intrinsic-factor and Disease-Models--Animal

Human autoimmune gastritis is an organ-specific autoimmune disease of the stomach. It is characterized by the development of disease-specific autoantibodies and a pathology that specifically targets specialized cells within the gastric environment. The autoantigens associated with this disease have been defined as the gastric H+/K+ ATPase and intrinsic factor. The development of experimental disease models has been pivotal in our contemporary understanding of autoimmunity. Here we review mouse models of autoimmune gastritis and their relevance to human autoimmune gastritis associated with pernicious anemia. We appraise some historical as well as recent studies of experimental autoimmune gastritis (EAG), highlighting key findings that have formed the basis of our current understanding of the etiology and mechanism(s) associated with autoimmune gastritis. A precise understanding of the pathogenesis of autoimmune gastritis will permit the design of innovative and rational therapeutic strategies to prevent, arrest, ameliorate or reverse the disease.

Topics: Anemia, Pernicious; Animals; Autoimmune Diseases; Disease Models, Animal; Gastritis; H(+)-K(+)-Exchanging ATPase; Intrinsic Factor; Mice; Mice, Inbred C3H; Parietal Cells, Gastric

Topics: Animals; Cobalt Isotopes; Disease Models, Animal; Intestinal Absorption; Intrinsic Factor; Malabsorption Syndromes; Pancreas; Pancreatectomy; Pancreatic Diseases; Rats; Tissue Extracts; Vitamin B 12

Skin epidermis constitutes the exterior barrier that protects the body from dehydration and environmental assaults. Barrier defects underlie common inflammatory skin diseases, but the molecular mechanisms that maintain barrier integrity and regulate epidermal-immune cell cross-talk in inflamed skin are not fully understood. In this study, we show that skin epithelia-specific deletion of Ovol1, which encodes a skin disease‒linked transcriptional repressor, impairs the epidermal barrier and aggravates psoriasis-like skin inflammation in mice in part by enhancing neutrophil accumulation and abscess formation. Through molecular studies, we identify IL-33, a cytokine with known pro-inflammatory and anti-inflammatory activities, and Cxcl1, a neutrophil-attracting chemokine, as potential weak and strong direct targets of Ovol1, respectively. Furthermore, we provide functional evidence that elevated Il33 expression reduces disease severity in imiquimod-treated Ovol1-deficient mice, whereas persistent accumulation and epidermal migration of neutrophils exacerbate it. Collectively, our study uncovers the importance of an epidermally expressed transcription factor that regulates both the integrity of the epidermal barrier and the behavior of neutrophils in psoriasis-like inflammation.

Topics: Animals; Dermatitis; Disease Models, Animal; DNA-Binding Proteins; Epidermis; Inflammation; Intrinsic Factor; Keratinocytes; Mice; Neutrophils; Psoriasis; Skin; Transcription Factors

Researchers have developed murine lymphopenic, non-lymphopenic, transgenic, spontaneous and infectious agent based models to induce an experimental autoimmune gastritis (EAG) for the study of human organ-specific autoimmune disease. These models result in a chronic inflammatory mononuclear cell infiltrate in the gastric mucosa, destruction of parietal and zymogenic cells with autoantibodies reactive to the gastric parietal cells and the gastric H+/K+ ATPase (ATP4), arguably hallmarks of a human autoimmune gastritis (AIG). In the case of AIG, it is well documented that, in addition to parietal cell antibodies being detected in up to 90% of patients, up to 70% have intrinsic factor antibodies with the later antibodies considered highly specific to patients with pernicious anemia. This is the first report specifically investigating the occurrence of intrinsic factor antibodies, cobalamin deficiency and pernicious anemia in EAG models. We conclude, in contrast to AIG, that, in the three EAG models examined, intrinsic factor is not selected as a critical autoantigen.

Topics: Anemia, Pernicious; Animals; Autoantibodies; Autoantigens; Autoimmune Diseases; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gastritis; H(+)-K(+)-Exchanging ATPase; Immunoblotting; Intrinsic Factor; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Vitamin B 12; Vitamin B 12 Deficiency

Experimental autoimmune gastritis (AIG), defined by the appearance of auto antibodies to parietal cells, was induced by neonatal thymectomy in BALB/c nu/+mice 3 days after birth. Vitamin B12 absorption and intrinsic factor in the stomach extract decreased compared with those in AIG-negative control groups. No decrease of the serum A/G ratio in AIG-bearing mice was observed. Although development of anemia, as evaluated by a decrease in hematocrit value, was poor until 12 mo of age and the gastric mucosa was hypertrophic, the AIG resembled human pernicious anemia rather than Ménétrier's disease. Adoptive transfer of spleen cells, but not sera, of AIG-bearing nu/+ into BALB/c nu/nu mice caused AIG in all animals 1 mo later, indicating the involvement of lymphocytes in the induction mechanism of AIG. Cytofluorometric and immunohistochemical analysis of lymphocytes in the gastric mucosa revealed T-cell infiltration at an early stage (1.5-3 mo) followed by B cell infiltration (6 mo). When the fraction enriched with parietal cells, which were intensively stained with sera of AIG-bearing mice and fluorescent antibody to mouse immunoglobulin G, was injected into the foot pads of AIG-bearing nude mice, typical delayed-type hypersensitivity reaction was observed in all animals. This was not seen in the mice injected with the cell fraction enriched with chief cells, although a few of them were stained by the immunofluorescent technique. Thus, the delayed-type hypersensitivity reaction seems to be directly involved in the mechanism of tissue damage.

