epidermal-growth-factor and Autoimmune-Diseases

The inflammatory bowel diseases known as Crohn's disease (CD) and ulcerative colitis (UC) are related autoimmune conditions with a complex etiology composed of genetic and environmental factors. Genetic studies have revealed 200 susceptibility loci for inflammatory bowel diseases, but these only account for a small fraction of the genetic heritability of the disease. We employed pathway-based approaches to identify genes that cooperatively make contributions to the genetic etiology of CD.. We exploited the largest CD dataset (20,000 cases + 28,000 controls) and UC dataset (17,000 cases + 33,500 controls) to date. We conducted a meta-analysis of 5 CD cohorts of European ancestry using 3 pathway-based approaches and further performed replication studies in an independent cohort genotyped on the Immunochip and in another pediatric cohort of European ancestry. Similar meta-analysis was performed for UC cohorts.. In addition to the multiple immune-related pathways that have been implicated in the genetic etiology of inflammatory bowel diseases before, we found significant associations involving genes in growth factor signaling for CD. This result was replicated in 2 independent cohorts of European ancestry. This association with growth factor activity is not unique to CD. We found a similar significant association with UC cohorts.. Our findings suggest that genes involved in pathways of growth factor signaling may make joint contributions to the etiology of CD and UC, providing novel insight into the genetic mechanisms of these diseases.

Topics: Autoimmune Diseases; Colitis, Ulcerative; Crohn Disease; Cytokines; Databases, Genetic; Epidermal Growth Factor; Gene Ontology; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Intercellular Signaling Peptides and Proteins; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Quantitative Trait Loci; Receptors, Cytokine; Signal Transduction; STAT Transcription Factors; White People

Inflammation involves a series of complex biological processes mediated by innate immunity for host defense against pathogen infection. Chronic inflammation is considered to be one of the major causes of serious diseases, including a number of autoimmune/inflammatory diseases, cancers, cardiovascular diseases, and neurological diseases. Milk fat globule-epidermal growth factor 8 (MFG-E8) is a secreted protein found in vertebrates and was initially discovered as a critical component of the milk fat globule. Previously, a number of studies have reported that MFG-E8 contributes to various biological functions including the phagocytic removal of damaged and apoptotic cells from tissues, the induction of VEGF-mediated neovascularization, the maintenance of intestinal epithelial homeostasis, and the promotion of mucosal healing. Recently, emerging studies have reported that MFG-E8 plays a role in inflammatory responses and inflammatory/autoimmune diseases. This review describes the characteristics of MFG-E8-mediated signaling pathways, summarizes recent findings supporting the roles of MFG-E8 in inflammatory responses and inflammatory/autoimmune diseases, and discusses MFG-E8 targeting as a potential therapeutic strategy for the development of anti-inflammatory/autoimmune disease drugs.

Topics: Animals; Autoimmune Diseases; Epidermal Growth Factor; Glycolipids; Glycoproteins; Humans; Inflammation; Lipid Droplets; Macrophages

Healthy human labial salivary glands produce epidermal growth factor (EGF). In Sjögren's syndrome (SS), EGF staining is diminished. SS is also associated with chronic autoimmune corpus gastritis. We therefore hypothesized that EGF secretion would be diminished in SS and that this could affect gastric target cells.. Salivary EGF secretion in SS was compared to that in healthy controls using an enzyme-linked immunosorbent assay (ELISA). EGF receptor (EGFR) immunoreactive cells in the gastric corpus of healthy human subjects were analysed using immunostaining.. Salivary secretion of EGF was diminished in SS patients (232.4, range 52.6-618.4, vs. 756.6, range 105.3-1631.6 pg/min, p = 0.002). Proton-pump positive parietal cells were mostly EGFR immunoreactive whereas very few pepsinogen I (PGI)-positive cells were EGFR positive.. As EGF is relatively acid resistant, salivary gland-derived EGF might participate in an exo/endocrine mode of parietal cell maintenance in the gastric corpus. Deficiency of salivary gland-derived EGF in SS patients may cause impairment of gastric parietal cells resulting in exposure of immunogenic cryptic antigens and loss of immunological self-tolerance.

