Enhanced peripheral T-cell apoptosis in chronic hepatitis C virus infection: association with liver disease severity.

BACKGROUND/AIMS: It has been suggested that enhanced T-cell apoptosis in hepatitis C virus (HCV) infection may lead to down-regulation of their cellular immune response, thus contributing to the persistency of HCV infection. In the present study we have investigated the role of bcl-2 and nuclear factor kappa B (NFkappaB) in dexamethasone-induced apoptosis of peripheral T cells in chronic HCV infection. METHODS: The expression of bcl-2 and NFkappaB in peripheral T cells as well as spontaneous and dexamethasone-induced T-cell apoptosis were studied in HCV-infected patients (n=21), hepatitis B virus (HBV)-infected patients (n=14) and healthy individuals (n=19). These parameters were correlated with markers of autoimmunity and disease severity. RESULTS: NFkappaB, but not bcl-2 expression, was significantly decreased in the HCV-infected patients. This decrease was associated with the presence of mixed cryoglobulins (MC) and rheumatoid factor and was positively correlated with alanine aminotransferase (ALT) levels and histological activity index (HAI). Both spontaneous and dexamethasone-induced T-cell apoptosis were enhanced in HCV-infected patients; however, only the latter was correlated with the presence of MC, ALT levels and HAI. CONCLUSIONS: We confirm previous reports that enhanced T-cell apoptosis in HCV infection may play an important role in disease severity. Decreased expression of NFkappaB is important in the development of peripheral T-cell apoptosis, thus contributing to viral persistence and autoimmunity in these patients.

Immune aberrations in B and T lymphocytes derived from chronic urticaria patients.

To investigate the pathophysiology of chronic urticaria (CU) in light of the abundant evidences that it is an autoimmune disease and to define some cellular markers in B/T lymphocytes that could be of pathogenic significance, we investigated 14 patients suffering from CU, compared to 7 contact dermatitis patients and 10 normal control individuals. We tested the expression of CD5, B7.1 (CD80), CD23, and CD25 on B cells and of CD(40L)) and CD25 on T cells from all studied individuals. We also tested B cell proliferation upon their activation followed by dexamethazone induced inhibition of proliferation. The expression of bcl-2 protein in activated lymphocytes from normal individuals was compared to that of contact dermatitis and CU patients. CD(40L) expression was found significantly higher on in (vitro activated CD3 [with phorbol myristate acetate (PMA) and ionomycine Ca2+ at 12 hr of culture] from CU patients compared to that of contact dermatitis and normal individuals. Whereas the proliferation of activated B cells from CU patients was higher, dexamethazone-induced inhibition of B cell proliferation was found statistically similar in both groups yet lower in B cells from most severe CU patients. We demonstrate a higher bcl-2 expression in activated B and T lymphocytes of severe CU patients compared to that of moderate CU and both contact dermatitis and normal individuals. The increased expression of CD(40L) on activated T cells might play a role in the polyclonal increased B cell proliferation of CU patients. This increased proliferation accompanies the finding that activated B and T lymphocytes from these patients demonstrate increased bcl-2 expression. The resistance of some B cells to dexamethazone-induced inhibition of proliferation encourages us to investigate the possibility that B cells from some CU patients might develop rescue mechanisms from activated cell death. These findings provide further evidence that CU is indeed an autoimmune disease, although its precise nature has yet to be fully elucidated.

Anticardiolipin antibodies and acute myocardial infarction in non-systemic lupus erythmatosus patients: a controlled prospective study.

PURPOSE: To examine the prevalence of anticardiolipin antibodies (ACLA) in relatively young patients with acute myocardial infarction (MI) and their role in subsequent coronary and thromboembolic events in the post-MI period. PATIENTS AND METHODS: In 124 relatively young survivors (aged 65 or younger) of acute MI, ACLA were measured in a controlled prospective study on admission and 3 months later. Myocardial reinfarction and thromboembolic events during a mean follow-up period of 19 +/- 3 months were diagnosed by standard tests. RESULTS: Seventeen (14%) of the 124 patients were ACLA positive (either IgM or IgG) upon admission compared with 2 out of 76 (3%) of the control group matched for age and coronary risk factors (P < 0.01). The levels of ACLA remained unchanged in all but 1 patient 3 months later. During the follow-up period the rate of thromboembolic events and myocardial reinfarction was significantly higher in the ACLA-positive patients as compared with the ACLA-negative group: 41% versus 4% (P < 0.0001) and 35% versus 10% (P < 0.05), respectively. Using logistic regression, high titer of ACLA was found to be the only independent risk factor for subsequent thromboembolic events or myocardial reinfarction after acute MI. CONCLUSIONS: High prevalence of ACLA was found in relatively young survivors of acute MI. The presence of ACLA is a marker for increased risk of subsequent myocardial reinfarction and thromboembolic events after acute MI.

Increased thromboembolic incidence in anti-cardiolipin-positive patients with malignancy.

This study was undertaken to determine the prevalence of anti-cardiolipin antibodies (ACLAs) in patients with malignancy and to investigate a possible association of ACLAs with thromboembolic events in such patients. The study included 216 patients with solid and non-solid malignancies and an age-matched control group of 88 healthy subjects. ACLA levels were measured and related to thromboembolic phenomena (diagnosed by imaging methods) that occurred within 12 months of the diagnosis of cancer. Forty-seven patients (approximately 22%) with cancer were ACLA positive as compared with only three subjects (approximately 3%) in the control group (P < 0.0001). The ACLA-positive cancer patients had a significantly higher rate of thromboembolic events than ACLA-negative cancer patients: 13 of 47 (28%) vs 24 of 169 (14%), respectively (P < 0.05). High titres of either IgG-ACLA or IgM-ACLA were found in 10 out of 13 ACLA-positive cancer patients with thrombotic complications, but in only 2 out of 34 cancer ACLA-positive patients without thromboembolic events (P < 0.0001). In four cancer patients in whom ACLA levels were followed ACLA decreased after successful surgery/chemotherapy treatment and remained negative and thromboembolic free for 12 months of follow-up. Patients with malignancies show an increased prevalence of ACLA. Furthermore, ACLA-positive patients, mainly those with high titres, are much more prone to thromboembolic events.

