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Biomedical subjects

B Hemmer

Publications and source records attributed to B Hemmer.

At least 55 records · Page 3Linked to original sources
PubMed1997

Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone.

CD4+ class II-restricted T cells specific for self antigens are thought to be involved in the pathogenesis of most human autoimmune diseases and molecular mimicry between foreign and self ligands has been implicated as a possible mechanism for their activation. In this report we introduce combinatorial peptide libraries as a powerful tool to identify cross-reactive ligands for these T cells. The antigen recognition of a CD4+ T cell clone (TCC) specific for myelin basic protein peptide (MBP) (86-96) was dissected by the response to a set of 220 11-mer peptide sublibraries. Based on the results obtained with the libraries for each position of the antigen, artificial peptides were found that induced proliferative responses at much lower concentrations than MBP(86-96). In addition stimulatory ligands derived from protein sequences of self and microbial proteins were identified, some of them even more potent agonists than MBP(86-96). These results indicate that: (a) for at least some autoreactive CD4+ T cells antigen recognition is highly degenerate; (b) the autoantigen used to establish the TCC represents only a suboptimal ligand for the TCC; (c) a completely random and unbiased approach such as combinatorial peptide libraries can decrypt the spectrum of stimulatory ligands for a T cell receptor (TCR).

Amino Acid Sequence↗
PubMed1997

Modifications of peptide ligands enhancing T cell responsiveness imply large numbers of stimulatory ligands for autoreactive T cells.

In this report, we demonstrate for autoreactive T cell clones that single amino acid modifications of the antigenic ligand can result in not only abrogated, decreased, or unmodified, but also increased, T cell responsiveness (superagonist ligands). We further studied the effects of combinations of multiple substitutions with different effects in single peptides. Experiments with peptides carrying multiple amino acid exchanges revealed that the final outcome of TCR ligation by a given ligand is the integration of negative, neutral, and positive effects of each single residue. In addition, the introduction of superagonist substitutions together with nonconservative modifications of primary and secondary TCR contacts resulted in stimulatory ligands. These findings indicate that: 1) the specificity of a single TCR is highly degenerate; 2) ligands exist for autoreactive T cells that have higher agonist activity than the autoantigen itself; 3) the rules to search for cross-reactive epitopes in autoimmunity should take into account that amino acids at certain positions within an antigenic peptide may exert superagonist activity and compensate for the negative effects of residues at other positions that would otherwise not be tolerated.

Amino Acid Sequence↗
PubMed1997

Human autoreactive CD4+ T cell clones use perforin- or Fas/Fas ligand-mediated pathways for target cell lysis.

It is well established that target cell lysis by MHC class I-restricted CD8+ T cells is an important defense mechanism during infections with intracellular pathogens or against tumor targets. On the other hand, little is known about the physiologic role and the mechanisms of cytotoxicity of CD4+ MHC class II-restricted T cells. We have recently demonstrated that human autoreactive CD4+ T cells specific for one candidate autoantigen of multiple sclerosis, myelin basic protein, can mediate cytotoxicity. In the present report, we analyze the cytolytic mechanisms employed by these cells. We show that individual T cell clones, regardless of their cytokine phenotype, can be noncytotoxic or lyse target cells via either perforin- or Fas/Fas ligand-mediated cytotoxicity.

Autoantigens↗
PubMed1997

T cell response to myelin basic protein in the context of the multiple sclerosis-associated HLA-DR15 haplotype: peptide binding, immunodominance and effector functions of T cells.