Topics: Adult; Aged; Autoimmune Diseases; Case-Control Studies; Chief Cells, Gastric; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; ErbB Receptors; Female; Gastric Mucosa; Gastritis; Humans; Immunohistochemistry; Middle Aged; Parietal Cells, Gastric; Saliva; Sjogren's Syndrome; Young Adult

A prominent pathological feature of murine autoimmune gastritis is a pronounced mucosal hypertrophy. Here, we examined factors that may be responsible for inducing this hypertrophy. Because gastrin is known to be both an inducer of gastric mucosal cell proliferation and is elevated in autoimmune gastritis, mice deficient in gastrin were thymectomised at day 3 and assessed for autoimmune gastritis. Gastrin-deficient mice showed all the characteristic features of murine autoimmune gastritis, including gastric unit hypertrophy due to hyperproliferation and accumulation of immature epithelial cells, decreases in the number of zymogenic and parietal cells, and autoantibodies to the gastric H+/K+-ATPase. Hence, gastrin is not required for either the establishment of chronic gastritis or development of the typical pathological features of this disease. We also examined mRNA levels of a number of gastric mucosal growth factors in RNA samples from mice with hypertrophic autoimmune gastritis. Members of the Reg family, RegIIIbeta and RegIIIgamma, were greatly elevated in mice with hypertrophic gastritis, whereas RegI and amphiregulin (an EGF receptor ligand) were more modestly and/or inconsistently induced. These data demonstrate that induction of gastric mitogenic factors, such as members of the Reg family, can be achieved in inflammatory situations by gastrin-independent pathways. Members of the Reg family, in particular RegIIIbeta and RegIIIgamma, are good candidates to be involved in inducing the mucosal hyperproliferation in autoimmune gastritis. These findings are likely to be of relevance to other gastric inflammatory conditions.

Topics: Amphiregulin; Animals; Autoantibodies; Autoimmune Diseases; Chronic Disease; EGF Family of Proteins; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Gastrins; Gastritis; Gene Expression; Glycoproteins; Growth Substances; H(+)-K(+)-Exchanging ATPase; Heparin-binding EGF-like Growth Factor; Hypertrophy; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Proteins; RNA, Messenger; Transforming Growth Factor alpha

Epithelial cells appear to play an important role in the initiation and maintenance of autoimmune lesions in the salivary glands of patients with Sjogren's syndrome. Therefore, the detailed study of immunological function of salivary gland epithelial cells (SGEC) may provide useful information for the understanding of Sjögren's syndrome pathogenesis. In this report we aimed to formulate a protocol for the establishment of human non-neoplastic SGEC lines as a tool for the study of the physiology and pathophysiology of these cells. Pointing towards a practical approach, we sought to establish SGEC lines from quite a limited amount of biopsy tissue obtained during the diagnostic evaluation of patients. Herein, the favorable conditions for the long-term maintenance of human non-neoplastic SGEC lines are presented and involve the successive application of a serum-containing and a serum-free culture medium, supplemented with essential epithelial growth factors. This protocol has been found reliable and convenient, as attested by the reproducible establishment of non-neoplastic SGEC lines. The analysis of SGEC phenotypic features, as well as a coculture system for the study of interactions between epithelial cells and lymphocytes, are also described. Such techniques may provide valuable means for the functional and molecular investigation of human SGEC and particularly for the study of Sjögren's syndrome and other disorders of glandular epithelia.

Topics: Apoptosis; Autoimmune Diseases; Biopsy; CD4-Positive T-Lymphocytes; Cell Communication; Cell Culture Techniques; Cell Division; Coculture Techniques; Culture Media; Culture Media, Serum-Free; Epidermal Growth Factor; Epithelial Cells; Humans; Leukemia, T-Cell; Phenotype; Reproducibility of Results; Salivary Glands; Sjogren's Syndrome; T-Lymphocytes; Time Factors

