Biomedical subjects
Publications and source records attributed to R Gerli.
A 38-year-old woman suffering from primary Sjögren's syndrome for 2 years developed angiofollicular hyperplasia (multicentric Castleman's disease). In Sjögren's syndrome (SS) a number of findings indicate the presence of a B-cell hyperactivity that may evolve to a lymphoproliferative disorder. This report adds another pathological event to the complex spectrum of lymphoproliferative diseases in SS.
BACKGROUND: Immune system derangement is characteristic of alcoholic liver cirrhosis. However, in vitro studies have never clarified the alcohol-induced T-lymphocyte dysfunction. The aim of this study was to examine any discrete phenotypical and functional abnormalities and possible impairment in transmembrane signal-transduction pathways that, if present on lymphocytes of patients with alcoholic cirrhosis, would also be reproducible after in vitro ethanol exposure of normal T cells. METHODS: Lymphocytes from 25 patients were analyzed for their in vitro proliferative functions, intracellular Ca2+ fluxes, and inositol 1,4,5-triphosphate (IP3) generation. The same procedures were applied to normal T cells exposed in vitro to ethanol. RESULTS: Lymphocytes failed to respond to anti-CD3 and anti-CD2 after in vitro stimulation, with decreased intracellular Ca2+ mobilization and IP3 generation but showed normal proliferative response to phytohemagglutinin. In vitro ethanol incubation of normal T lymphocytes resulted in rearrangement of the membrane CD45 antigen, favoring the expression of high-molecular-weight isoforms, and showed a poor blastogenic response to anti-CD3 and anti-CD2 with a decrease in intracellular Ca2+ mobilization and IP3 production. After a 6-month period of ethanol withdrawal, some patients had normalization of phenotypic and functional alterations. CONCLUSIONS: The T-lymphocyte response to specific polyclonal activators may be severely impaired in alcohol abusers. However, it seems reversible after a period of controlled ethanol withdrawal.
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The mechanisms governing the induction of IgG subclasses by T-helper cells in humans were investigated. As preliminary bulk-culture experiments had indicated that a direct B cell contact with viable T cells was an essential requirement for optimal IgG subclass production, 256 CD4+ human T cell clones were preactivated with PHA and cultured in direct contact with autologous B cells. These clones induced IgG production in a strikingly subclass-specific fashion. Moreover, the distribution of subclass-specific helper clones was very similar to the IgG subclass profile observed in serum and peripheral lymphoid tissue plasma cells (IgG1 approximately 60%, IgG2 approximately 30%, IgG3 approximately 5-10%, IgG4 less than or equal to 5%) and unlike that observed in resting B cells (which is IgG1 approximately 40% and IgG2 approximately 50%). It would, therefore, seem that a predominance of T cells capable of delivering IgG1-specific, as opposed to IgG2-specific, help is an essential factor for the preferential induction of IgG1 antibodies during B cell proliferation and differentiation. There was no relationship between IL2, IL4, IL6, and IFN-gamma secreted by the T-helper clones and their IgG subclass induction patterns. In addition, only a few supernatants were able to reproduce the helper effects of the clones themselves. Therefore, direct contact of B cells with helper clones is crucial for IgG-subclass production in humans.
Subjects with Down's syndrome (DS), or trisomy 21, have an increased susceptibility to infections, malignant diseases and autoimmune phenomena. Various arms of the immune system are severely impaired in trisomic patients. We found that the proportion of blood lymphocytes bearing the gamma/delta T-cell receptor (TCR) was significantly higher in adults with trisomy 21 than in age- and sex-matched healthy controls. Interestingly, the increase was mainly due to an over-expansion of cells which bear non-covalently bound gamma/delta chains on their surface. This contrasts with the normal blood picture, where the great majority of gamma/delta T cells express the disulphide-linked form of the TCR. The fact that trisomic gamma/delta T cells are both numerically and phenotypically unbalanced provides further evidence that immunological abnormalities are integral features of DS.
The functional relevance of a direct ethanol effect on the membrane structure of T lymphocytes and accessory cells (APC), as well as on signal transduction systems was studied in ten normal subjects. Ethanol incubation (80 mM for 24h) of highly purified T cells increased the number of CD4+/CD45RA+ lymphocytes. In contrast, ethanol exposure induced a drop in CD14+/LFA-3+ APC values. These changes were accompanied by faulty T-cell proliferation in response to anti-CD3 and anti-CD2 mAb and inhibition of CD3- and CD2-mediated rises in intracellular calcium and, to a lesser extent, inositol 1,4,5-triphosphate levels. These data clearly indicate that a membrane-specific ethanol interaction both modifies surface glycoproteic and/or glycolipidic structures and alters transmembrane transduction of the activation signals.
