The pattern of a T(H)1 cytokine in autoimmune thyroiditis.

This study performed on 51 patients with autoimmune thyroiditis and 15 healthy subjects was aimed at correlating the activation of T cells and the secretion of inflammatory cytokine with echography and thyroid functional assays. A significant increase of activated T cells was observed in Hashimoto patients illustrated by an increased percentage of CD3+ CD25+ T cells (P < 0.01). Similarly, increased amounts of IL-2, TNF-alpha and IFN-gamma were in the serum of patients compared with the control group in which these cytokines are barely detectable. An in vitro study shows a significant increase of IL-2 and TNF-alpha upon the exposure to Concanavalin A. These results suggest that T(H)1 secreting inflammatory cytokines may contribute to pathogenesis of autoimmune thyroiditis.

Balkan endemic nephropathy, the haematopoietic system and the environmental connection.

We previously reported the detection of an increased subpopulation of cytotoxic T lymphocytes in patients with Balkan (endemic) nephropathy (BEN) and in area controls (individuals free of clinical syndrome but born in a BEN endemic area and having a family history of BEN). Extending the flow-cytometric analyses to other populations of peripheral blood leucocytes, we found a decrease in the proportion of B lymphocyte subset and an increased proportion of eosinophils in BEN patients and in area controls. Although these numerical alterations cannot be categorically linked to the aetiopathogeny of the disease, it is presumed that they can be induced by the same factor(s) causing the kidney damage, through a direct haemato- and lymphotoxic effect.

Proinflammatory cytokines production and PMN-elastase release from activated PMN cells in the periodontal disease.

The aim of this study was to evaluate the local changes in the crevicular gingival fluid (CGF) determined by the inflammatory and immune response in periodontitis and gingivitis. The selected patients presented gingivitis (n = 9) and periodontitis: aggressive periodontitis (n = 21) and adult periodontitis (n = 8). The crevicular fluid was provided from the gingival and periodontal pocket. The measurement of PMN-elastase in the CGF, using the ELISA method, showed a significant (p < 0.01) increase of the enzyme concentration in the aggressive periodontitis group (62.1 +/- 3.91 ng/ml) comparing to the gingivitis group (33.04 +/- 4.14 ng/ml) but also the increase (p < 0.05) of this enzyme in the adult periodontitis (43.6 +/- 2.16 ng/ml) comparing to the gingivitis, which indicated the evolutive aspects of the inflammatory reaction in these diseases. The increased production of PMN-E is the result of the activation of polymorphonuclear cells (PMN) as a reaction of the microbial attack. Degranulation and release of proteolytic enzymes including elastase, which present cytotoxic capacities, follow the activation of neutrophil granulocytes (PMN). The activated granulocytes release proinflammatory cytokines IL-1, TNF-alpha which augment the inflammatory immune response. The aggressive periodontitis group showed an increased CGF level of IL-1 (780.4 +/- 104 pg/ml) comparing to the gingivitis group (275.5 +/- 78 pg/ml) (p < 0.01). TNF-alpha also presented an increased level (p < 0.01) in the aggressive periodontitis group (16.3 +/- 2.3 pg/ml) comparing to the gingivitis group (4.1 +/- 1.2 pg/ml) as a consequence of the periodontium destruction and of the tissular necrosis in the former group. In conclusion, our study shows a significant increase of the PMN-elastase and proinflammatory cytokines level in CGF of patients with gingivitis and periodontitis. The intensity of the inflammatory response in these diseases is strongly correlated to the activation of the neutrophil granulocytes which release these biological active molecules that could be used as evolution markers of the disease.

Th1 cytokines in autoimmune thyroiditis.

This study was performed on a lot of 51 patients and intends to correlate the autoimmune thyroiditis to the synthesis of Th1 cytokines and to the activation of T lymphocytes. We find out that CD25, an activation marker of T lymphocytes, is significantly increased in these patients. We also find out that certain cytokine serum levels are increased (IL-2, TNF-alpha, IFN-gamma). These cytokines correspond to the secretor profile of the Th1 subset. Mononuclear cell culture supernatants showed an increased level of IL-2 and TNF-alpha in samples stimulated with ConA in comparison to unstimulated samples from the same patient, suggesting the existence of an expansioned Th1 and CD8+ cytotoxic population.

Inverse correlation between IgG-antihinge region and antierythrocyte autoantibody in chronic benign and malignant cold agglutination.

Previous reports provided evidence of an immunosuppressive role of natural anti-F(ab')2 antibodies. If suppressive anti-F(ab')2 antibodies also regulated the autoantibody production in cold agglutination, one would expect high titers of anti-F(ab')2 to be associated with low titers of cold agglutinins. Indeed, our previous studies revealed an inverse correlation between IgG-anti-F(ab')2 and cold agglutinins. Many previous experiments focused on anti-F(ab')2 of an antiidiotypic nature. Recent epitope mapping showed that anti-F(ab')2 of healthy persons is not an antiidiotype but recognizes a hinge region sequence. We attempted to answer the question whether this IgG-antihinge antibody is responsible for the previously described association between anti-F(ab')2 and cold agglutinins. IgG-antihinge and IgG-anti-F(ab')2 antibody was determined and statistically analyzed in the serum of 334 patients with cold agglutination. Our experiments revealed a strong correlation between the concentrations of antihinge and the previously described anti-F(ab')2 antibody. The anti-F(ab')2 activity was competitively inhibited by a synthetic hinge peptide. Moreover, patients with high antihinge titers had low cold agglutinin titers, and vice versa. A stratification according to cold agglutinin specificity and disease etiology showed that the inverse correlation is present only in anti-I and anti-i patients suffering from monoclonal B-lymphocyte proliferation. In conclusion, our results confirm the correlation previously described for anti-F(ab')2 antibody and antierythrocyte autoantibody and define for the first time an association between an idiotype-independent anti-IgG autoantibody and cold agglutinin.

