Nota bene: evolutionary biology. The male's dilemma.
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Animals↗
Biomedical subjects
R B Gallagher
Publications and source records attributed to R B Gallagher.
Population biology of lymphocytes.
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Animals↗
What are we? Where did we come from? Where are we going?
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Animals↗
Intestinal gluten sensitivity: snapshots of an unusual autoimmune-like disease.
Gluten-sensitive disease is activated in genetically susceptible individuals by the ingestion of wheat protein (gluten). Breakdown in normal tolerogenic processes to dietary gluten is likely to play a primary pathogenic role. The disease is characterized by several autoimmune-type features and provides a model for studying autoimmune processes. A recent meeting emphasized the need for a clearer picture of the molecular interactions between disease triggering agents, molecules of the immune system and other products of disease susceptibility genes.
Autoimmune Diseases↗
Mucosal and systemic IgA anti-gliadin antibody in celiac disease. Contrasting patterns of response in serum, saliva, and intestinal secretions.
Serum IgA anti-gliadin antibody estimation is a recognized screening method for celiac disease. However, celiac disease is primarily a small intestinal mucosal disorder, and so we have examined the possibility that secreted, mucosal IgA anti-gliadin antibody might provide a more relevant measure of gluten sensitivity than that obtained from serum tests. Serum IgA anti-gliadin antibody and serum, salivary, and small intestinal aspirate IgA anti-gliadin antibody were measured by enzyme-linked immunosorbent assay. Serum IgA and IgG anti-gliadin antibody were markedly increased in untreated celiacs (N = 31) as compared to normals (N = 20) or disease controls (N = 39) (P less than 0.0001). Levels were lower in treated (N = 30) than untreated celiacs (P less than 0.001). In intestinal aspirates both untreated and treated patients had similar levels of IgA anti-gliadin antibody (P = 0.48), but both were significantly higher than in controls (P less than 0.01). Salivary IgA anti-gliadin antibody, by contrast, was not increased in celiac patients as compared to controls. Serum IgA anti-gliadin antibody was the most sensitive (84%) and specific (95%) test for detecting untreated celiac disease. It was also the most useful in patient follow-up where it provides an early objective indicator of adherence to a gluten-free diet. Mucosal IgA responses to gliadin in celiac disease appear to be compartmentalized, with different portions of the gastrointestinal tract functioning as separate immunological organs. Our results also demonstrate that serum and secretory IgA production are under independent control.
Adult↗
Hard graft? Future challenges in transplantation.
A small group of transplantation surgeons, immunologists and molecular biologists gathered in Vienna in early February to discuss the prospects for organ transplantation. Participants at the meeting were challenged with setting goals for transplantation research and with speculating on how this research might influence the practice of transplantation in the next two decades. Some goals were set, but the most vigorous discussion focused on the existing barriers that stand in the way of achieving these goals.
Antigens↗
To B, or not to B: that is the question.
Irrespective of the prevailing fashion, Germinal Centre Conferences (GCC) have treated the immune system in a determinedly holistic manner. At the recent 10th GCC* the advantages of this approach were demonstrated in elegant new schema for lymphocyte development, accessory cell function, tolerance and autoimmunity, and for the organization and function of mucosal defence. This report concentrates on only one aspect of the meeting - the development of an integrated view of the natural history of B cells.
Animals↗
Signal transmission pathways and lymphocyte function.
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Animals↗
Diagnosis and treatment of gluten-sensitive enteropathy.
Celiac disease is defined as a GSE. The small intestinal histological appearance of villous atrophy with crypt hyperplasia, inflammatory cell infiltrate of the lamina propria, and epithelial cell abnormalities is characteristic but not pathognomonic of the disorder. Confirmation of the diagnosis depends on histological improvement when gluten is removed from the diet and deterioration following gluten reintroduction. The pathogenesis of celiac disease appears to require interaction between a number of factors both intrinsic (genetic susceptibility, activation of the immune system) and extrinsic (gluten susceptibility, activation of the immune system) and extrinsic (gluten and possibly other environmental factors). The diagnosis of GSE may be delayed or missed unless the clinician is aware of the broad clinical spectrum of disease presentation. Although celiac disease is widely perceived as a malabsorption syndrome of childhood, the diagnosis is increasingly being made for the first time in adult life. A significant number of patients have no GI symptoms whatsoever. Small intestinal biopsy through the endoscope is the initial and definitive investigation. Most patients show excellent clinical and histological response to a gluten-free diet. The commonest reason for poor response is continuing intentional or inadvertent gluten intake. A minority of patients develop complications, in particular intestinal malignancy, including enteropathy-associated T-cell lymphoma.
Celiac Disease↗
Complement activation within the coeliac small intestine is localised to Brunner's glands.
Complement activation may play an important role in the pathogenesis of coeliac disease. In the present study immunohistochemical localisation of C3 and of a neoantigen exposed only on the terminal C5b-9 complement complex has been performed on small intestinal biopsy sections from newly diagnosed untreated coeliac patients, from coeliac patients on long-term gluten-free diet and from disease controls. Levels of C3 were markedly increased in treated coeliac patients compared with controls. Staining of C3 was concentrated subepithelially and within the centre of the lamina propria. No staining was detected at these sites using antibody to the neoantigen, however, strongly suggesting that the increased levels of C3 seen in the coeliac patients was the result of increased extravasation of serum proteins rather than complement activation. Surprisingly, complement activation was detected within the glands of Brunner. Positive staining using anti-C5b-9 neoantigen was found in all coeliac patients, both treated and untreated. Three of the 13 disease controls also showed reactivity with this antibody. This novel finding suggests that Brunner's glands, hitherto largely neglected structures, may play an important role in the development of coeliac disease.
