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Biomedical subjects

S Rath

Publications and source records attributed to S Rath.

At least 109 records · Page 6Linked to original sources
PubMed1989

A novel MHC class II epitope expressed in thymic medulla but not cortex.

The repertoire of receptors expressed by peripheral T cells is the result of two selective events that occur during intrathymic development. Positive selection expands cells able to recognize foreign peptides presented by self MHC molecules, and negative selection eliminates cells reactive to self MHC molecules and associated self peptides. Chimaera studies suggest that, at least in the case of T cells recognizing MHC class II, interaction with thymic cortical epithelial cells is responsible for the former, whereas thymic medullary cells, of bone marrow origin, mediate the latter. This view of thymic development is supported by recent morphometric analyses, showing that autoreactive cells are found in thymic cortex but not medulla. Although numerous studies have shown that MHC class II molecules are expressed in both sites, none provides any explanation for the differential selection of T cells that is observed. Here, we describe a novel MHC class II epitope which is found on cells in thymic medulla but not cortex. The antibody to this epitope reacts with about 10% of class II molecules on B cells and may be recognizing a self peptide-MHC complex. These results provide the first evidence for differential expression of class II epitopes in different tissues and are compatible with the hypothesis that different ligands, rather than different affinity thresholds for the same ligand, are involved in positive and negative selection of the T-cell repertoire.

Animals↗
PubMed1989

Isotype switching by a microinjected mu immunoglobulin heavy chain gene in transgenic mice.

Immunization of transgenic mice carrying an immunoglobulin mu heavy chain resulted in a response dominated by expression of the transgene variable region. Unexpectedly, in a large proportion of the antibody produced by immunized mice, the transgene variable region was associated with IgG rather than IgM. This demonstrates that the transgene can undergo an isotype switch. Four transgenic founder lines all exhibited transgene isotype switching despite the likelihood of random chromosomal integration of the transgene. In addition one of the lines was analyzed by breeding studies and the transgene was found to be genetically unlinked to the immunoglobulin heavy chain (Igh) locus. These results indicate that a precise chromosomal location is not required for isotype switching and suggest the possibility that the isotype switching process can occur interchromosomally.

Animals↗
PubMed1989

Cross-linking and conformational change in T-cell receptors: role in activation and in repertoire selection.

TCRs undergo a series of interactions with ligands during development. We have characterized the interaction of a TCR with its ligand and the attendant co-receptor and co-ligand structures. This characterization has led to the model in which the TCR not only binds to class II MHC, but also binds to CD4 co-receptors and co-ligands such as Mls. We have shown that both cross-linking and conformational change in the TCR are required for optimal T-cell activation. Finally, we have used the observation that a particular self-peptide found abundantly associated with class II MHC in the periphery is essentially lacking from thymic cortical epithelium to argue that positive selection for self-MHC recognition may occur by a novel process in the thymic cortex. A TCR recognizing class II MHC with low affinity could either be multiply cross-linked in the absence of conformational change, which here would be driven by a unique peptide, or could be conformationally changed without cross-linking due to the rarity of the individual high-affinity peptide on thymic cortical epithelial cells. Either proposal leads to a partial signal one delivered via the TCR, which we refer to as signal one-half. This signal one-half would induce the cell to repress its other co-receptor molecule and to undergo maturation events such as up-regulation in TCR expression. Such cells are then rigorously screened for activating interactions with autologous structures, such as Mls. The threshold for clonal deletion is set very low to avoid autoreactivity. By this combination of signaling events, a mature TCR repertoire is generated that has the functional characteristics observed in immune systems.

Animals↗
PubMed1989

Route-related variation in the immunogenicity of killed Salmonella enteritidis vaccine: role of antigen presenting cells.

In order to assess the role of the route of immunization on the immunogenicity of killed Salmonella vaccine, mice were immunized with killed S. enteritidis by intraperitoneal (i.p.) and intradermal (i.d.) routes. Whereas the former was non-immunogenic, the i.d. immunization generated an excellent delayed-type hypersensitivity response; further, i.p. immunization could even suppress the subsequent i.d. immunization. Since the peritoneal macrophages (MO) are known to be particularly low in Ia or MHC-class II antigens, so essential for antigen presentation, the non-immunogenicity by i.p. route was thought to be due to their poor presentation efficiency. Poly I: poly C, an interferon inducer, is known to enhance the MHC-class II expression; hence effect of poly I: poly C treatment on the immunogenicity of the killed vaccine by i.p. route was tested and indeed the non-immunogenicity was corrected. Poor efficiency of presentation of S. enteritidis antigen by peritoneal cells and its improvement by prior poly I: poly C treatment was further confirmed by in vitro lymphocyte transformation test using primed T cells and peritoneal cells from normal and poly I: poly C treated mice. Poly I: poly C treatment also enhanced expression of Ia antigens on peritoneal cells.