Although the relative and absolute numbers of CD3+ cells (T lymphocytes) were similar in eight children with acquired Toxoplasma gondii infection and 10 uninfected age- and sex-matched healthy controls, the proportion of cells bearing the gamma delta T-cell receptor was significantly higher in the subjects with acute toxoplasmosis. The great majority of gamma delta T cells from the infected patients expressed covalently bound gamma delta chains on their surface, i.e. were BB3+ lymphocytes. Since the gamma delta T-cell subsets exert both restricted and unrestricted major histocompatibility complex cytotoxicity, further research is needed to elucidate the role of gamma delta T cells in the control of this coccidian protozoan infection.
Abnormalities in IgG subclass distribution were sought in serum samples and bronchoalveolar lavage fluid from 15 patients with alcoholic liver disease to explain their increased susceptibility to bacterial respiratory infections. Serum IgG4 deficiency alone or in association with low IgG2 levels was revealed in approximately 30% of patients with alcoholic liver disease. This fact prompted us to further investigate the immunoglobulin concentrations in broncho-alveolar lavage fluid, paying special attention to the distribution of IgA and IgG subclasses. IgA levels were found to be normal or slightly elevated. However, there were substantial defects in total IgG and IgG1 concentrations, often associated with reduced IgG2 and IgG4 levels, in approximately 70% of patients with alcoholic liver disease, which proved to be closely correlated with the number and type (pneumonia) of bacterial respiratory infections. A prospective study of intravenous immunoglobulin substitutive therapy involving two patients with recurrent pneumonia and very low serum IgG2 values demonstrated a reduction in the number of respiratory infectious episodes as well as an increase in both serum and, to a lesser extent, bronchoalveolar lavage fluid IgG1 and IgG2 levels. We identified immune defects that may represent an important pathogenetic mechanism that, when considered together with the alcohol-related suppression of alveolar macrophage and ciliary functions and the inhibition of leukocyte migration into the lungs, should help clarify the complex relationships between alcohol and immune defense.
Clinical and immunological changes after immunotherapy (ITS) for respiratory allergy were evaluated in 29 subjects during a one year follow up period. No adverse effects were noted with alum-absorbed allergen extracts. However, only patients receiving ITS for grass pollens demonstrated clinical improvement and blocking IgG increase as compared with those with multiple allergen sensitivity.
The authors report the clinical details and progress over 15 years of 2 siblings with giant axonal neuropathy with multisystem involvement. Changes in intermediate filaments (IF) were found in myelinated and unmyelinated fiber axons of the peripheral nerve and in Schwann cells, endothelial cells of skin vessels, skin fibrocytes and melanocytes, confirming a generalized disorder of IF organization.
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Immune system derangement in cirrhotic patients with evidence of malnutrition is a well-recognized characteristic of chronic alcohol abuse. However, in vitro studies on cellular immune function performed with lectin mitogens have produced conflicting results. The recent development of more accurate immunological techniques for studying lymphocyte transformation, that use monoclonal antibodies directed against surface structures (CD3 and CD2) involved in antigen recognition, as well in adhesion functions, prompted us to study discrete in vitro T-cell hypo-responsiveness in a series of alcoholic liver disease (ALD) patients with no evidence of malnutrition or hepatic cirrhosis. The results indicated that the CD2 pathway is markedly defective in ALD T lymphocytes, accompanied by reduced interleukin-2 (IL-2) receptor expression upon in vitro activation. This defect cannot be reversed by the addition of recombinant IL-2 (rIL-2) or rIL-1. Faulty intracellular signal transduction by protein kinase C (PKC) and defective intracellular Ca2+ mobilization may be responsible for the CD2 pathway impairment. The addition of small amounts of phorbol 12-myristate, 13-acetate, but not Ca2+ ionophore A23187, is able to overcome the defect, thereby suggesting a direct PKC involvement. The hypothesis of a direct ethanol effect on transmembrane signal transduction systems is suggested by the demonstration of an expansion of circulating virgin (naive) T cells (CD3+/UCHL1-low) that binds tyrosine phosphatase (CD45RA antigen) on their surface.
