
LFA-1 and ICAM-1 molecule expression in jejunal mucosa from children with autoimmune enteropathy.
The expression of adhesion molecules by cells of the small intestinal mucosa was compared in gut biopsies from children with autoimmune small intestinal enteropathy and normal controls and related to HLA-DR expression by the same tissue. Jejunal biopsies were stained by IFL with monoclonal antibodies to LFA-1 (TS1/22 and CD11a/25.3.1) and ICAM-1 (RR1/1 and 84H10) molecules. LFA-1 and ICAM-1 positive cells were observed in the lamina propria in all cases and the counts were increased in autoimmune enteropathy compared with controls. In addition, in 4 of 7 cases of autoimmune enteropathy crypt enterocytes were positives for ICAM-1 when stained with RR1/1 and 3 of the 4 were also positive for LFA-1 when stained with both LFA-1 reagents. We speculate on the role of adhesion molecule expression in autoimmune enteropathy.
Adolescent↗
Transfection with SV40 gene of human pancreatic endocrine cells.
At present, only islet cell lines of animal origin have been successfully generated (e.g. RIN, HIT). A fully differentiated human beta cell line would be advantageous for diabetes research. We now report the generation of a human endocrine pancreatic cell line obtained by transfection using a plasmid containing the early region of SV40 viral DNA. Viral integration and transcription was assessed by Southern and Northern blotting. This cell line has been growing continuously for more than 2 years and maintains several of the characteristics of the parental cells from which they were generated. The presence of Neuron Specific Enolase, Protein Gene Product 9.5, cytokeratin, microvilli, cytoplasmic electrodense granules and the secretion of insulin, glucagon and somatostatin supports the neuroendocrine origin of this cell line. However, hormone production progressively decreased and finally stopped at passage 8. Flow cytometric analysis showed that HLA expression in this cell line is readily induced by IFN-gamma and modulated by TNF-alpha. The establishment of this human endocrine cell line indicates the feasibility of immortalizing human islets by transfection with viral oncogenes. To obtain a fully differentiated cell line it may be necessary to use other DNA constructs which immortalize the cells without fully transforming their phenotype.
Antigens, Viral, Tumor↗
De novo HLA class II and enhanced HLA class I molecule expression in SV40 transfected human thyroid epithelial cells.
Human thyroid follicular cells normally synthesize and express HLA Class I molecules but in glands affected by autoimmune or neoplastic diseases they express Class II molecules. We have investigated the effect of SV40 virus transformation on the expression of MHC molecules in human thyrocytes. Primary cultures of human thyroid from two different glands were transfected with the plasmid pX-8, containing the 'early' region of SV40 virus, and two continuous lines of thyrocytes were obtained. The cell lines maintained features of parental thyroid epithelial cells showing the characteristic cytokeratin filament network, microvillar protrusion and tight junctions. In addition, the SV40-transfected cells responded to graded doses of TSH with increased c-AMP production. Thyrocytes from both cell lines hyperexpressed Class I molecules and a significant proportion of them also acquired constitutive Class II expression, as determined by indirect immunofluorescence (IFL), flow cytometry and Northern blotting hybridization using a DR beta probe. These cells were found to be normally up-regulated by interferon (IFN)-gamma. Indirect IFL and flow cytometry analysis were used to detect and quantify the expression of HLA-DR, DP and DQ subregions. A co-ordinated expression (DR greater than DP much greater than DQ), reminiscent of the inappropriate HLA expression found in thyroid autoimmune disease in vivo and of the in vitro regulation in normal thyrocytes, was observed. Clones derived from these cell lines differed in their level of constitutive Class II expression and in their sensitivity to Class II induction by IFN-gamma. In conclusion, these thyroid cell lines could provide a useful tool for further investigation of HLA gene regulation in thyroid cells and for elucidating on the mechanism involved in the inappropriate HLA expression described in autoimmune and neoplastic diseases of the thyroid.
Autoantigens↗
Chronic diarrhea and malnutrition--histology of the small intestinal lesion.