Animals↗
PubMed1989

Modified posterior soft tissue release for management of severe knee flexion contracture.

A modified posterior soft tissue release has been used in treating severe flexion contracture of the knee in 30 patients (36 knees). The operative technique has been modified with respect to the skin incision, and lengthening of the medial hamstrings. It is performed without a tourniquet. Postoperative skeletal traction was applied with gradual increasing weight to rapidly correct residual deformity. The deformity was fully corrected in 30 knees. The only complication was superficial skin necrosis over a small area, which occured in two knees. In six knees, 10 degrees of flexion deformity persisted after treatment. In four additional knees, 10 degrees of flexion deformity recurred due to lack of continued therapy. The modified posterior soft tissue release operation gave good results without any serious complications.

Adolescent↗
PubMed1989

Hansen's disease: computed tomography findings in peripheral nerve lesions.

Hansen's disease induces hypertrophic neuropathy. Computed tomography was performed on ulnar, median, peroneal and tibial posterior nerves where there is clinically presumed lesion. The CT findings (diameter and density) have correlated well with intra-operative findings. The computed tomography is a reliable method to study peripheral nerve lesions in Hansen's disease patients.

Female↗
PubMed1988

An inhibition enzyme immunoassay for estimating relative antibody affinity and affinity heterogeneity.

A method to measure the relative affinity of antibodies using an inhibition enzyme immunoassay is described. It is validated using monoclonal antibodies of defined affinity characteristics and by comparison with conventional methods of affinity measurement. The method allows measurement of the relative affinity of low levels of antibody, and the calculation of an empirical estimate of the heterogeneity of affinity in antibody populations.

Animals↗
PubMed1988

Determination of the functional affinity of IgG1 and IgG4 antibodies to tetanus toxoid by isotype-specific solid-phase assays.

Two solid-phase assays have been used to measure the affinity of IgG1 and IgG4 antibodies to tetanus toxoid (TT) in whole sera. In the first assay, low affinity antibodies were selectively inhibited from binding to solid-phase antigen by a mild chaotropic agent and in the second assay, high affinity antibodies were preferentially inhibited from binding by low concentrations of free antigen. Results from both assays suggest that IgG4 antibodies to TT are of lower functional affinity than IgG1 antibodies and that, in addition, IgG4 responses to TT display a more restricted affinity heterogeneity.

Antibodies, Bacterial↗
PubMed1988

Functional affinity of IgM rheumatoid factor in patients with rheumatoid arthritis and other autoimmune diseases.

The functional affinity of IgM rheumatoid factors (RF) was measured in 31 patients with rheumatoid arthritis (RA), 24 with systemic lupus erythematosus (SLE), 13 with Sjögren's syndrome (SS), and in 13 seropositive healthy individuals. The functional affinity of IgM RF from patients with RA was significantly lower than in the other clinical groups studied. In addition, there was a significant inverse correlation between functional affinity and titre of IgM RF in all the groups. These results suggest that the usual mechanisms of affinity based selective pressure (somatic diversification and antigen selection) may operate differently for autoantibodies to serum antigens such as IgG.

Antibody Affinity↗
PubMed1988

Anti-idiotypic humoral and cellular responses to antibody to hepatitis B surface antigen in hepatitis B viral infections.

In order to investigate regulatory significance of humoral and cellular responses to the idiotypic (Id) determinants on the antibody to hepatitis B surface antigen (anti-HBs), they were studied in acute hepatitis B and in chronic HBV infection. The results were compared with humoral and cellular responses of the same patients to hepatitis B surface antigen (HBsAg). In acute hepatitis B, the responses to HBsAg, were delayed until 3-4 weeks after the onset of clinical symptoms. However, the leucocyte migration inhibition (LMI) and the lymphocyte transformation (LTT) responses to affinity purified anti-HBs were found to be evolved very early in the course of acute hepatitis B, though anti-Id antibodies were absent. The majority of chronic HBV carriers showed a poor humoral and cellular response to HBsAg. Ten out of 38 chronic carriers showed anti-Id antibodies which recognized a major cross-reactive idiotype (CRI) on the anti-HBs molecule. Twenty-five out of 38 chronic carriers also showed LMI response to the Id determinants on the anti-HBs. LMI response induced by anti-HBs could be blocked by a specific Balb/c anti-Id antibody which also recognized the CRI. Thus, in both acute and chronic HBV infections, the anti-Id humoral and cellular responses correlated with poor humoral and cellular responses to HBsAg, indicating regulatory significance.

Acute Disease↗
PubMed1988

IgG subclass composition of antibodies to HBsAg in circulating immune complexes from patients with hepatitis B virus infections.

