The Sydney System: auto-immune gastritis.

The association of gastric auto-immunity with chronic gastritis has been recognized for more than 30 years. Despite this, little is known about the initiation of auto-immune gastric mucosal injury or the role of gastric auto-antibodies in this disease process. The current review describes recent progress in our understanding of these fundamental questions on the origin and progression of auto-immune gastritis. In addition, evidence is presented (epidemiologic, clinical, pathologic and experimental) that strongly supports the view that auto-immune gastritis is a distinctive category of chronic gastritis with significant long-term sequelae.

Substances that interfere with guaiac card tests: implications for gastric aspirate testing.

Previous studies have shown that acidic pH and several ingestible substances can cause misleading guaiac tests of gastric aspirates. In this in vitro study, over 100 foods, beverages, and drugs were diluted to concentrations potentially present in the stomachs of outpatients being evaluated for gastrointestinal bleeding. These were mixed with known concentrations of blood and tested with different brands of guaiac cards. Decreased guaiac test sensitivity was associated with activated charcoal, dimethylaminoethanol, red chile, N-acetylcysteine, rifampin, red Jell-O (General Foods Corp, White Plains, NY), orange juice, Pepto-Bismol (Norwich Eaton Pharmaceuticals, Norwich, NY), simethicone, spaghetti sauce, and several red wines. Chlorophyll and methylene blue-containing tablets produced false-positive results, but other blue and blue-green colored tablets did not, except at high concentrations. Previously described false-negative results with vitamin C, bile, and certain antacids were confirmed, as were false-positive results with iodide, bromide, cupric sulfate, iron salts, and hypochlorite. Physicians should exercise caution when interpreting guaiac card tests of gastric aspirates, especially in the outpatient setting.

The CD4 Leu 8- T helper cell in colonic mucosa: a quantitative and functional analysis.

CD4 T cells in the colonic lamina propria are primarily B cell helper as identified by their surface phenotype CD4 Leu 8- (CD4 Leu 8+:CD4 Leu 8- ratio = 1:3.5). This is in contrast to autologous peripheral blood where CD4 Leu 8+ cells predominate (CD4 Leu 8+:CD4 Leu 8- ratio = 2.4:1). Functionally CD4 Leu 8- T cells isolated from the colon are able to provide autologous peripheral blood B cell help comparable to that of peripheral blood CD4 Leu 8- T cells. Immunoperoxidase staining of colonic tissue sections confirmed the relative lack of Leu 8 staining cells in the lamina propria and that when present these cells are located in the outer margins of lymphoid follicles.

Histological response and antigen transmission in the lymph nodes of athymic nu/nu mice inoculated with Crohn's disease tissue filtrates.

Lymph node histology and antigen transmission in the nu/nu mouse in response to animal inoculation with Crohn's disease tissue filtrates were re-evaluated. We found that a hyperplastic lymph node response in nu/nu mice occurred with Crohn's disease (CD), ulcerative colitis (UC), or other intestinal disease (OID) tissue inoculations. In addition, antigen transmission to lymph nodes as detected by indirect immunofluorescence using CD sera was observed in all inoculation groups. The immunofluorescent reaction also occurred independently of lymph node histology. Thus, we confirm that CD sera recognize an antigen(s) expressed in lymph nodes of athymic mice inoculated with CD tissue filtrates. The antibody (or antibodies) in CD sera was not specific for this 'CD antigen or antigens', however, as tested in the nu/nu mouse system, because the CD sera antibodies also recognised antigens in UC inoculated and OID inoculated animals.

Peripheral blood mononuclear-cell interleukin-2 production, receptor generation and lymphokine-activated cytotoxicity in inflammatory bowel disease.

The interleukin-2 pathway is essential for the normal immune response to antigen stimulation; we have examined the possibility that this may underlie abnormal peripheral blood lymphocyte immunoregulatory function that has been observed in patients with inflammatory bowel disease. We studied 11 patients with Crohn's disease and 5 with ulcerative colitis, all with quiescent disease activity. Peripheral blood mononuclear cells were isolated from these patients and from healthy age- and sex-matched controls. Interleukin-2 production after mitogen and phorbol-myristate acetate stimulation was similar in both groups: 381 +/- 71 (mean +/- SE) U/ml by control cells and 451 +/- 70 by patient cells. Interleukin-2 receptor generation was also measured pre- and poststimulation by labeling with anti-Tac antibody. This was 10.45 +/- 1 and 69.95 +/- 3.85% for control cells and 11.41 +/- 1.38 and 60.9 +/- 4.25% for patients cells. Finally, we examined the response of these cells to interleukin-2 stimulation by generating cells with direct cytotoxicity to 51Cr-labeled Daudi-cell targets. Control cells caused 59.5 +/- 46% 51Cr release, whereas patient cells caused 50.8 +/- 5.18% release. None of the above results achieved statistical significance. We conclude that the peripheral blood interleukin-2 pathway is normal in inactive inflammatory bowel disease.

