Atrophic Gastritis and Pernicious Anemia
A malfunctioning immune system can target the stomach lining, resulting in autoimmune gastritis, characterized by chronic inflammation of the gastric mucosa. Persons with autoimmune gastritis may progress to pernicious anemia (PA). Autoimmune gastritis is characterized by the presence of serum autoantibodies against gastric parietal cells, H+/K+−ATPase (proton pump), and the cobalamin-absorbing protein, intrinsic factor.
Immunologic Findings. Antibodies against a lipoprotein cytoplasmic component of gastric parietal cells can be detected by immunofluorescence in up to 90% of PA patients and in about 60% of patients with atrophic gastritis without hematologic abnormalities. These antibodies may also be demonstrated in patients with other autoimmune diseases, such as thyroiditis. In addition, antibodies can be found in asymptomatic patients and in those older than 60 years.
Histologic Findings. Atrophic gastritis, which almost always accompanies PA, is characterized by destruction of the gastric mucosa, with lymphocytic infiltration and the absence of parietal and chief cells. The lesions are associated with decreased synthesis of gastric acid and intrinsic factor. Intrinsic factor normally binds ingested vitamin B12 at one site and binds to receptors in the distal ileum at another site. Therefore, vitamin B12 transport across the ileum is affected.
Vitamin B12 (Cobalamin) Transport. Cobalamin transport is mediated by three different binding proteins capable of binding the vitamin at its required physiologic concentrations—intrinsic factor, transcobalamin II, and the R proteins (Table 1).
Table1. Vitamin B12 (Cobalamin)–Binding Proteins
Intrinsic factor (IF), a glycoprotein, is synthesized and secreted by the parietal cells of the mucosa in the fundus region of the stomach in several mammalian species, including human beings. In a healthy state, the amounts of IF secreted by the stomach greatly exceed the quantities required to bind ingested cobalamin in its coenzyme forms. At a very acidic pH, cobalamin splits from dietary protein and combines with IF to form a vitamin-IF complex. Binding by IF is extraordinarily specific and is lost with even slight changes in the cobalamin molecule. This complex is stable and remains unabsorbed until it reaches the ileum. In the ileum, the vitamin-IF complex attaches to specific receptor sites present only on the outer surface of microvillous membranes of ileal enterocytes.
The release of this complex from the mucosal cells, with subsequent transport to the tissues, depends on transcobalamin II (TCII). TCII is a plasma polypeptide synthesized by the liver and probably by several other tissues. TCII, which turns over very rapidly in plasma, acts as the acceptor and principal carrier of the vitamin to the liver and other tissues, as with IF. Receptors for TCII are observed on the plasma membranes of a wide variety of cells. TCII is also capable of binding a few unusual cobalamin analogues. TCII also stimulates cobalamin uptake by reticulocytes.
The R proteins compose an antigenically cross-reactive group of cobalamin-binding glycoproteins. The R proteins bind cobalamin and various cobalamin analogues. Their function is unknown, but they appear to serve as storage sites and as a means of eliminating excess cobalamin and unwanted analogues from the blood circulation through receptor sites on liver cells. R proteins are produced by leukocytes and perhaps other tissues. They are present in plasma as transcobalamin I and transcobalamin III, as well as in saliva, milk, and other body fluids. Transcobalamin I probably serves only as a backup transport system for endogenous cobalamin. Endogenous vita min is synthesized in the human GI tract by bacterial action, but none is adsorbed.
Autoimmune Liver Disease
Autoimmune processes are believed to be the possible cause of chronic liver disease. Hypergammaglobulinemia, prominent lymphocyte and plasma cell inflammation of the liver, and the presence of one or more circulating tissue antibodies are typically manifested. These manifestations suggest an organ-localized autoimmune pathogenesis.
Autoimmune hepatitis (AIH), formerly known as chronic active hepatitis is an inflammatory condition most common in young women. It is characterized by prominent lymphocyte and plasma cell inflammatory changes, which start in the portal tracts. In some patients, this condition results from a chronic viral infection or inflammation, but in others a number of immunologic abnormalities are present to varying degrees in addition to hypergammaglobulinemia and an elevated erythrocyte sedimentation rate (ESR). A defect in immunoregulation is often demonstrated, which may lead to unrestrained immunoglobulin production.
Antinuclear autoantibody using HEp-2 cells will have differing levels of reactivity depending on factors such as the disease activity or multiple ANA specificities. A homogeneous staining pattern is the most frequent pattern particularly in active AIH. The frequency of positive ANA tests is about 70% in AIH. In remission, the frequency of ANA positivity decreases and the ANA pattern is replaced by a speckled pattern in almost 40% of cases. Other significant antibodies can include an atypical perinuclear ANCA (pANCA) in one type of AIH with a frequency of 65% positivity. In addition, AIH is characterized by auto antibodies to cytoskeletal proteins that support cellular structure, contractility, and locomotion: microfilaments. These autoantibodies to cytoskeleton can be studied by immunofluorescent light (IFL) methodology.
These patients display ANAs and anti–smooth muscle anti bodies. A high and persistent titer of antismooth antibodies is suggestive of the autoimmune form of chronic active hepatitis or viral disorders such as infectious mononucleosis.
In some cases this disease is referred to as lupoid hepatitis. Patients with aggressive chronic active hepatitis have a poor prognosis, and a significant rate of mortality is reported 5 years after diagnosis.
Idiopathic Biliary Cirrhosis
Idiopathic biliary cirrhosis is a slowly progressive disease that starts as an apparently noninfectious inflammation in the bile ducts of young to middle-aged women. An increased familial incidence has been noted.