The purpose of this study was to quantitate the jejunal lesion in Gambian children with chronic diarrhea-malnutrition syndrome. There were 40 subjects (20 male, 20 female) with a mean age of 19.7 months. All were severely malnourished, with marasmus in 30, marasmic kwashiorkor in 9, and kwashiorkor in 1. Of subjects tested, 70% were anergic to intradermal challenge with either purified protein derivative or candidin. Jejunal biopsies, performed on every subject after admission to hospital, were studied by computerised image analysis and immunocytochemistry. A spectrum of mucosal changes that varied from "normal" to "flat" was seen. Mucosae with "normal" architecture revealed infiltration of villous epithelium by small lymphocytes, while crypt hypertrophy was invariably present. At the other extreme, the surface epithelium of flat mucosae was less severely infiltrated, although heavy lymphoid infiltrates persisted within crypt epithelium. Immunohistochemical studies revealed that most intraepithelial lymphocytes were of the CD8 + phenotype. Mucosal morphology did not relate to clinical, biochemical, or anthropometric data for each child. These findings are consistent with an intestinal reaction to some environmental antigen (dietary, microbial, or both) of the cell-mediated type. This interpretation is strengthened by the expression of major histocompatibility class 2D locus alloantigens on crypt epithelial cells in the absence of gut-reactive autoantibodies.
Biopsy↗
Autoimmune enteropathy and colitis: is there a generalised autoimmune gut disorder?
Children with protracted diarrhoea, circulating enterocyte autoantibodies, and an enteropathy showing features of inappropriate HLA molecule expression on the jejunal crypt epithelium, often present with persistent blood and mucus in their stools. Eight children with autoimmune enteropathy were investigated for the presence of associated colonic disease. Six children with protracted diarrhoea, no circulating autoantibodies, and an enteropathy (in five of them) undergoing colonoscopy were used as control subjects. In all eight patients, but not in the control subjects, there was macroscopic and microscopic evidence of an accompanying colitis of variable severity, thus indicating that a more generalised intestinal disorder was present, which might affect the whole intestine. Aberrant expression of DR molecules on the colonic surface and crypt epithelium was also detected. Autoimmunity may play a role in the colitis.
Autoantibodies↗
On the pathogenesis of type 1 (insulin-dependent) diabetes mellitus: facts, areas still under development and new perspectives.
The observations emerged from the pancreatic transplant experiments in identical twins indicate that Type I diabetic patients maintain memory cytotoxic T cells for several years and these can be "re-awakened" when Class I identical beta cells are re-introduced into the diabetic melieu. In addition, these data have shown that these lymphocytes can (in a matter of a few weeks) cause rapid irreversible decompensation of beta cell function. From this, an important lesson is learnt: cytotoxic T cells, when generated in sufficient number against beta cells do not leave much "breathing space" for these cells. This has important implications for explaining the long latency period preceding the acute onset of Type I diabetes. ICA, when produced, seem unable to cause gross damage to beta cells. They persist for several years in the blood, but beta cell function remains apparently unaltered. It is only when cytotoxic T cells, with fine specificity for beta cells are generated that the 'killing cycle' is completed. Whether these cells are present all the time, and kept under tight control by active suppressor mechanisms or whether they appear only after an environmental trigger (e.g., retroviruses) is unknown. If the former is the case, this would give strong support to the suggested important role of suppressor T cells in the pathogenetic circuit. Some evidence for this has been produced (rev. in [116]) but, obviously, it requires confirmation (see debate which followed [116]). If, on the other hand, the latter is experimentally confirmed, one can return to the theory that cytotoxic T cells acquire the characteristics of autoreactivity by expressing receptors on their surface in a configuration which enables combination with self-autoantigens (rev. in [45]). In summary, the study of the etiopathogenesis of Type I diabetes and human autoimmunity in general has attracted a great deal of interest among immunologists. It is only by further dissecting the various limbs of the undesirable immune response against beta cells and, by trying to formulate novel hypotheses, sometimes against accepted dogmas [32], that the complete picture will be finally disclosed. At this stage it will be possible to design effective therapy trials, so that Type I diabetes and other related autoimmune disorders ultimately may be prevented.
Autoantibodies↗
Retrovirus-like sequences in Graves' disease: implications for human autoimmunity.
On Southern blotting of DNA extracted from thyroid glands of five patients with Graves' disease, two probes (720 bp and 942 bp) for gag human immunodeficiency virus type 1 (HIV-1) gave a positive hybridisation signal in all samples tested. DNAs from peripheral blood mononuclear cells hybridised with the 720 bp gag HIV-1 probe in three of the five patients, none of whom had antibodies to HIV-1. Negative results were obtained with DNA from normal thyroid glands, thyroid neoplasms, various unrelated normal tissues, and virus-infected human cell lines. The intensity of the signal and the pattern of bands observed with the DNA of Graves' patients were heterogeneous and, in general, were not the same in the thyroid glands and peripheral blood mononuclear cells of individual patients. Similarly, no correlation was found between the positive hybridisation signals and other genetic and immunological indices or the duration of anti-thyroid drug treatment at the time the patients were investigated. The findings suggest the presence of a novel retrovirus, and the retrovirus-like sequences seem to be closely associated with thyroid autoimmunity.