Healing of benign gastric ulcer: comparison of cimetidine and placebo in the United States.

Recently the Food and Drug Administration approved cimetidine for the treatment of benign gastric ulcer. Approval was based in part on the results of our large multicenter trial involving 172 patients with benign gastric ulcer between 0.5 and 2.5 cm in diameter: 87 were randomly assigned to receive cimetidine (300 mg four times daily) and 85 to receive placebo. Cimetidine treatment resulted in significantly more rapid healing than placebo; after 2 and 6 weeks of therapy, 10.0% and 44.8% of patients receiving placebo were healed, as compared to 22.6% and 65.1% receiving cimetidine. The results of our study were compared with the time-response curve previously published (0, 4, and 8 weeks of therapy). The combined data yielded linear healing rates for the first 8 weeks of therapy (r greater than 0.99 for both cimetidine and placebo). These studies can be used to define expectations for healing of benign gastric ulcer, and we recommend follow-up intervals of 8 and, if unhealed, 16 weeks.

Natural killer cells and spontaneous cell-mediated cytotoxicity in the human intestine.

Spontaneous cell-mediated cytotoxicity (SCMC) has been investigated in mononuclear cells (MNC) isolated from intestinal mucosa and autologous peripheral blood from human subjects. The proportion of cells with the NK-K phenotype (Leu 7+) were substantially lower in intestinal MNC than in autologous peripheral blood. SCMC of K-562 target cells when tested at an effector to target (E:T) ratio equivalent to that used for peripheral blood MNC was markedly deficient in intestinal MNC. This was not due to the effect of EDTA and collagenase used in the isolation process. However, at high E:T, ratios, significant cytotoxicity was demonstrated for most intestines examined probably reflecting a low proportion of effector cells within the intestinal MNC population. SCMC in both intestinal and autologous peripheral blood MNC were similarly related to the Leu 7+:T ratios used in the assay indirectly suggesting that the Leu 7+ cell may be responsible for the observed cytotoxicity. It is concluded that the apparent functional difference between similar cells derived from different sites may be largely related to differing proportions of effector cells. The findings indicate the need for specific definition of the effector cell and suggest that intestinal SCMC in health and various disease states requires re-appraisal.

Natural killer cell function and lymphocyte subpopulation profiles in inflammatory bowel disease.

Peripheral blood natural killer (NK) cell activity and lymphocyte subpopulation profiles were studied in 23 patients with inflammatory bowel disease (IBD) and in 16 healthy control subjects. NK activity was assessed by a 4-hr 51Cr release assay using K-562 erythroleukemia cell line targets. Both monocyte depleted and nondepleted lymphocyte preparations were tested using 50:1 and 25:1 effector to target cell ratios. Lymphocyte subpopulation profiles were determined by incubation of cell suspensions with the monoclonal anti-lymphocyte antibodies (OK-M1, OK-T4, Leu-4 and Leu-2) labeling with goat anti-mouse FITC and sorting by flow cytometry on the fluorescence-activated cell sorter (FACS). NK activity in patients with IBD showed wide variation, but mean activity was not significantly different from normal controls. Analysis of patient subgroups by disease activity, disease type, duration or treatment also failed to reveal significant differences from controls. Parallel measurements of peripheral blood lymphocyte subpopulations using these phenotypic markers revealed no significant differences between patients with IBD and control subjects.

Immunoregulatory mechanisms in nonspecific inflammatory bowel disease.

Little is known of either the etiology or the pathogenesis of nonspecific inflammatory bowel disease (IBD). One hypothesis proposes the presence of a disorder of immune regulation as an initiating or perpetuating mechanism of continued bowel wall inflammation in these diseases. This chapter examines the basis for this proposal and reviews recent studies directed toward the demonstration of defective immunoregulatory mechanisms in IBD.

Immunity to cytopathic agents associated with Crohn's disease: a negative study.

Serum and peripheral blood lymphocytes from 10 patients with Crohn's disease and 10 healthy subjects were examined for immunological reactivity against chick embryo cell cultures displaying cytopathic effects after inoculation with 0.2 micro filtrates prepared from Crohn's disease intestinal tissues. Although the assay systems (indirect immunofluorescence, lymphocyte transformation, and cytotoxicity) yielded positive results using well-characterized cytopathic viruses (mumps, measles), neither Crohn's disease nor healthy subjects showed immune reactivity to the chick embryo cell cultures inoculated with Crohn's disease intestinal tissues in any of the assay systems. These experiments provide evidence against the hypothesis that the in vitro cytopathic effect on chick embryo cell cultures produced by Crohn's disease intestinal filtrates are caused by a replicating virus or viruses.

