Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate effects of circulating myelin basic protein (MBP) on the endocrine pancreas, we injected bovine MBP to Djungarian hamsters and studied the morphological changes induced by MBP and its immunocytochemical distribution by electron microscopy. After a treatment time of 5-40 min, some islets appeared severely damaged, especially at their peripheries and near the intraislet capillaries, while others showed minor or no changes. MBP-induced extracellular changes included partial disintegration of the collagen filament network surrounding the islet and the blood vessels. These changes correlated with the association of MBP with the collagen filament bundles and related structures. Intracellularly, the effect of MBP included formation of vacuoles, dilatation of rough ER and Golgi membranes, swelling and aggregation of mitochondria, and disruption of the membranes of part of the insulin and glucagon granules, as well as damage to some plasma membranes. In the damaged B cells, 16-62% of the insulin granules exhibited an enlarged pale core, compared to 1-2% in the control B cells. MBP was shown to associate with mitochondria and with various intracellular membranes in all islet cells. In the B cells, MBP was localized to the membranes of insulin granules, and it also associated with the cores of the granules. In the A cells, the association of MBP to the glucagon granules was mainly with the outsides of the membranes. Interaction of MBP with the secretion granules is suggested to play a role in MBP-induced insulin and glucagon release, and some hormone might be released by leakage. Association of MBP with mitochondria, Golgi structures, and ER may lead to changes in various cellular functions.
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PMID:Myelin basic protein induces morphological changes in the endocrine pancreas. 951 Jan 42

The role of the thymus in the induction of tolerance to peripheral antigens is not yet well defined. One impending question involves how the thymus can acquire the diversity of peripheral nonthymic self-Ags for the process of negative selection. To investigate whether peripheral Ags are synthesized in the thymus itself, we have determined the expression of a panel of circulating and cell-bound peripheral Ags, some of which are targets of autoimmune diseases, at the mRNA level in total thymic tissue and in its main cellular fractions. Normalized and calibrated RT-PCR experiments demonstrated the presence of transcripts of nonthymic self-Ags in human thymi from 8 days to 13-yr-old donors. Out of 12 glands, albumin transcripts were found in 12; insulin, glucagon, thyroid peroxidase, and glutamic acid decarboxylase (GAD)-67 in six, thyroglobulin in five, myelin basic protein and retinal S Ag in three, and GAD-65 in one. The levels of peripheral Ag transcripts detected were age-related but also showed marked interindividual differences. Cytokeratin-positive stromal epithelial cells, which are a likely cellular source for these, contained up to 200 transcript copies of the most expressed peripheral Ags per cell. These results implicate the human thymus in the expression of wide representation of peripheral self-Ags and support the view that the thymus is involved in the establishment of tolerance to peripheral Ags. The existence of such central mechanism of tolerance is crucial for the understanding of organ-specific autoimmune diseases.
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PMID:Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens. 983 72

The mechanism by which tolerance is broken in the induction of autoimmunity is unknown. Simple, well-characterized antigens suggest that molecular complementarity may play a key role in breaking tolerance. Experimental allergic encephalomyelitis can be induced using myelin basic protein combined with muramyl dipeptide. These molecules bind specifically to each other. Insulin antibodies can be induced when insulin is combined with glucagon, to which it binds. These cases suggest that molecular complementarity may alter the processing of "self" proteins. Antigenic complementary yields molecularly complementary immune responses (i.e., idiotypic-anti-idiotypic), undermining immune system regulation. In addition, complementarity insures that the antibodies (or T cells) directed against one antigen will molecularly mimic the other antigen, and vice versa, so that "self" and "nonself" will be confused. If at least one complementary antigen mimics a "self" protein, then an unregulated, self-sustaining immune response against tissue results. This testable theory of antigenic complementarity in autoimmunity is reviewed.
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PMID:Antigenic complementarity in the induction of autoimmunity: a general theory and review. 1741 97

Evidence is reviewed that complementary proteins and peptides form complexes with increased antigenicity and/or autoimmunogenicity. Five case studies are highlighted: 1) diphtheria toxin-antitoxin (antibody), which induces immunity to the normally non-antigenic toxin, and autoimmune neuritis; 2) tryptophan peptide of myelin basic protein and muramyl dipeptide ("adjuvant peptide"), which form a complex that induces experimental allergic encephalomyelitis; 3) an insulin and glucagon complex that is far more antigenic than either component individually; 4) various causes of experimental autoimmune myocarditis such as C protein in combination with its antibody, or coxsackie B virus in combination with the coxsackie and adenovirus receptor; 5) influenza A virus haemagglutinin with the outer membrane protein of the Haemophilus influenzae, which increases antigenicity. Several mechanisms cooperate to alter immunogenicity. Complexation alters antigen processing, protecting the components against proteolysis, altering fragmentation and presenting novel antigens to the immune system. Complementary antigens induce complementary adaptive immune responses (complementary antibodies and/or T cell receptors) that produce circulating immune complexes (CIC). CIC stimulate innate immunity. Concurrently, complementary antigens stimulate multiple Toll-like receptors that synergize to over-produce cytokines, which further stimulate adaptive immunity. Thus innate and adaptive immunity form a positive feedback loop. If components of the complex mimic a host protein, then autoimmunity may result. Enhanced antigenicity for production of improved vaccines and/or therapeutic autoimmunity (e.g., against cancer cells) might be achieved by using information from antibody or TCR recognition sites to complement an antigen; by panning for complements in randomized peptide libraries; or using antisense peptide strategies to design complements.
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PMID:How to Make a Non-Antigenic Protein (Auto) Antigenic: Molecular Complementarity Alters Antigen Processing and Activates Adaptive-Innate Immunity Synergy. 2617 68


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