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Biomedical subjects

R H Lin

Publications and source records attributed to R H Lin.

15 recordsLinked to original sources
PubMed1992

Breaking T cell tolerance with foreign and self co-immunogens. A study of autoimmune B and T cell epitopes of cytochrome c.

The initiation of autoimmune B cell and T cell responses by self Ag or by foreign pathogens (molecular mimics) is not well understood. In the present study, cytochrome c (cyt c) was used as a model autoantigen to investigate how self-proteins are involved in the priming of autoimmune T cell responses. Immunization with foreign cyt c has been extensively analyzed in previous studies as a model for both humoral and cellular immune responses. Mice do not, however, make antibody or T cell responses to immunization with self (mouse) cyt c. In addition, T cell tolerance can be broken by autoreactive B cells that are readily elicited by immunization with cross-reactive foreign cyt c. These immune B cells presumably bind self cyt c and process and present the self Ag to stimulate an autoreactive T cell response. Autoreactive T cell clones derived by this mechanism are all specific for determinants within amino acids 1-80 of the cyt c protein presented by I-Ek. No T cell responses were observed to the carboxyl terminal 81-104 fragment that dominates the response to foreign cyt c. All clones derived in this study are stimulated by a polypeptide encompassing amino acids 54-68 and utilized the V beta 8.2 TCR gene. In contrast, T cells stimulated by foreign cyt c did indeed respond to fragment 81-104 and appear to utilize alternate TCR genes. Our data demonstrate that B cells specific for linear determinants distributed along the entire length of the foreign cyt c molecule can provide the stimulus required for breaking T cell tolerance to self cyt c. The applications of this work to understanding the mechanisms of autoimmune disease are discussed.

Amino Acid Sequence↗
PubMed1992

An MHC interaction site maps to the amino-terminal half of the T cell receptor alpha chain variable domain.

We have used cloned T cell receptor (TCR) genes from closely related CD4 T cell lines to probe the interaction of the TCR with several specific major histocompatibility complex (MHC) class II ligands. Complementarity determining region 3 (CDR3) equivalents of both alpha and beta TCR chains are required for antigen-MHC recognition. Our data provide novel information about the rotational orientation of TCR-MHC contacts in that exchange of the amino terminal portion of the TCR alpha chain containing the putative CDR1 and CDR2 regions results in both gain and loss of MHC class II specificity by the resulting receptor. These two TCRs differ primarily in recognition of polymorphisms in the second hypervariable region of the MHC class II alpha chain. These results document the involvement of CDR1 and/or CDR2 of the TCR alpha chain in MHC recognition and suggest a rotational orientation of this TCR to its MHC ligand.

Amino Acid Sequence↗
PubMed1992

T and B cell receptors discriminate major histocompatibility complex class II conformations influenced by the invariant chain.

Direct recognition of major histocompatibility complex (MHC) molecules may occur when T cells are positively selected in the thymus and also during recognition of non-self MHC molecules. Since peptide recognition and binding of particular monoclonal antibodies is strongly influenced by the invariant chain (Ii) of the class II molecule, we have asked whether Ii also affects recognition of non-self MHC molecules by T cells. We find that Ii binding alters MHC class II conformation as detected by a monoclonal antibody, and that this alteration is retained in cell surface MHC class II molecules after Ii dissociates. This altered conformation also affects recognition by allogeneic T cells. Normal T cells and T cell clones preferentially recognize MHC class II molecules that have been associated with Ii, suggesting that thymic selection may be influenced by MHC conformation independently of specific peptide binding.

Animals↗
PubMed1992

Reduction of blood PO2 decrease and PCO2 increase during asphyxia by paramedian reticular nucleus in cats.