The IgG subclass of antibody associated with hepatitis B surface antigen (HBsAg) in circulating immune complexes (CIC) from patients with either acute or chronic hepatitis B virus (HBV) infections was measured using an isotype and antigen-specific ELISA. All patients were HBsAg positive but were negative for free anti-HBs antibody. The subclass of antibody associated with HBsAg in CIC in both groups was predominantly IgG1 and IgG4. This is in contrast to free anti-HBs in convalescent sera from patients recovering from HBV infection, which are highly restricted to IgG1 and IgG3. The finding of high levels of IgG4 antibodies in CIC suggest that CIC containing this subclass may be cleared less efficiently than CIC containing antibodies of other subclasses. Formation of these CIC may be an important factor in the progression of infection to chronicity and may also be involved in the antigen-specific immunosuppression seen in early acute and chronic HBV infections.

Acute Disease↗
PubMed1987

Hemodynamic effects of oral isosorbide-5-mononitrate and dinitrate in ischemic heart failure.

Isosorbide-5-mononitrate (ISMN), the main metabolite of isosorbide dinitrate (ISDN) was recently introduced in clinical use. The hemodynamic effects of oral ISMN and ISDN, administered in equal doses, were studied in a randomized, crossover fashion in 20 patients with pump failure of ischemic etiology. Baseline hemodynamic criteria for admission into the study were: pulmonary capillary wedge pressure (PCW) of at least 20 mmHg and systolic arterial pressure (AP) above 90 mmHg. Hemodynamic parameters were serially measured and systemic vascular resistance was calculated up to 6 h postadministration of either ISMN or ISDN single dose (40 mg). Maximal effects obtained were statistically significantly different from baseline. While ISMN and ISDN appeared to be equipotent in reducing the filling pressure, with a maximum effect reached in 60-120 min, the mononitrate maintained its effects for a longer period.

Administration, Oral↗
PubMed1987

Mechanisms of liver cell damage in acute hepatitis B.

Markers of hepatitis B viral infection and the evolution of immune response to these were compared with serum alanine aminotransferase (ALT) levels in adult male and non-pregnant and pregnant female patients with acute hepatitis B from the time of onset of disease to the seventh week. In the adult male and non-pregnant female patients, the peak ALT levels of about 360 IU/litre, seen at the time of onset, gradually declined during the course of the disease. Significantly, even in the seventh week, the median ALT level was abnormal (80 IU/litre). In contrast, the disease was mild in pregnant patients and the ALT levels declined rapidly, returning to normal by the third week. Markers associated with HBV replication, i.e., serum HBV-DNA and HBeAg, declined early in the course of the disease in both groups. The anti-HBc-IgM and anti-HBe responses were well evolved early in the course of the disease in both groups. HBsAg was present in the serum in large amounts (1-1.5 X 10(4) AU/100 microliter) early in the course of the disease and remained so up to the seventh week. Even the pregnant patients who had recovered clinically by the fourth week continued to have HBsAg in their sera in large amounts in spite of normal ALT levels. LMI and LTT responses to HBsAg, which were practically absent in the first week, gradually increased to a peak during the fourth week and remained elevated up to the seventh week in adult male and non-pregnant female patients. In contrast, LMI response to HBsAg was absent in pregnant patients with acute hepatitis B even up to the fourth week Thus, continued liver cell necrosis after the fourth week, as indicated by raised ALT levels, may be associated with T cell responses to HBsAg.

Acute Disease↗
PubMed1987

Virological markers and antibody responses in fulminant viral hepatitis.

Clinical profiles, serological markers, and antibody responses to antigens of hepatitis B virus (HBV) were studied in patients with fulminant viral hepatitis. Whereas hepatitis A and B were found to be uncommon causes (6.9% and 12.2%, respectively), non-A, non-B (NANB) hepatitis was found to be the most common cause of fulminant hepatitis (80.9%). As against this, the incidence of hepatitis B and NANB hepatitis was very similar in nonfulminant acute viral hepatitis in adults (41.2% and 51.9%, respectively). Pregnancy with labour was an important precipitating factor for development of fulminant hepatitis of the NANB type only; 32% of fulminant NANB hepatitis patients were pregnant women and 22.6% had a history of labour preceding hepatic coma. Only 0.8% of nonfulminant NANB hepatitis cases were pregnant women. Another major precipitating factor for the development of the fulminant form of NANB hepatitis was concomitant chronic HBV carrier state. A total of 38.6% of fulminant NANB hepatitis patients were HBV carriers, whereas only 19.2% of nonfulminant acute NANB hepatitis cases were HBV carriers. Sera of 32 chronic HBV carriers with fulminant NANB hepatitis and 10 cases of fulminant hepatitis B were tested for delta antibody, and all were nonreactive. The antibody responses of the fulminant hepatitis B patients to the antigens of HBV were found to be greater compared to those of patients with nonfulminant acute hepatitis B. Antibody responses of chronic HBV carriers with fulminant NANB hepatitis to antigens of HBV were found to be depressed in comparison with those of chronic asymptomatic carriers.

Acute Disease↗