No consensus has been obtained about the question whether autoantibodies, in particular antiphospholipid antibodies (aPL), may cause thrombosis by inhibiting thrombomodulin (TM) mediated protein C activation. In order to clarify the mechanism by which autoantibodies inhibit TM-mediated protein C activation, we have screened 12 patients with autoimmune diseases for the presence of circulating autoantibodies inhibiting TM function. In a cross-sectional study we found that IgG fractions from two patients (who were aPL negative) inhibited TM mediated protein C activation in an assay system using purified components. A longitudinal study of six patients with a history of thrombosis of which two were aPL positive showed that all had at some time circulating antibodies inhibiting TM function, suggesting that the presence of these antibodies is transient. Three different TMs were used to identify the epitope of the antithrombomodulin antibodies (aTM): rabbit TM, which contains the entire TM molecule; Solulin, which contains the extracellular part of TM, and rEGF-TM, which contains the six epidermal growth factor (EGF) domains of TM. We showed that the aTM inhibited protein C activation mediated by all three TMs, indicating that the aTM are directed against the region containing the EGF domains. When TM was incorporated in phospholipid vesicles, no inhibition by these aTM could be demonstrated. In addition, protein C activation mediated by cultured endothelial cells (EC) could not be inhibited by aTM. The lack of inhibition of TM in phospholipid vesicles and EC-TM by a TM suggests that aTM only inhibit soluble TM. In conclusion, we demonstrated the transient presence of circulating autoantibodies directed against the region of TM containing the EGF domains in SLE patients with a history of thrombotic complications. We postulate that the presence of antibodies to soluble TM may be, in addition to aPL, a risk factor for the occurrence of thrombosis in patients with autoimmune diseases.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Epitopes; Female; Humans; Immunoglobulin G; Longitudinal Studies; Male; Middle Aged; Protein C; Protein C Inhibitor; Thrombomodulin; Thrombosis

Experimental autoimmune uveoretinitis was induced in female Lewis rats with bovine retinal soluble antigen (S-antigen). Tissue changes and immunoreactivities of transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), and extracellular matrix compounds in the anterior segment (ciliary body) were investigated by immunocytochemical methods. Control animals received adjuvant only. The immunized animals were sacrificed at day 0, 3, 7, 14, 20, and 30 postimmunization. Tissue changes that occurred at the peak of inflammation (day 14) included destruction of the inner basement membrane, epithelial cell loss, distortion of the ciliary stroma, and loss of epithelial basal infoldings. Ciliary body architecture was regenerated almost completely by day 30. Basement membrane laminin and collagen type IV levels did not change much during the inflammatory process. Fibronectin labeling level peaked at day 14 postimmunization. Collagen type V level was low at day 14 and elevated at day 20 and day 30. TGF-beta immunoreactivity peaked at day 14 and remained elevated thereafter. EGF labeling did not increase until day 20 and was maximal at day 30. Labeling of both growth factors was principally confinded to the stromal regions. The presence of TGF-beta and EGF in the ciliary stroma at well defined intervals suggests a coordinated effect upon the synthesis and reorganization of the extracellular matrix and possibly upon the inflammatory cell population in the anterior tissue.

Topics: Animals; Antigens; Arrestin; Autoimmune Diseases; Ciliary Body; Disease Models, Animal; Epidermal Growth Factor; Extracellular Matrix Proteins; Eye Proteins; Female; Immunohistochemistry; Phosphodiesterase Inhibitors; Rats; Rats, Inbred Lew; Transforming Growth Factor beta; Uveitis

Parotid saliva was collected over a 12-min period from 24 insulin dependent diabetic patients with varying degrees of autonomic neuropathy and 12 age and sex matched non-diabetic controls. Epidermal growth factor (EGF) concentrations in saliva were measured by radio-immunoassay. The EGF concentrations in diabetics with no autonomic neuropathy or with combined autonomic neuropathy were equivalent but secretion of EGF was significantly elevated at the 6- and 12-min periods of collection in diabetic patients with early or established autonomic neuropathy. It is postulated that when parasympathetic autonomic neuropathy is present a relative "over-activity" of the sympathetic innervation promotes release of salivary EGF. This sympathetic predominance may maintain salivary EGF concentration despite the elevated salivary flow and volume which is associated with parasympathetic autonomic neuropathy.

Topics: Autoimmune Diseases; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 1; Epidermal Growth Factor; Female; Humans; Male; Parotid Gland; Saliva; Sympathetic Nervous System