Effects of activation of paramedian reticular nucleus (PRN) on the systemic arterial blood pressure (SAP), heart rate, renal nerve activity (RNA), and changes of the partial pressure of the arterial blood oxygen (PO2) and carbon dioxide (PCO2) during asphyxia were studied in cats anesthetized with chloralose (40 mg/kg) and urethane (400 mg/kg). During a 35-s period of asphyxial anoxia, SAP and RNA increased while heart rate decreased significantly. The arterial blood PO2 decreased by 64.6 +/- 4.7% while the PCO2 increased by 54.6 +/- 6.3%. Electrical stimulation of PRN produced a mild to moderate decrease of the SAP, heart rate, and RNA, but arterial PO2 and PCO2 did not change significantly. When PRN was stimulated simultaneously with asphyxia, increases of SAP and RNA and changes of blood gases subsequent to asphyxia reduced significantly. Arterial PO2 decreased only 54.0 +/- 4.9% while the PCO2 increased 39.4 +/- 10.5% (p < 0.01). Similar effects were observed in the venous blood from inferior vena cava. In addition, when the arteriovenous difference of PO2 and PCO2 was compared, simultaneous PRN stimulation during asphyxia produced a higher PO2 reserve (66.3%) and less PCO2 production (-7%) than without PRN stimulation; PO2 54.2%, PCO2 (-2.9%). The results suggest that PRN is a structure that can exert inhibition over a wide spectrum of body functions; not only autonomic system but probably also metabolism.

Animals↗
PubMed1992

Correlation of cardiovascular and respiratory responses to glutamate excitation of pressor areas of the medulla in cats.

Cardiorespiratory responses, including changes of systemic arterial pressure (SAP), renal or splanchnic sympathetic nerve activity (SNA) and phrenic nerve activity (PNA), were elicited by microinjection of monosodium glutamate solution (0.5 M, 100 nl) into the dorsal (DM) and rostral ventrolateral medulla (RVLM) in 15 vagotomized cats anesthetized by urethane-chloralose and paralyzed by gallamine triethiodide. Artificial ventilation was adjusted to keep the end-tidal CO2 concentration at 4.0-0.5%. Sixty two pressor and 17 non-pressor sites were stimulated. Most of the stimulations inhibited the PNA. The responses of SNA was variable, showing increases, decreases or no change. Inhibition of SNA during SAP increase was not secondary to baroreceptor activation as the inhibition persisted in carotid sinus/aortic denervated animals. Although various combinations of changes of SNA and PNA were observed, their temporal courses were similar in many instances. Attenuation of SNA and PNA was synchronized, suggesting that these changes are coupled in the stimulating sites. The findings suggest that some neurons in DM and RVLM act as a functional unit to modulate cardiorespiratory functions whereas others simply coexist in the same area independent from each other.

Animals↗
PubMed1991

Induction of autoreactive B cells allows priming of autoreactive T cells.

A novel mechanism for breaking T cell self tolerance is described. B cells induced to make autoantibody by immunization of mice with the non-self protein human cytochrome c can present the self protein mouse cytochrome c to autoreactive T cells in immunogenic form. This mechanism of breaking T cell self tolerance could account for the role of foreign antigens in breaking not only B cell but also T cell self tolerance, leading to sustained autoantibody production in the absence of the foreign antigen.

Animals↗
PubMed1991

Effects of elevated plasma magnesium concentration on cerebrospinal fluid levels of magnesium in neonatal swine.

To determine whether magnesium (Mg) can cross the blood brain barrier in developing swine, simultaneous measurements of [Mg] in plasma and cerebrospinal fluid (CSF) were made during experimental elevation of plasma [Mg] in 12 swine of differing postnatal age. All were anesthetized with Saffan and maintained at normal arterial blood gas composition. Aortic pressure and heart rate were monitored. Plasma and CSF samples, drawn at the beginning and end of a 60-min intravenous infusion of MgCl2 in all animals and every 10 min during the infusion in three, were analyzed for [Mg] and osmolality. CSF [Mg] increased in all animals as plasma [Mg] increased. There were no changes in CSF osmolality. The differences between plasma and CSF [Mg] was smallest in the youngest animals. These results indicate that Mg crosses the blood brain barrier in neonatal swine and suggest that the blood brain barrier is still maturing within the first postnatal month.

Aging↗
PubMed1990

Unusual observations on hypermagnesemic levels and cardiorespiratory effects in neonatal swine.