Antigens↗
The subclass profile and complement activating potential of anti-alpha-gliadin antibodies in coeliac disease.
In a randomly selected group of coeliac patients, alpha-gliadin antibodies (AGA) of subclasses IgG1 and IgG3 were significantly elevated (p less than 0.01) in comparison to both normal and disease control groups. This result was, however, influenced by increased total AGA levels in the coeliac patients. AGA subclass profiles of cohorts of coeliac and normal controls matched for total IgG AGA were therefore compared. It was found that IgG3 AGA levels were higher in the coeliac group (p = 0.006) while IgG4 titres were higher in the control group (p = 0.005). Titres of IgG1 and IgG2 AGA did not differ between the two groups. Because of the marked differences between the ability of IgG3 and IgG4 to activate complement, alpha-gliadin-specific complement fixation was measured. Using randomly selected coeliac and normal sera, the patient group activated highly significantly greater quantities of complement than controls (p less than 0.01). Furthermore, when samples matched for total IgG AGA were compared, sera from coeliac patients were again found to activate greater amounts of complement than sera from controls (p = 0.024). Thus AGA in coeliac sera are both structurally and functionally distinguishable from AGA in normal control sera.
Adolescent↗
Altered immunological reactivity in alveolar macrophages from patients with sarcoidosis.
Lung macrophages may play an important role in the pathogenesis of pulmonary sarcoidosis. In this study, the ability of pulmonary macrophages and blood monocytes from sarcoidosis patients, normal controls and disease controls to provide the accessory signal necessary for the concanavalin A-induced activation of normal blood T cells was examined. Blood monocytes from all groups supplied a significantly greater accessory signal than lung macrophages. The accessory capacity of lavage macrophages from sarcoidosis patients varied over a wide range and correlations were sought between these values and other parameters of disease activity. Whilst there was no correlation with clinical parameters, accessory function of alveolar macrophages correlated significantly with the percentage of T helper cells in bronchoalveolar lavage (BAL) fluid (p less than 0.05) and, more closely, with the T helper:T suppressor ratio in BAL fluid (p less than 0.01). This interrelationship between macrophage activity and the T cell infiltrate favours the probability that both cell types participate in the sarcoid disease process and raises the possibility that T cells of both helper and suppressor phenotypes contribute to the pathogenesis.
Adult↗
Studies on the interaction between alpha-gliadin and HLA and T cell receptor molecules in coeliac disease.
Coeliac disease has a known strong linkage with the HLA complex and has also recently been linked to the T cell receptor genes but the mechanism whereby these genes confer susceptibility is not known. This study has examined two possible mechanisms: (i) direct, lectin-like binding of alpha-gliadin (the causative agent of CD) to HLA or TcR molecules and (ii) antigenic cross-reactivity between alpha-gliadin and HLA or TcR molecules. A flow cytometer was used to assess interactions between alpha-gliadin, anti-alpha-gliadin antibodies (raised in both coeliac patients and in rabbits) and EBV-transformed B cell lines from coeliac patients and HLA-matched and mismatched normal controls. The B cell lines were shown to express HLA-DP, -DQ and -DR antigens which are also found on coeliac intestinal epithelial cells. After incubating B cell lines with alpha-gliadin over a wide range of concentrations, no binding of alpha-gliadin to any of the cell lines could be detected with either of the gliadin-specific antibodies. This suggests that HLA molecules do not bind to alpha-gliadin in a lectin-like fashion. In contrast to the B cell lines, alpha-gliadin binding to peripheral blood monocytes could be demonstrated. This binding occurred equally to patient and control monocytes and was not influenced by HLA allotype. The second possibility tested was that alpha-gliadin and the disease-associated HLA molecule bear antigenic similarities. However, neither rabbit anti-gliadin serum nor purified human alpha-gliadin antibody bound directly to the B cell lines. Using peripheral blood T cells similar results were obtained; no binding of alpha-gliadin or antibodies to alpha-gliadin was found. Thus this study shows that the HLA and TcR associations with CD are not explained by the direct binding of alpha-gliadin to these molecules nor by a sharing of antigenic determinants between alpha-gliadin and these molecules.
B-Lymphocytes↗
Susceptibility to coeliac disease involves genes in HLA-DP region.
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Celiac Disease↗
Studies on the accessory requirement for T lymphocyte activation by concanavalin A.
In this study we have examined the interactions between accessory cells (AC) and T cells in response to Con A. Highly purified peripheral blood T cells and AC exposed to a variety of treatments were used. We found that untreated AC provided optimal help for T cell proliferation and this was not mediated by soluble factors since whole cells could not be replaced with supernatants from activated AC. Furthermore, cycloheximide-treated AC were able to supply the accessory signal although unable to elaborate soluble activation factors. To find out more about the accessory signal, we examined the ability of monocytes mildly fixed with glutaraldehyde to supply help. These cells were completely unable to perform as AC, although they were viable and had unaltered surface antigen expression. They could not secrete activation factors, but this alone could not explain their inability to supply help because this function was not restored with the addition of soluble activation factors. This indicated that AC-T cell contact was of prime importance to accessory function. To investigate the possibility that AC work by cross-linking structures on the lymphocyte surface, we attempted to substitute for the soluble Con A plus AC with Con A bound to the surface of erythrocytes. Comparable stimulation was observed, suggesting that the cross-linking of Con A-bound structures on the lymphocyte surface generates the accessory signal.
Antigen-Presenting Cells↗