Topics: Anemia, Pernicious; Animals; Animals, Newborn; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Disease Models, Animal; Female; Gastric Mucosa; Gastritis; Hypersensitivity, Delayed; Immunization, Passive; Intrinsic Factor; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Parietal Cells, Gastric; Thymectomy; Vitamin B 12

A specific gastritis was induced in BALC/c (+/?) mice by thymectomy within 3 days after birth (25 to 45 per cent) or in BALB/c (nu/nu) mice by the injection of spleen cells (10(7)) from neonatally thymectomized mice (70 per cent). Normal peripheral lymphoid cells, irrespective of the sex and dose, were generally ineffective in inducing gastritis in nude mice, while thymus cells were partially effective (30 per cent). The induced gastritis was characterized by a loss of chief and parietal cells and by varying degrees of lymphoid cell infiltration along thickened muscularis mucosa. The fundic mucosa was replaced by mucous necklike immature cells, and there was a rise of pH of the gastric juice. Argyrophilic endocrine cells escaped the inflammation and increased in number. The gastritis induced in nude mice was generally more severe and was often followed by severe macrocytic anemia. Megaloblast-like large immature erythroid cells were numerous in the spleens of affected mice. Antiparietal cell antibodies (IgG) were always demonstrated by an indirect immunofluorescence test in the sera of gastritis-developing mice, but were absent in sera of normal or untreated conventional nude mice. These findings suggest a new animal model of pernicious anemia in man.

Topics: Anemia, Macrocytic; Animals; Animals, Newborn; Autoimmune Diseases; Disease Models, Animal; Female; Gastric Mucosa; Gastritis; Immunoglobulin G; Immunoglobulin M; Intrinsic Factor; Male; Mice; Mice, Nude; Spleen; Thymectomy

The effect of partial pancreatectomy (80-90%) on vitamin B(12) absorption was studied in the rat. The absorption of 5 ng of (57)Co-labeled vitamin B(12) was significantly reduced from 70 +/-2.5% (mean +/-SE) in control and sham-operated rats to 32 +/-2.6% in partially pancreatectomized rats. Hog pancreatic extract (0.17 g/kg) improved vitamin B(12) absorption from 30.0 to 61.0% in partially pancreatectomized rats but did not alter vitamin B(12) absorption in control rats. Chloramphenicol did not enhance vitamin B(12) absorption in partially pancreatectomized rats with pancreatic extract-improved vitamin B(12) malabsorption. The partially pancreatectomized rats with pancreatic extract-improved vitamin B(12) malabsorption were sacrificed and the stomach and small bowel studied in vitro to further define the pathogenesis of the vitamin B(12) malabsorption. Rat gastric intrinsic factor stimulated vitamin B(12) uptake by intestinal sacs prepared from partially pancreatectomized rats 3.1-fold. Gastric intrinsic factor prepared from partially pancreatectomized rats was as effective in promoting vitamin B(12) uptake by rat intestinal sacs as intrinsic factor prepared from control rats. These data indicate that partially pancreatectomized rats develop an abnormality in the absorption of labeled vitamin B(12) which can be corrected by pancreatic extract. The vitamin B(12) malabsorption is due to neither an alteration in gastric intrinsic factor activity nor an impairment of the intrinsic factor-vitamin B(12) receptor in the intestine. It is suggested that in the partially pancreatectomized rats the intrinsic factor-vitamin B(12) complex exists in a form which is not available for absorption.

Topics: Animals; Body Weight; Chloramphenicol; Cobalt Isotopes; Disease Models, Animal; Gastric Mucosa; Intestinal Absorption; Intestine, Small; Intrinsic Factor; Malabsorption Syndromes; Male; Pancreas; Pancreatectomy; Rats; Vitamin B 12

Topics: Anemia, Pernicious; Animals; Body Weight; Disease Models, Animal; Fluorescent Antibody Technique; Gastric Acidity Determination; Gastric Juice; Gastric Mucosa; Gastritis; Guinea Pigs; Humans; Immunoelectrophoresis; Immunoglobulin G; Intestinal Mucosa; Intrinsic Factor; Rats; Sodium Chloride; Solutions; Time Factors