A natural IgA-anti-F(ab')2gamma autoantibody occurring in healthy individuals and kidney graft recipients recognizes an IgG1 hinge region epitope.

Natural anti-IgG autoantibodies are found both in healthy individuals and in patients with certain diseases. One group of these Abs recognizes epitopes located in the F(ab')2 region of the IgG molecule. The immunoregulatory role of these Abs in healthy individuals, graft rejection, and disease was previously studied, usually with a focus on the characterization of anti-idiotypic Abs. In the present study, we characterize the epitope recognized by an anti-F(ab')2gamma autoantibody of the IgA isotype, which occurs in the serum of healthy individuals and kidney transplant recipients. The autoantibody described herein reacts strongly with F(ab')2gamma but only poorly with Fab(gamma) fragments, a binding pattern pointing to an epitope located in the hinge region. Using synthetic peptides, we identified a conformational epitope that overlaps the middle and part of the lower hinge region. Structural analyses of peptide constructs showed that a defined conformation of the first three residues of the lower hinge is required for a full expression of the epitope. Binding of IgA to the hinge region of IgG1 covers part of the physiologically active Fc domain, immobilizes the Fab arms, and thereby can be expected to exert immunoregulatory functions.

Identification of a novel subset of T lymphocytes in patients with Balkanic nephropathy.

Balkanic Nephropathy (BN) is characterized by: an incidence limited to a geographic area: a familial character and a slow progressive evoluation towards chronic renal failure associated with the symmetrical reduction of the kidney size. The etiology of BN is unknown. The aim of our study was to find out the immune alterations in BN pathology. In the BN patients we identified a novel subset of the CD3+ CD16+ and CD56+ T cells expressing the phenotypic characteristics of both T lymphocytes and NK cells. The analysis of various subpopulations of lymphocytes, however, showed no quantitative differences in comparison with healthy subjects and healthy subjects from the endemic area.

CD3+, CD16+, CD56+ cells: a novel subset of T lymphocytes from patients with Balkanic nephropathy.

Balkanic Nephropathy (BN) is characterized by: an incidence limited to a geographic area; a familial character and a slow progressive evolution towards chronic renal failure associated with the symmetrical reduction of the kidney size. The aim of our study was to find out the immune alterations in BN pathology. The analysis of various subpopulations of peripheral lymphocytes obtained from patients with BN showed no quantitative differences in comparison with healthy subjects and healthy subjects from the endemic area. In the BN patients we identified a novel subset of the CD3+, CD16+, CD56+ cells expressing the phenotypic characteristics of both T lymphocytes and NK cells.

Quantitative structure-activity relations by the MTD-method for binding of nonapeptides to the HLA-A2.1 molecule.

Binding of large series of nonapeptides to the HLA-A2.1 molecule was studied by a group of Sette in order to predict strongly binding peptides with possible therapeutic interest. Here we establish QSAR-s for these series. The MTD-method was used for steric requirements concerning amino acidic side chains as well as side chain hydrophobicities. Binding of these peptides to the HLA-A2.1 molecule is favored by a lipophylic character of side chains for the anchor position 2 and 9 and for positions 1,3 and 6 and by steric features that allow predictions for some modified amino acidic residues in these positions that should increase the peptide-HLA-molecule affinity.

Molecular aspects concerning antigen oligopeptide selection by MHC class I molecules.

T cells can recognize the antigen only if it is associated with self MHC molecules on the surface of antigen presenting cells (APC). There are several characteristic parameters defining interaction of MHC molecule with antigenic peptides giving circumstances for specific antigen presentation and an individualized immune response. Here are assessed some size and conformational parameters of the peptides presented by MHC class I molecules-lengths, widths, van der Waals volumes and surfaces-using COSMIC 2.0 software. The peptides derived from HIV gp 160 are obtained from literature and are known to be active and inactive in a cytotoxicity assay. An increased tendency for beta- or beta-like structures and volumes close to those of the MHC binding site are encountered in the case of active peptides.

DNA topology and V(D)J recombination: a tentative connection.

Gene recombination is the fundamental basis of immunoglobulin (Ig) and T cell receptor (TCR) diversity. Although several specific and nonspecific enzymatic equipments were revealed to be necessary for Ig and TcR gene assembly, almost nothing is known about the developmental and tissue specific control of recombination and the individual functions of the heptameric and nonameric signals and 12/23 spacers in this process. According to certain conformational and functional respects, we consider the nonamer a DNA insertion site to the nuclear scaffold, in relation with its structural homology to the satellite (5'-ACAAACC-3') and microsatellite repetitions, involved in DNA-nucleoskeleton impact. A topological control for V(D)J recombination is proposed, through different accessibilities of the substrates in the catalytic site, defined by a specific nonamer-mediated insertion to the nuclear scaffold. Recognition of heptamer and nonamer sequences by RAG proteins is followed by the assembly of an asymmetric recombinant complex. Even more important in this assembly may be the role of nonamer which, through DNA flexibilization and bending, could participate at the formation of the enzyme core. This core with the attached DNA could have a nucleosome-like geometry, a motif present in certain DNA processing enzymatic systems. Such an assumption emerges from the close homology of the nonamers with the DNA mobilization intergenic sequences (CA5-6T), found in many eukaryotic organisms.