Adolescent↗
Pathogenesis of type I (insulin-dependent) diabetes: possible mechanisms of autoimmune damage.
By definition, autoimmunity is a circumvention of self-tolerance. Considering the complex network of control mechanisms which initiate and regulate immune responses to foreign agents and maintain the natural state of self-tolerance, autoimmunity may result from a weakening of this delicate equilibrium at various levels. Several hypotheses have therefore been put forward to explain the 'active' immunization process against self-constituents which are normally tolerated.
Autoantigens↗
Influence of tumor necrosis factor-alpha on the modulation by interferon-gamma of HLA class II molecules in human thyroid cells and its effect on interferon-gamma binding.
Cytokines are important modulators of immunological reactions, but it has been postulated that they might act on other unrelated epithelial cells. We studied the effects of recombinant interferon-gamma (rIFN gamma) and recombinant tumor necrosis factor-alpha (rTNF alpha) on normal human thyroid cells. We found that the combination of these two cytokines enhanced HLA class II molecule expression on these cells compared with the effect of rIFN gamma alone. This was proven by both immunofluorescence as well as a more sensitive and quantitative RIA. rTNF alpha alone had no effect on HLA class II molecule induction on the same thyrocytes, suggesting a synergistic rather than an additive action in combination with rIFN gamma. The addition of 600 U/ml rTNF alpha to low dose rIFN gamma (10 U/mL) enhanced class II expression by 50%, as quantified by RIA. We also demonstrated that normal thyrocytes possess distinct receptors for the two cytokines and that rTNF alpha probably augments IFN gamma binding, since it increased when the cells were first incubated with rTNF alpha. This increased binding provides an explanation for the synergistic action of rTNF alpha in enhancing class II molecule expression by rIFN gamma. We conclude that the presence of receptors for these cytokines on human thyroid cells gives a direct demonstration of their potential biological action on cells normally not involved in the immunological circuit. The phenomenon might also explain their direct or indirect involvement in vivo, such as in influencing inappropriate HLA class II molecule expression in epithelial cells affected by autoimmunity.
Binding Sites↗
Differential expression and regulation of major histocompatibility complex (MHC) products in neural and glial cells of the human fetal brain.
The cells of the central nervous system (CNS) have the peculiarity of physiologically expressing very low levels of HLA molecules. In multiple sclerosis (MS), however, as in endocrine autoimmune diseases, there is a marked increase of HLA expression in the tissue (i.e. the plaques) and this is attributable not only to infiltrating cells but also to the astrocytes. To gain an insight into the regulation of HLA in the different cell types in the CNS and to compare it to that observed in the endocrine organs, we have studied the effect of the lympho/monokines interferon (IFN)-alpha and -gamma, tumour necrosis factor (TNF)-alpha, and interleukin (IL)-2 and other agents on this aspect of the biology of human fetal brain cells in culture. A two-colour immunofluorescence technique which combines antibodies to diverse CNS cell markers and monoclonal antibodies (MoAbs) to the non-polymorphic region of HLA molecules was used throughout this study. In control cultures, only astrocytes expressed MHC class I, but after incubation with either IFN-gamma or TNF-alpha oligodendrocytes acquired class I expression. Surprisingly, astrocytes became spontaneously class II positive in culture and this was greatly enhanced by IFN-gamma. Other agents such as IL-2, epidermal growth factor, phorbolmyristate acetate and lectins had no effect. The expression of HLA molecules in the cells of the CNS both in basal conditions and in response to lymphokines is therefore selective and highly heterogenous, thus reflecting their intrinsic biological diversity. These findings may help to explain the features of the immunopathology of MS and also of latent viral infections of neural cells.
Astrocytes↗
HLA product expression and lymphocyte subpopulations in jejunum biopsies of children with idiopathic protracted diarrhoea and enterocyte autoantibodies.