Antibodies to synthetic polyribonucleotides in spouses of patients with inflammatory bowel disease.

Serum from patients with inflammatory bowel disease (I.B.D.) and their unaffected spouses bound significantly more synthetic single-stranded (poly.rA) and double-stranded (poly.rA.poly.rU) R.N.A. but not KB cell D.N.A. than did serum from age-matched controls and their spouses. Binding activity resided in Ig fractions and was predominantly of IgM class. A significant corelation was observed between the amount of double-stranded but not single-stranded R.N.A. bound by serum from patients and from their respective spouses. These findings provide indirect support for the presence of R.N.A. viruses in patients with I.B.D. and the transmission of such agents to their close personal contacts.

Lymphocytotoxic antibodies in patients with inflammatory bowel disease and their spouses--evidence for a transmissible agent.

Serum lymphocytotoxic antibodies (LCA) were detected in twenty-seven out of fifty-three (51%) patients with inflammatory bowel disease (IBD) and in twenty-three out of their fifty-three (43%) unaffected spouses. The prevalence of LCA in both groups was significantly increased (P less than 0.001) compared to that in age- and sex-matched controls (11%) or in control spouses (6%). Concordant expression of LCA occurred in sixteen out of the fifty-three (30%) patient-spouse pairs compared to only one out of the fifty-three (2%) control-spouse pairs (P less than 0.001). In contrast to the LCA results, heterophile antibody titres were similarly distributed in all four study groups. It is suggested that LCA may represent markers of infectious agents in IBD and that their occurrence in unaffected close contacts of patients may indicate transmission of such agents to these subjects.

Direct immunochemical detection of prostaglandin-E and cyclic nucleotides in human malignant tumors.

Immunofluorescent localization of prostaglandin-E (PGE), cyclic AMP (CAMP), and cyclic GMP (cGMP) was studied in tumor tissues from 40 patients with a variety of solid tumors. Representative normal tissues served as controls. Rabbit antisera specific for PGE or the cyclic nucleotides were used, and the reactions observed were correlated with the degree and type of lymphocytic reaction at the tumor margins. Strong PGE immunofluorescence was detected in tumor cells in 27 of 42 malignancies; by contrast nine of 13 normal tissues showed weak PGE reactions, cAMP was detected in 30 of the 42 malignancies; cGMP was noted in only seven of the 42 malignant tissues and in none of the normal tissues studied. The most common malignant tumor profile (17/42) was that of positive PGE and cAMP and negative cGMP staining. Tumors showing strong staining with anti-PGE or cAMP demonstrated a distinct trend towards heavier lymphocytic infiltration with a predominance of T cells at their margins, although this association did not reach statistical significance in the present material.

Lymphocytotoxins in acute and chronic hepatitis. Characterization and relationship to changes in circulating T lymphocytes.

Serum lymphocytotoxicity (LCT) was detected in 49% of fifty-one patients with acute viral hepatitis and 72% of twenty-nine patients with chronic hepatitis. LCT was not detected in ten chronic carriers of hepatitis B surface antigen. Characterization of LCT revealed it to be active at physiologic temperatures and to be reactive against both T and B lymphocytes. The occurrence of LCT was transient in acute hepatitis and intermittent in chronic hepatitis. There was a significant inverse relationship between the percentage change in LCT over time and peripheral blood T-cell proportions amongst the patients studied. These findings indicate the importance of liver damage in the appearance of LCT and suggest that LCT may contribute to depressed lymphocyte function in liver disease.

Tissue T and B cell infiltration of primary and metastatic cancer.

Immunofluorescent techniques were utilized to identify the types of infiltrating lymphocytes adjacent to human malignant tumors arising from a wide range of anatomic sites. 24 of 29 primary tumors and 5 of 8 metastatic lesions showed varying degrees of lymphocytic infiltration. T cells predominated in the infiltrates in primary tumors (mean 80%, range 50-100%) and this pattern was evident regardless of anatomic site or the presence or absence of metastatic spread. By contrast, B cells predominated at the margins of three of five tumor metastases. Mononuclear cells bearing the Fc receptor were not a prominent component of the infiltrates associated with either primary tumors or metastases, but tumor cell binding of fluoresceinated IgG aggregates was observed in 12 of 29 primary tumors. A significant reduction in peripheral blood T cell numbers occurred in a third of the patients studied. This decrease was not clearly related either to the extent of local tumor T cell infiltration or to the presence of disseminated disease. These preliminary findings provide a descriptive analysis of the local and systemic distributions of immunocompetent cells in cancer.