In previous studies "anchoring filaments" of human lymphatic capillaries have been shown to consist of microfibrils having histochemical and ultrastructural characteristics similar to elastin-associated microfibrils. When not associated with an elastin component, these microfibrils are referred to as "oxytalan microfibrils." In this study, alpha-glycol-containing carbohydrates and glycoconjugated sulfate groups, originating from sulphydryls and/or disulfide bridges, have been detected in anchoring filament microfibrils of human lymphatic capillaries by Thiery reaction (PA-TCH-SP) and "Hight Iron Diamine" cytochemical method (HID), respectively. Both of these chemical groups belong to the putative glycoprotein of which the microfibrils are constituted. Similar molecular characteristics have been demonstrated in elastic fiber microfibrils and oxytalan microfibrils of connective tissue. These findings suggest a close molecular similarity among these different types of microfibrils. Thus, whatever their individual location or denomination (anchoring filaments, oxytalan fibers, or elastin-associated microfibrils), these microfibrils form an uniform population of fibrous elements. These findings further support a structural (and functional) continuity between the lymphatic capillary wall and the elastic network of adjacent connective tissues previously described and termed "Fibrillar Elastic Apparatus" (FEA). Of interest, endothelial cells also selectively react positively to the PA-TCH-SP and HID methods.
Our laboratories previously reported that the proportion of lymphocytes bearing the gamma/delta T-cell receptor (TcR) is twofold greater in human milk lymphocyte suspensions than in autologous and heterologous blood samples. The present investigation shows that gamma/delta colostral T cells preferentially express non-covalently bound gamma/delta chains, whereas only a few display the disulphide-linked form of the TcR. This contrasts with the picture in the blood, where the distribution of these two nonoverlapping subpopulations is proportionally inverse. These findings are further evidence that the colonization of the mammary gland during lactation by immune system cells is the result of a selective homing process.
The expression of gamma/delta T cell receptor (TCR) on peripheral blood CD3+ cells circulating in 74 patients with different systemic autoimmune diseases was evaluated. There was a significant increase in the gamma/delta T cell number only in patients with primary Sjögren's syndrome (SS) and in untreated patients with systemic lupus erythematosus (SLE). Unlike healthy subjects, a subgroup of patients with SLE and SS displayed a marked increase in gamma/delta T cells. Immunosuppressive treatment of patients with active SLE led to a normalization of the gamma/delta T cell number. Analysis of surface phenotype showed that when patient gamma/delta T cells were expanded in the peripheral blood, they were not activated but bore "memory" markers. In addition, they preferentially expressed the disulfide linked form of the TCR, except in progressive systemic sclerosis where the nondisulfide form was displayed. Serial determinations in single patients demonstrated that the gamma/delta T cell increase is a persistent immunological feature in these patient subgroups.
IgE-mediated allergic reactions to drugs may be diagnosed on the basis of anamnestic criteria, clinico-pathological manifestations as well as by the measurement of allergen-specific IgE. The concordance of these diagnostic procedures was investigated in 50 patients with a history of sensitivity to penicillin (12), sulphamethoxazole (9) or both (14), aspirin (2) and pyrazolones (13). All subjects displayed chronic urticaria/angioedema syndrome. Optimal concordance values were observed for penicillin and sulphamethoxazole, while no specific IgE were detected in the ASA-sensitive group. False positive results were noted in pyrazolone-sensitive patients with high total IgE levels. Based on these results, serological methods that detect drug-specific IgE may be carefully used as complementary diagnostic procedure only in those patients in whom an adverse reaction to antibiotics is suspected.
Naive (unsensitized) and memory (antigen-primed) T cells can be phenotypically distinguished on the basis of the high or low intensity with which they express a number of immunologically relevant lymphocyte membrane antigens, including CD45R, CDw29, UCHL1, LFA-1, LFA-3, CD2 and Pgp-1. Here we report that in contrast to the two major T cell subsets found in the blood, milk T lymphocytes are almost exclusively composed of the one which exhibits the CD45Rlow, CDw29, UCHL1, LFA-1high memory T cell phenotype. In addition, while milk and autologous blood cells expressed similar levels of CD3 surface antigens, CD2 and ICAM-1 expression was approximately twofold greater on the milk T lymphocytes. This agrees with the finding that whereas colostrum T cells respond poorly to PHA, they proliferate and produce interferon-gamma normally when stimulated with either the anti-CD3 or anti-CD2 monoclonal antibodies. The selective colonization of the mammary gland during lactation by a population of T lymphocytes which displays the phenotype and functional characteristics of memory T cells may be one of the mechanisms whereby the suckling infant benefits form its mother's immunological experience.