Mature enterocytes from normal human small intestine express HLA Class II molecules, whereas the immature enterocytes of the crypts are devoid of these products. By the use of the Avidin/Biotin immunofluorescence technique, we examined HLA Class I and II expression on cryostat sections of jejunum biopsies from 10 children with idiopathic protracted diarrhoea (IPD) and circulating enterocyte autoantibodies (Ec-Abs). The results were compared with those obtained on gut specimens from nine children with protracted diarrhoea but no evidence of circulating Ec-Abs and from one child affected by gluten-sensitive enteropathy. HLA Class I expression was similar in control and pathological specimens but jejunum biopsies from children with IPD and high titres of Ec-Abs (greater than or equal to 1:64) showed 'inappropriate' Class II molecule expression in the crypt epithelial cells. This was in contrast with normal or only mildly increased Class II reactivity in the mature villi enterocytes. Conversely, jejunum biopsies from children with IPD but with low levels of Ec-Abs (less than or equal to 1:4) possessed a moderate but distinct decrease of Class II expression in mature enterocytes with a decreased number of CD3 and CD8 intraepithelial lymphocytes. It is speculated that quantitative and qualitative variations of HLA product expression in the gut epithelium of children with IPD could reflect the severity of the autoimmune process underlying the clinical picture and point to heterogeneities within the autoimmune enteropathy syndrome.
Antibodies, Monoclonal↗
Gastric cell c-AMP stimulating autoantibodies in duodenal ulcer disease.
Gastric cell c-AMP stimulating antibodies (GCS-Ab) were studied in 30 patients with duodenal ulcer (DU) disease. Semipurified immunoglobulin (Ig) preparations from 13/30 patients stimulated c-AMP production in parietal cell enriched gastric cell suspensions obtained from male guinea pig stomachs. Maximum stimulation (varying between 260 and 547%) was reached after four hours incubation with 2 and 4 mg/ml Ig concentrations. The 13 patients with gastric cell stimulating antibodies (GCS-Ab), all male patients, developed the disease at a younger age (nine of 13 under the age of 30), had a longer duration of symptoms (mean 18.4 years), and had a higher incidence of DU in their families (61%). Eight of 13 (61%) in the GCS-Ab+ group did not respond to anti-H2-R drugs, whereas in the negative patients only three of 17 (18%) were classified as 'non-responders'. Remarkably few conventional autoantibodies were detected in our series. Gastric cell stimulating antibodies are a new addition to the growing list of receptor antibodies in human diseases and the described in vitro test should provide an easier tool for screening large populations.
Adult↗
HLA molecule expression on chronic pancreatitis specimens: is there a role for autoimmunity? A preliminary study.
This study was prospectively carried out in order to clarify if an aberrant expression of HLA-DR molecules could take part in the pathogenesis of chronic pancreatitis. Pancreatic specimens from 12 chronic pancreatitis patients and nine controls were examined. Strong HLA-DR expression was observed in 6/12 chronic pancreatitis patients and in 1/9 controls. Moreover, lymphocytic foci with large numbers of activated cells were found only in chronic pancreatitis. The four HLA-DR - patients had a marked increase of fibrous tissue with small portions of acinar tissue, whereas the six patients with strong positivity had the greatest dilatation and hyperplasia of the ducts. These findings are similar to those observed in immune diseases, such as thyroiditis and primary biliary cirrhosis (PBC), and suggest that autoimmune phenomena are involved in chronic pancreatitis.
Adult↗
HLA antigens in chronic pancreatitis.
Since immunological and hereditary factors may be important in chronic pancreatitis, histocompatibility antigens of classes I and II were studied in 50 British Caucasian patients, after exclusion of insulin-dependent diabetics for whom HLA associations are recognised. Chronic pancreatitis was defined by at least two independent criteria, and only subjects with alcohol-related and idiopathic disease were included. In 22 patients (21 male), weekly ethanol intake had chronically exceeded 100 g (usually substantially so); the remaining 28 had idiopathic chronic pancreatitis (ICP). Twenty patients (40%) had autoantibodies, in 11 (22%) to gastric parietal cells. Nine of those with ICP (three male) had parietal cell antibody, more than expected for the age/sex distribution. There were overall increased frequencies of HLA Cw5 and B44. In ICP there were increased frequencies of HLA A25 and Cw1, and a decreased frequency of B7. In patients with alcohol-related disease there were increased frequencies of Cw5 (50.0% vs control 15.9%), B44 (54.5% vs 29.4%), and DR4 (61.1% vs 33.6%). The increased frequency of Cw5 in alcohol-related disease alone remained significant after correction (p less than 0.05). A hypothesis that hereditary and possibly immunological factors may contribute to the aetiology of chronic pancreatitis is supported.
Alcoholism↗