Patients exhibit increased serum IgM, depression of cellular immunity, with prominent decreases in suppressor T cells common, and associated autoimmune disorders. It is believed that tissue damage results from an unmodulated attack against host tissue antigens. Antimitochondrial antibodies directed against the cellular ultrastructures, mitochondria, can be displayed. A high titer of antimicrobial antibody strongly suggests primary biliary cirrhosis (PBC); an absence of mitochondrial antibodies is strong evidence against PBC. Other forms of liver disease, however, frequently exhibit low mitochondrial antibody titers.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is the collective name given to Crohn’s disease (CD) and ulcerative colitis (UC). A major gene has been identified in these disorders. The Centers for Dis ease Control and Prevention (CDC) estimates that IBD, which is more common among Ashkenazi Jews than other groups, affects more than 1 million Americans. When researchers examined more than 300,000 single nucleotide polymorphisms (SNPs), the variations that occur when a nucleotide (molecular subunit of DNA) is altered, it was discovered that the frequency of variations in the receptor gene for interleukin-23 (IL-23) is significantly different for those with IBD. A coding variant that apparently protects against IBD is found less frequently in patients with IBD than in healthy patients.
Many factors (e.g., genetic susceptibility, diet) affect the onset and development of IBD. The crux of the disease is an abnormal immune response to harmless bacteria in the gut that benefits the host by providing energy and nutrients. In IBD patients, these microorganisms become a target for attack by the immune system. The inflammation seen in IBD patients has been linked to the following:
• Presence of increased levels of inflammation-promoting cytokines
• Protein molecules used by cells of the immune system to communicate with each other
Studies have suggested that one cytokine, IL-12, is a crucial mediator of this disease. IL-12 causes inflammation by activating a class of different immune cells, type 1 helper T (Th1) cells, which in turn secrete proinflammatory molecules such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). These pathways have been suggested as therapeutic targets for human IBD.
The discovery of IL-23 has led some to question the central role of IL-12 and Th1 cells in IBD. Newer studies have indicated that IL-12 and IL-23 are closely related molecules that share a common subunit known as p40. IL-23 has been associated with the activation of a new class of proinflammatory T cells called Th17. These cells secrete the proinflammatory cytokine IL-17, which mediates the inflammatory response in organs such as the brain and joints. Intestinal inflammation is still associated with large increases in IL-17 production in the intestines. Innate immune cells present in inflamed intestines (e.g., granulocytes, monocytes) have been found to contribute to the increased production of IL-17.
Immune Markers. The following serologic markers have been found to be useful in the diagnosis and differentiation of CD and UC:
• Deoxyribonuclease (DNase I)–sensitive perinuclear antineutrophil cytoplasmic autoantibody (p-ANCA). IBD-associated p-ANCA defines an antibody to a nuclear antigen that is sensitive to DNase I.
• Anti–Saccharomyces cervisiae antibody (ASCA). This is present in the sera of up to 70% of CD patients.
• Pancreatic antibody. This is observed in approximately 30% of CD patients.
• Anti–outer membrane porin from Escherichia coli (anti OmpC). An IgA response to OmpC is observed in 55% of CD patients.
Celiac Disease
Celiac disease is a lifelong autoimmune intestinal disorder found in individuals who are genetically susceptible. There are also associated clinical disorders of an immune basis (Box 1). Damage to the mucosal surface of the small intestine is caused by an immunologically toxic reaction to the ingestion of gluten and interferes with the absorption of nutrients. Celiac disease is unique in that a specific food component, gluten, has been identified as the trigger. Gluten is the common name for the offending proteins in specific cereal grains that are harmful to those with celiac disease. These proteins are found in all forms of wheat (e.g., durum, semolina, spelt, kamut, einkorn, faro) and related grains (rye, barley, triticale) and must be eliminated.
Box1. Clinical Immune Disorders Associated With Celiac Disease
In recent years, key laboratory diagnostic assays comprise testing for autoantibodies against tissue transglutaminase (anti-tTG) or endomysium (EmA) antibodies against deamidated gliadin peptides and the celiac disease (CD)-associated human leukocyte antigens (HLA) DQ2 and DQ8.
New European guidelines have results in two algorithms of testing: symptomatic patients versus asymptomatic patients. For symptomatic patients, the algorithm begins with determination of specific anti-TG antibodies of class IgA in parallel with total IgA or specific IgG measured in parallel testing. If the anti-tTG antibody titer is more than 10 above the upper normal limit, the endomysium (EmA) is positive, and compatible HLA results are found, it is not necessary to perform a small bowel biopsy as was done in the past. Diagnostic tests should be done on individuals on a gluten-containing diet. A biopsy is needed only if serologic and genetic findings are inconclusive. In asymptomatic patients with a high risk factor for CD, e.g., patients with diabetes type 1, Down’s syndrome, autoimmune thyroid or liver disease, Turner’s syndrome, Williams’ syndrome, or selective Ig A deficiency and patients with first-degree relatives of CD patients, HLA-DQ2/ DQ8 determination is the first-line of analysis that can be followed up with specific antibody testing. Asymptomatic patients require a duodenal biopsy for a definite diagnosis of CD.
Other Gastrointestinal Tract Immunologic Disorders
Examples of other immunologic disorders related to the GI and hepatobiliary tracts include GI allergy, Whipple’s disease, immunoproliferative intestinal disease (alpha heavy-chain dis ease), and infectious hepatitis. Allergy of the GI tract is an IgE-mediated hypersensitivity to food substances that involves the GI tract and, in some cases, the skin and lungs. Examples of systemic autoimmune disease caused by mucosal immune abnormalities are IgA nephropathy (Berger’s disease), Henoch-Schönlein purpura, and diseases associated with circulating IgA complexes in the kidney and vasculature. Immunoproliferative intestinal disease is characterized by monoclonal B cells that produce an aberrant alpha heavy chain.
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