In this study, we evaluated the role of the two functional HLA-DR heterodimers, DR2a (DR alpha paired with the beta chain encoded by DRB5*0101) and DR2b (DR alpha paired with the beta chain encoded by DRB1*1501), that are coexpressed in the multiple sclerosis (MS)-associated haplotype HLA-DR15 Dw2, in presenting myelin basic protein (MBP) peptides to MBP-specific T cell lines (TCL). Our results show that both HLA-DR molecules serve as restriction elements for HLA-DR15-restricted TCL. Slightly higher numbers of TCL use DR2a as restriction element, and the epitopes contained in the immunodominant C-terminal region (131-159) are uniquely restricted by DR2a. The immunodominant middle epitope (81-99) is recognized in the context of both DR2a and DR2b, but this specificity strongly dominates the DR2b-restricted T cell response. Overall, immunodominance in the MBP-specific T cell response correlated well with peptide binding to DR2a or DR2b, demonstrating that the affinity of MHC-peptide interactions is important for shaping the T cell response to this autoantigen. Furthermore, we show that binding of the middle MBP peptide to HLA-DR15 molecules prevents cleavage by cathepsin D, a protease abundantly found in endosomal processing compartments, and thus contributes to its immunodominance. Surprisingly, the restriction element employed by MBP-specific T cell clones influenced the effector function (i.e., cytotoxic activity) of T cells irrespective of their peptide fine specificity.

Alleles↗
PubMed1997

Human T-cell response to myelin basic protein peptide (83-99): extensive heterogeneity in antigen recognition, function, and phenotype.

Multiple sclerosis (MS) is considered a T cell-mediated autoimmune disease, and myelin proteins are the most likely candidate autoantigens. Based on experiments performed in experimental allergic encephalomyelitis (EAE), innovative immunotherapies have been developed that target either the specific trimolecular complex of encephalitogenic T cells, consisting of T-cell receptor (TCR), major histocompatibility complex (MHC; HLA in humans) class II molecule, and autoantigenic peptide, or the effector functions of these cells. To provide the basis for the transfer of these specific immunotherapies to MS, we extensively characterized the human T-cell response to one major myelin epitope, the myelin basic protein peptide (83-99). We analyzed restriction element, TCR usage and affinity, fine specificity, cytokine production, cytolytic activity, and expression of surface molecules on 41 T-cell clones (TCCs) derived from MS patients and normal controls. We demonstrate a high degree of complexity of recognition patterns as well as of functional phenotypes among T cells responding to the same epitope. In contrast to results from animal models, these findings indicate that the design of epitope-based specific immunotherapies for MS is more difficult than previously thought.

Antigens↗
PubMed1996

Human T lymphocytes specific for the immunodominant 83-99 epitope of myelin basic protein: recognition of golli MBP HOG 7.

Myelin basic protein (MBP) is a candidate autoantigen in the disease multiple sclerosis. Although MBP was thought to be sequestered behind the blood-brain barrier, isoforms of MBPs have recently been demonstrated in lymphoid tissues. These isoforms, termed golli MBPs, contain sequences that are shared with "classic" MBP within the CNS. In the present study, we have determined that epitopes within golli MBP isoforms may be recognized by human T lymphocyte clones specific for classic MBP. Ten of 12 T-cell clones recognized golli MBP. Although 11 clones were specific for the immunodominant 83-99 sequence, the clones differed with respect to human leukocyte antigen (HLA) restriction, T-helper phenotype, cytolytic activity, and T-cell receptor usage. Greater responses to classic MBP than to golli MBP suggested a difference in the ability of the two proteins to be processed and to present epitopes therein. These data advance the hypothesis that golli MBP sequences expressed within lymphoid tissues may be recognized by classic MBP-specific T lymphocytes during central or peripheral tolerance.

Antibody Specificity↗
PubMed1996

Cytokine phenotype of human autoreactive T cell clones specific for the immunodominant myelin basic protein peptide (83-99).