Premature ovarian failure--the prognostic application of autoimmunity on conception after ovulation induction.

OBJECTIVE: To assess whether the presence of autoimmune activity in patients with premature ovarian failure (POF) can predict the response to ovulation induction and conception. DESIGN: Assessment of autoimmune activity in patients with POF, correlating the response to ovulation induction with this autoreactivity. SETTING: Tertiary care academic center. PATIENTS: Forty women with POF, 15 of them treated by ovulation induction because of infertility. INTERVENTIONS: All patients were tested for the presence of autoimmune activity, antibodies against various tissues, and 15 of them were treated with combinations of hMG/hCG, glucocorticosteroids as immunosuppressant, and some of them also with a long-acting GnRH agonist. Those patients not interested in infertility were put on hormone replacement therapy (HRT). MAIN OUTCOME MEASURES: Serum E2 and P were measured during ovulation induction as well as follicular diameter monitoring by transvaginal sonography. Achievement of gestations and their outcome were monitored in the group in which ovulation induction was accomplished. RESULTS: Antibodies against thyroglobulin, nuclear antigens, heart, tissue gluten, or increased levels of immunoglobulin (Ig)M, or decreased levels of complement C3 and C4 were significantly different in the patients with POF than in the control population. Autoreactivity of at least one class of the tested antibodies was found in 31 of 40 patients (77%). In 15 patients with autoimmune activity who have undergone ovulation induction using hMG/hCG, 14 pregnancies were achieved in 8 patients. Two of the pregnancies were spontaneous, and 12 were generated by hMG/hCG and fluocortolone, with or without pretreatment with GnRH-a. Twelve healthy babies were generated by 10 gestations, 3 ended in spontaneous abortions (23%), and 1 is ongoing. All the nonspontaneous pregnancies were achieved in the first three cycles of ovulation induction. CONCLUSIONS: Patients with POF and autoimmune activity, suggesting an autoimmune etiology to the ovarian failure, may respond to ovulation induction and have a conception rate of approximately 40% in three cycles. Those who do not conceive in three treatment cycles have a very low probability to conceive; therefore, further attempts of ovulation induction should be discouraged. However, some patients may spontaneously conceive in association with HRT.

Immunofluorescent antigluten antibody test. Titer and profile of gluten antibodies in celiac disease.

Circulating antibodies to gluten fractions have been detected in most patients with celiac disease during gluten ingestion. The various detection techniques, however, are rather complex and inadequate for routine clinical use. Recently, a new indirect immunofluorescent method, named the antigluten antibody (AGA) test, has been developed. To establish the reliability of the test we compared six groups of patients: (1) 15 patients with biopsy-proved celiac disease of whom 13 had positive test results (the other two had already been receiving a gluten-free diet for two to three weeks); (2) 13 malnourished patients without celiac disease who had damaged mucosa, of whom only two had positive test results; (3) 21 patients with celiac symptomatology but normal mucosa, of whom four had positive test results; (4) 42 patients with other intestinal tract diseases, of whom seven had positive test results; (5) 28 patients with extraintestinal diseases, of whom only two had positive test results; and (6) 26 patients with autoimmune diseases, of whom five had positive test results. All patients with celiac disease who had positive test results and who were receiving a gluten-containing diet had titers of 1:40 to 1:80 in the IgG class, while all other patients with positive AGA test results had a low titer of 1:10 to 1:40, in the IgM class mainly. We conclude that the AGA test is an effective screening tool for patients with celiac disease and may serve as a practical index of dietary gluten avoidance.

Autoantibodies to epithelial cells (intercellular substance) and their correlation with clinical activity of pemphigus vulgaris.

The presence of autoantibodies to intercellular substance of squamous epithelium was studied in the sera of 46 patients suffering from pemphigus vulgaris. This study suggests that in the majority of patients suffering from the severe form of the disease the autoantibody titer can be used as a guide to prednisone therapy. However, in patients with a mild or moderate form, no such correlation is established.

Aspects of immunosuppression during Plasmodium berghei infection in rats.

Depression in immunological responsiveness was manifested in phase with parasitaemia in rats infected with Plasmodium berghei. The spleen was the most affected organ. The response of spleen cells to phytohaemagglutinin (PHA) and the number of plaque forming cells among spleen cells of rats injected with sheep red blood cells (SRBC), were reduced especially at peak parasitaemia. At the onset of the disease the spleen was activated and the responses were amplified. Antibody titres in the serum revealed basically the same picture. Malaria changed also the dose response to antigens so that an overdose of SRBC that normally causes 'immune paralysis' gave rise to significant numbers of plaque forming cells (PFC) in the spleen even in very sick rats. Infection with P. berghei influenced in different ways the two concurrent infections studied: Trypanosoma lewisi and Nipponstrongylus brasiliensis. The severity of trypanosomiasis was proportional to the P. berghei parasitaemia, while the number of the nematodes was not influenced by the malaria in any case. The immunity against T. lewisi depends on the activity of an intact spleen whereas the immunity against N. brasiliensis depends mainly on the mesenteric lymph nodes. The overall results suggest that in malaria the immunological functions of the spleen are severely impaired.