II. The late asthmatic responses

Immediate asthmatic responses have been regarded as the characteristic type of asthmatic response to follow exposure to inhaled allergens in patients with extrinsic asthma. They begin within minutes, clear within one to three hours and are inhibited by disodium cromoglycate but not by corticosteroids. They involve the reaction of antigen with antibodies usually of the IgE class. In recent years allergen inhalation tests have demonstrated the frequent occurrence of late asthmatic responses, either following immediate responses (dual responses) or occurring in isolation. The late asthmatic responses begin two to six hours after the allergen challenge, are prolonged and often severe, and are inhibited by both disodium cromoglycate and corticosteroids. The mechanisms involved in their provocation are not clearly understood but from the allergic viewpoint they may involve the participation of IgG ± IgM antibodies and/or IgE antibodies. Late asthmatic responses explain the frequent occurrence of allergen-induced prolonged asthma. Their features suggest that they are more important than immediate responses in the pathophysiology of asthma.     

Acute hepatotoxin exposure effects lymphoid and accessory cell types in inbred mice

The effect of acute hepatotoxin exposure on in vivo and in vitro immune responses were investigated in inbred mice. Splenic anti-SRBC PFC responses were slightly enhanced by carbon tetrachloride or galactosamine administration 5 hr prior to immunization. Whereas splenic anti-SRBC PFC responses were slightly enhanced in euthymic mice exposed to carbon tetrachloride 5 hr prior to immunization, immune responses to the TI antigens, Fl-LPS, Fl-Ficoll, and TNP-LPS, were significantly suppressed. Athymic mice receiving similar hepatotoxin exposure elicited enhanced immune responses to the TI immunogens, thereby suggesting that the activities of B cells and macrophages are enhanced in treated animals and in euthymic mice, T suppressor cells are also activated. By admixture of purified B- and T-cell and macrophage populations from either carbon tetrachloride-treated or control animals, it was demonstrated that hepatotoxin exposure also induces suppressor T cells regulating immune responses to the T-dependent antigen, SRBC, and that macrophages from treated animals are more functional. Further, B-cell responsiveness is enhanced. In addition to these observations, an active factor could be demonstrated in sera from hepatotoxin-treated animals which augments immune responses to SRBC in normal mice and promotes immune responses to this antigen in athymic mice. These findings indicate that the effects of acute hepatotoxin exposure are multifocal, influencing the activity of lymphoid and accessory cells.     

Influence of altitude, habitat and microhabitat on thermal adaptation of cicadas from Southwest Texas (Hemiptera: Cicadidae)

The thermal responses of 12 cicada species inhabiting Big Bend National Park, Texas, USA are investigated to determine the influence of altitude, habitat and microhabitat. The park provides an opportunity to analyze the thermal responses in animals from a variety of habitats and altitudinal gradients within a limited geographic range. The data suggest that thermal responses of cicadas are adaptations to their specific habitats. No thermal responses are significantly correlated with body size. The maximum voluntary tolerance temperature (an upper behavioral thermoregulatory point) and heat torpor temperatures show significant correlations with altitude. Variability in thermal responses can also be related to the characteristics of the microhabitat selected or the behavioral pattern of a species.     

Auditory steady-state responses to multiple simultaneous stimuli

Steady-state responses can follow multiple simultaneous auditory stimuli. If the stimuli are modulated at different rates, responses specific to each stimulus can be assessed by measuring in the frequency domain response the spectral component corresponding to the rate of modulation. When each stimulus has a different carrier frequency or different ear of presentation, the responses when 8 stimuli are presented simultaneously are not significantly different than when each stimulus is presented alone. Since significant responses can be recognized down to intensities that average 14 dB above behavioral threshold, this technique may be useful in objective audiometry. It is also possible to record steady-state responses to multiple modulations of the same carrier frequency. In this case, the amplitude of the responses when the stimuli are combined is smaller than when the stimuli are presented alone. The decrease in amplitude depends upon the number of concomitant stimuli and their relative intensities. These effects are probably due to the compressive rectification occurring during cochlear transduction, and the data may be used to model cochlear processing of auditory stimuli.     

Strong differential regulation of serum and mucosal IgA responses as revealed in CD28-deficient mice using cholera toxin adjuvant

In this study, we show that costimulation required for mucosal IgA responses is strikingly different from that needed for systemic responses, including serum IgA. Following oral immunization with cholera toxin (CT) adjuvant we found that whereas CTLA4-H1 transgenic mice largely failed to respond, CD28-/- mice developed near normal gut mucosal IgA responses but poor serum Ab responses. The local IgA response was functional in that strong antitoxic protection developed in CT-immunized CD28-/- mice. This was in spite of the fact that no germinal centers (GC) were observed in the Peyer's patches, spleen, or other peripheral lymph nodes. Moreover, significant somatic hypermutation was found in isolated IgA plasma cells from gut lamina propria of CD28-/- mice. Thus, differentiation to functional gut mucosal IgA responses against T cell-dependent Ags does not require signaling through CD28 and can be independent of GC formations and isotype-switching in Peyer's patches. By contrast, serum IgA responses, similar to IgG-responses, are dependent on GC and CD28. However, both local and systemic responses are impaired in CTLA4-Hgamma1 transgenic mice, indicating that mucosal IgA responses are dependent on the B7-family ligands, but require signaling via CTLA4 or more likely a third related receptor. Therefore, T-B cell interactions leading to mucosal as opposed to serum IgA responses are uniquely regulated and appear to represent separate events. Although CT is known to strongly up-regulate B7-molecules, we have demonstrated that it acts as a potent mucosal adjuvant in the absence of CD28, suggesting that alternative costimulatory pathways are involved.     