Mg is being used as a therapeutic agent in different clinical conditions, i.e. preeclampsia or eclampsia, and as a tocolytic agent to prevent premature delivery. For these reasons we decided to systematically investigate the cardiovascular and respiratory effects of excess Mg in 25 piglets less than 1 day to 3 months of age, lightly anesthetized with Saffan, tracheotomized, paralyzed with C-10 and artificially ventilated on 100% O2. A 1.0 M infusion of MgCl2 was given for 15-60 min, and arterial plasma samples were drawn before and at the end of the infusion for the determination of plasma Mg and Ca levels. Phrenic nerve activity was recorded monophasically simultaneously with arterial blood pressure, electrocardiogram, end-tidal CO2 and intratracheal pressure on a dynograph and on analog tape. In a subset of experiments (n = 6), spontaneous ventilation was monitored in piglets of different ages to determine the Mg concentration at which spontaneous ventilation ceased. Blood gases were measured at 45-min intervals, as well as both immediately before and after the MgCl2 infusion, and pCO2 and pH were maintained within normal limits. As a consequence of the high plasma concentration of Mg, mean arterial pressure and heart rate declined, and the inspiratory duration significantly decreased. Our results indicate that young piglets can survive high levels of plasma Mg (greater than 14 mM).

Animals↗
PubMed1989

A role of Ia-associated invariant chains in antigen processing and presentation.

Most native antigens require processing in a cellular compartment for efficient presentation to T helper cells. The cellular elements that permit processing are not known. We investigated a possible role of the class II MHC-associated invariant chains in antigen processing. Fibroblast cells that were transfected with class II genes were compared with fibroblasts supertransfected with the invariant chain gene for their capacity to present the fifth component of complement (C5) to C5-specific class II restricted T cell clones or influenza virus protein to a virus-specific T cell clone. Only fibroblasts supertransfected with the invariant chain gene were able to present native antigen, even at very low antigen concentration, whereas both fibroblast types could present cyanogen bromide-fragmented C5 or the virus peptide. Presentation of intact antigen but not of fragmented antigen was totally abrogated by treatment of fibroblasts with chloroquine. The invariant chain gene encodes two polypeptides, li31 and li41. Expression of either li31 or li41 was sufficient to render class II-expressing fibroblasts capable of presenting intact antigen.

Animals↗
PubMed1989

T cell immunity or tolerance as a consequence of self antigen presentation.

In this study we investigated the basis for immunity or tolerance to a mouse serum protein, the fifth component of complement (C5). In C5-deficient mice this protein is absent from serum and therefore they are not tolerized. Immunization of C5-deficient mice with C5-sufficient serum generates CD4+ T cells, which recognize C5 presented in the context of class II. No C5-specific responses were observed in T cells from C5-sufficient mice. We show that this self protein is processed and presented with class II by cells from C5-sufficient tolerant mice and can be recognized by C5-specific T cell clones and hybrids in the absence of exogenously added antigen. The stimulation of C5-specific T cells by C5-sufficient antigen-presenting cells is not a consequence of C5 secretion and subsequent processing in vitro but rather employs C5 peptide/class II complexes generated in vivo. We conclude that this self antigen is presented in normal mice in a form recognizable by T cells to induce and maintain immunological tolerance.

Animals↗
PubMed1989

Contribution between dorsal and ventrolateral regions of medulla oblongata in vasomotor function of cats.

In cats anesthetized with alpha-chloralose and urethane, the medulla oblongata was explored with electrical and/or chemical stimulation for vasopressor actions. Chemical stimulation included semimicroinjection of sodium glutamate or microinjection of dl-homocysteic acid (DLH). The dorsal (DM), particularly its dorsomedial (DMM) portion, and the ventrolateral (VLM) regions were found to be most sensitive to both electrical and chemical stimulation. In between these two regions there was an area in the ventral portion of the gigantocellular and the parvocellular reticular nuclei that was sensitive to electrical and somewhat sensitive also to chemical stimulation. The responses to chemical stimulation indicate the existence of perikarya in these three areas for vasopressor actions. The most active response of VLM followed microinjection of DLH into the region of nu. paragigantocellularis lateralis (PGL) and subretrofacial nu. These responses were about 30% greater than those from DM where the most active area was found in the DMM region including the nu. and tractus solitarius. When an extensive area of VLM was lesioned bilaterally with kainic acid (KA, 1 micrograms/100 nl), the resting systemic arterial blood pressure (SAP) fell 42% and the pressor response on DM stimulation fell by more than 80%. In contrast, after similar KA bilateral destruction of DM the resting SAP fell 38% and the pressor responses from 67%. When only a limited area in the PGL/subretrofacial nu. of the rostral VLM (3-4 pressor sites, 1 mm apart) on one side was lesioned, the resting SAP remained unaltered while the pressor response on the ipsilateral DMM decreased 76%. On the other hand, when a similar smaller KA lesion (3-4 sites) was made in the DMM, although the resting SAP did not change, the pressor response on stimulation of the ipsilateral rostral VLM decreased 28%. Further lesioning of the contralateral DMM then decreased the rostral VLM pressor response 62% without much alternation in the resting SAP. Results of the present experiments are in accordance with our previous results that neuronal perikarya for vasopressor action exist not only in VLM but also in DM (18,34) with the function of VLM slightly predominant over DM. It seems highly possible that reciprocal innervation exists between DM and VLM, at least between DMM and the PGL/subretrofacial nu. region.