Experimental allergic encephalomyelitis (EAE), an animal model resembling multiple sclerosis (MS), is mediated by myelin antigen-specific CD4+ T cells secreting cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-beta (TNF-beta), and the proinflammatory cytokine TNF-alpha-all associated with the T-helper-1 (Th1) T cell subset. Based on numerous similarities between MS and EAE, it has been postulated that Th1-like T cells are involved in the pathogenesis of MS. Production of proinflammatory cytokines such as IFN-gamma and, in particular, TNF-alpha/beta by autoreactive T cells is considered crucial for the initiation and amplification of inflammatory brain lesions and possibly also for direct myelin damage. In contrast, regulatory cytokines such as interleukin-4 (IL-4), IL-10, and IL-13, which are associated with the Th2-like phenotype, may play a role in the resolution of relapses. Although the human T cell response to myelin basic protein (MBP) is well characterized in terms of antigen specificity, HLA restriction, and T cell-receptor (TCR) usage, little is known about the cytokine pattern of these autoreactive T cells. To gain such information, conditions for studying cytokine secretion by human autoreactive T cell clones (TCC) were established. The cytokine secretion profile of human autoreactive CD4+ TCC, specific for myelin basic protein peptide (83-89) [MBP(83-99)], a candidate autoantigen in MS, was investigated. Our results show that TCC cytokine production in long-term culture was stable. In addition, the correlation of various cytokines within specific TCC revealed differences compared to murine T cells. The comparison of 30 human MBP (83-99)-specific TCC demonstrated heterogeneity in cytokine secretion, with a continuum between Th1- and Th2-like cells rather than distinct Th1 or Th2 subsets. These data are important for further investigation of the potential role of cytokines in the inflammatory process of MS, and provide a powerful tool to investigate therapeutic interventions with respect to their influence on cytokine secretion of autoreactive T cells.

Amino Acid Sequence↗
PubMed1996

Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87-99).

We have examined the functional consequences induced by interaction of DR2a-restricted myelin basic protein (MBP) (87-99)-specific T cell clones (TCC) with altered peptide ligands (APL) derived from MBP peptide (87-99). The immunodominant MBP peptide (87-99) has been implicated as a candidate antigen in multiple sclerosis (MS) by several lines of evidence. In the present study, we have defined the T cell receptor (TCR) contact residues for DR2a-restricted, (87-99)-specific T helper type 1 T cells to design APL suitable to modify the functions of such T cells potentially relevant for the pathogenesis of MS. We show that neutral (L-alanine substitutions) or conservative exchanges of the primary and secondary TCR contact residues lead to various alterations of T cell function, ranging from differences in interleukin-2 receptor up-regulation to anergy induction and TCR antagonism. The potential usefulness of APL as an immunomodulating therapy for DR2+ MS patients is discussed.

Amino Acid Sequence↗
PubMed1995

[A case of gustatory sweating and facial pain].

We report a case of a patient with gustatory sweating, a unilateral hyperhidrosis following a gustatory stimulus and an accompanying thermoregulatory hypohidrosis in the same area. Unusual features in this case are a possible association with a face pain and that the causing lesion can be localized in the brain-stem by neurological-topical reasoning. Most cases of gustatory sweating are caused by damage to the parotid gland.

Aged↗
PubMed1980

[Preliminary results of a pilot study on the influence of pemoline on cerebral concentrations of lactate, pyruvate, creatine, creatinephosphate, ATP, AMP, and ADP (author's transl)].

Cerebral lactate, pyruvate, ATP, ADP, creatine and phosphocreatine concentrations were determined in old, 600 g, rats during daily application of 20 mg pemoline (Tradon) (n = 11) and placebo (n = 10). After application for 21 days there were observed no significant differences in ATP, ADP, AMP, creatine and phosphocreatine concentrations between pemoline and placebo treated rats. On the other hand, in pemoline-rats, there was a significant decrease in pyruvate, lactate concentrations and in lactate/pyruvate ratio. On account of an increased dopamine turnover caused by pemoline, a possible increasing aerobic glycolysis and thus a greater energy production are still being discussed.

Adenosine Diphosphate↗
PubMed1977

Heart rate and ventilation in relation to venous [K+], osmolality, pH, PCO2, PO2, [orthophosphate], and [lactate] at transition from rest to exercise in athletes and non-athletes.

To evaluate to what metabolci event in contracting muscles heart rate (HR) and VE are related, time courses of femoral and cubital venous [K=], osomolality (OSM), pH, POC2, PO2, [lactate], and [orthophosphate] ([Pi]) at onset of exercise were studied in athletes (TR) and non-athletes (UT) and compared to time courses of HR and VE. During ischaemic work with the calf muscles it could be shown that most of these blood constituents were only released from contracting muscles. Thus their time courses reflected the metabolic events in working muscles being not essentially disturbed by non-working parts of the body. Ischaemic work induced, however, substantial increases of HR and VE. In the course of non-ischaemic bicycle work HR and VE rose more rapidly in TR than in UT but were lower in TR during the steady state. During non-ischaemic work only the increased of femoral venous [K=1 closely mimicked the cardiorespiratory transients in TR as well as in UT. None of the other femoral venous substances showed such a rapid change or such typical variations between TR and UT. Cubital venous [K=1 and [Pi] approached femoral venous concentrations only in second minute after start whereas pH, PCO2, and OSM increased mainly in venous outflow from contracting muscles. PO2 decreased in femoral venous blood of TR and UT, but in cubital venous blood it remained depressed only in UT. It was discussed that the cardiorespiratory adjustment during the initial stages of work was related to K+ release in working muscles and not to O2 consuming or H+ producing processes, nor to release of Pi or increase of OSM.