Animals↗
PubMed1989

An intracellular self protein synthesized in macrophages is presented but fails to induce tolerance.

Mice deficient for the fifth component of murine complement (C5), unlike normal mice, do not possess the secreted form of C5 in their body fluids and can be readily immunized to serum-derived normal C5. Although macrophages from C5-deficient mice do not secrete C5, they synthesize the precursor form (pro-C5). Therefore contact of T cells with autologous pro-C5 presented by macrophages is theoretically possible. We show that macrophages from C5-deficient mice can indeed stimulate a class II restricted C5-specific T cell clone without addition of exogenous C5. Immunization of C5-deficient mice with autologous pro-C5 induces vigorous C5-specific T cell proliferation and pro-C5 is recognized by C5-specific T cells in vitro, demonstrating that this protein fails to induce tolerance under physiological conditions. Thus, intracellular pro-C5 is processed and presented by C5-deficient macrophages and can activate T cell clones in vitro, yet is neither immunogenic nor tolerogenic for T cells in vivo.

Animals↗
PubMed1988

Pressor responses from electrical or glutamate stimulations of the dorsal or ventrolateral medulla.

In rats, rabbits, and cats anesthetized with alpha-chloralose and urethan, responses of the pressor areas of the dorsal portion (DM) and ventrolateral portion (VLM) of medulla and pons were compared. Electrical stimulation (monopolar square-wave pulses) on monosodium glutamate solution (Glu, 100-200 nl, 1 M) was delivered through an electrode-needle tubing connected to a Hamilton syringe for semimicroinjection. In all three of these species, pressor responses were elicited from both DM and VLM by either Glu or electrical stimulation. The most active parts of DM were found in the dorsomedial reticular formation of the rostral medulla to mid-medulla. In the pons and caudal medulla, the Glu-induced response was mild, although the electrically induced response was marked. Application of kainic acid (KA) to either DM or VLM produced an initial pressor response but was followed by a reduction of the pressure rise on subsequent electrical stimulation. Glu, unlike electrical stimulation, excites neural perikarya, not fibers of passage. KA initially excites the neural perikarya before causing damage that spares axons. These results thus suggest that both DM and VLM contain neural perikarya that mediate pressor effects.

Animals↗
PubMed1987

Study on the neuromuscular action of 4-aminopyridine in the mouse diaphragm.

4-Aminopyridine (4-AP), in concentrations ranging from 0.01 to 0.3 mM, increased indirectly evoked twitches of mouse diaphragm; directly evoked twitches were unaffected. 4-AP did not significantly affect the resting membrane potential, the amplitude and duration of muscle action potentials, the frequency and amplitude of m.e.p.p.s. or the half decay time of e.p.p.s. and m.e.p.p.s. However, e.p.p. amplitude and quantal content were increased by 4-AP in a concentration-dependent manner. On single stimulation of phrenic nerve 0.1 mM 4-AP induced repetitive e.p.p.s. Although 4-AP did not significantly affect compound action potentials evoked in the phrenic nerve, 4-AP caused repetitive firing to appear in phrenic nerve following single indirect stimulation of the nerve-muscle preparation. This repetitive firing was abolished by d-tubocurarine. In low Ca2+ (0.35 mM) Krebs solution 0.1 mM 4-AP induced muscle fasciculation accompanied by spontaneous giant e.p.p.s. and spontaneous muscle action potentials. In addition, 4-AP (0.1 mM) induced spontaneous repetitive firing of phrenic nerve axons; this was not inhibited by d-tubocurarine.

4-Aminopyridine↗