Blood↗
PubMed1976

Relationships of femoral venous [K+], PO2, osmolality, and [orthophosphate) with heart rate, ventilation, and leg blood flow during bicycle exercise in athletes and non-athletes.

The relationship of femoral venous [K+], [H+], osmolality (OSM), PO2, and [inorganic phosphate] ([Pi]) with heart rate (HR), ventilation (VE), and calculated leg blood flow (Q) were investigated during bicycle exercise in endurance trained (TR) and untrained (UT) test subjects. At a given VO2 the increases of [K+], OSM, [Pi] and the decrease of PO2 were significantly lower in TR than in UT. In the same proportion the increases of HR, VE, and Q were diminished. Thus in TR and UT identical and highly significantly correlated regression lines of [K+], [H+], OSM, [Pi] and PO2 with HR, VE, and Q were obtained. These constituents changed in the same proportion as the relative VO2 in TR and UT. No relationships with [Na+], [Ca++], and [ Mg++] were found. By means of a multiple regression analysis the partial influence of K+, H+, OSM, PO2, and Pi upon the total change of HR, VE and Q was estimated to compare with data from infusion experiments. The findings were discussed in view of the hypothesis that these candidates may provide linkage between metabolic events, circulatory, and ventilatory adjustments during work.

Adult↗
PubMed1975

Influences of exercise and endurance training on the oxygen dissociation curve of blood under in vivo and in vitro conditions.

In experiments with graded exercise of 15 men (6 untrained, 3 semitrained, 6 endurance-trained) the trained subjects showed a massive shift to the right of the in vivo O2 dissociation curve (ODC) of femoral venous blood. At a saturation of 20 to 25% (18 mkp/sec) Po2 was about 9 mm Hg higher for the trained than for the untrained group. The following factors play a role: 1. The 2,3-diphosphoglycerate [2,3-DPG] concentration was increased by 15 to 20% in the trained group which explains about 2 mm Hg of the diffenence in Po2-2. Exercise acidosis in the femoral venous blood depends to a large extent on CO2 in the trained, but on lactic acid in the untrained group. At low saturations the CO2-Bohr effect increases sharply thus having a greater importance in the trained subjects. This factor can explain about 2 mm Hg of the difference. However, influence of chloride and 2,3-DPG on the Bohr effect must be taken into consideration. 3. Since the large ODC-shift to the right of the trained group was not reproducible under in vitro conditions, it is suggested that a rapidly decaying unknown substance accounts for the remaining difference in Po2.

Acid-Base Equilibrium↗
PubMed1975

Effects of a multi-hour immersion with intermittent exercise on urinary excretion and tilt table tolerance in athletes and nonathletes.

The circulatory and diuretic responses of athletes and non-athletes to 6-h water i-mersion with intermittent swimming exercise (series I) as well as to 8-h inactive immersions (series II) were studied. With simultaneous intermittent exercise, the normally arising diuresis during a water bath was strongly suppressed in athletes and even abolished in nonathletes. In subsequent tilt table tests, 3 of 11 (27.3%) athletes of series I and 3 of 4 (75%) of series II collapsed, whereas all nonathletes tolerated the vertical position without any subjective complaints. By use of the so-called "orthostatic index" (4) the later group, however, was also shown to yield a substantially better orthostatic stability in series I than in series II. The protective effect of intermittent physical activity for simulation of the weightless state can possibly be explained by assuming a less-reduced plasma volume via a diminished urinary excretion.

Adaptation, Physiological↗