Transient bifurcations in neural error correction

This paper presents an investigation into the responses of neurons to errors in presynaptic spike trains. Errors are viewed, in nonlinear dynamical terms, as brief-duration changes in stationary presynaptic spike trains which induce transient responses in the postsynaptic cell. As these are generally large-magnitude transients, linearized neural models are not helpful. Instead, the responses of a full, nonlinear physiological model of a neuron that includes the recognized living prototype of an inhibitory synapse are analyzed. More specifically, the transients are examined in the context of the stationary behaviors that precede and succeed each error. It is shown that one and two dimensional bifurcation diagrams can be constructed from the transient responses--that there are marked changes in the transient responses at points that correspond to bifurcations in the stationary responses, qualitative changes in transients on either side of bifurcations, and only quantitative changes in transients between bifurcations.     

Anesthetic effects on pulmonary allergic responses in rats: changes in sensitivity to serotonin.

Subsequent to observations that pulmonary responses to antigen challenge are of different magnitudes in sensitized rats that are anesthetized with different drugs, we conducted studies to test whether the alterations in responses were due to changes in airway responsiveness to cholinergic or serotonergic challenge, opioid-receptor mediated events, or changes in mast cell mediator release. Immunoglobulin E-sensitized rats anesthetized with ketamine/urethan had larger changes in lung resistance and plasma histamine after pulmonary antigen challenge compared with rats anesthetized with fentanyl-droperidol. Blockade of opioid receptors with naloxone did not affect the responses. In unsensitized rats, airway responses to aerosolized methacholine were similar for the two anesthetics, indicating unchanged smooth muscle responsiveness; however, airway responses to intravenous serotonin were enhanced by ketamine and ablated by droperidol. We conclude that ketamine- and droperidol-induced alterations of pulmonary allergic responses are due to changes in sensitivity to serotonin and in mast cell mediator release. We speculate that mast cell mediator release may be modulated by a serotonin receptor-linked mechanism.     

Severe impairment of primary but not memory responses to influenza viral antigens in aged mice: costimulation in vivo partially reverses impaired primary immune responses

Profound alterations in humoral and cellular immune responses are a hallmark of aging, and understanding the immunobiology of aging is key to the success of preventive vaccination strategies. With aging, while recall or memory responses to influenza viral antigens for the most part remained unaltered, primary immune responses are severely impaired. The impaired primary responses are partly due to a lack of costimulation, as providing costimulation at the time of induction of primary immune responses against influenza virus vaccine partially reversed aged-related immune dysfunction and conferred enhanced protection. Inclusion of immunomodulators that up-regulate the expression of costimulatory molecules must be considered to improve the efficacy of vaccination in the elderly, particularly to novel immunogens.     

Humoral responses against coimmunized protein antigen but not against alphavirus-encoded antigens require alpha/beta interferon signaling

Viruses typically elicit potent adaptive immune responses, and live-virus-based vaccines are among the most efficient human vaccines known. The mechanisms by which viruses stimulate adaptive immune responses are not fully understood, but activation of innate immune signaling pathways in the early phase of the infection may be of importance. In addition to stimulating immune responses to viral antigens expressed in infected cells, viruses can also provide adjuvant signals to coimmunized protein antigens. Using recombinant Semliki Forest virus (rSFV)-based vaccines, we show that rSFV potently enhanced antibody responses against coimmunized protein antigens in the absence of other exogenously added adjuvants. Elicitation of antibody responses against both virus-encoded antigens and coimmunized protein antigens was independent of the signaling via Toll-like receptors (TLRs) previously implicated in antiviral responses. In contrast, the adjuvant effect of rSFV on coimmunized protein was completely abolished in mice lacking the alpha/beta interferon (IFN-alpha/beta) receptor (IFN-AR1), demonstrating that IFN-alpha/beta signaling was critical for mediating this effect. Antibody responses directed against virus-encoded antigens were intact in IFN-AR1(-/-) mice, suggesting that other signals are sufficient to drive immune responses against virally encoded antigens. These data provide a basis for the adjuvant effect of rSFV and show that different signals are required to stimulate antibody responses to virally encoded antigens and to antigens administered as purified protein vaccines, together with viral particles.     

Environmental stress responses in Lactobacillus: a review

Environmental stress responses in Lactobacillus, which have been investigated mainly by proteomics approaches, are reviewed. The physiological and molecular mechanisms of responses to heat, cold, acid, osmotic, oxygen, high pressure and starvation stresses are described. Specific examples of the repercussions of these effects in food processing are given. Molecular mechanisms of stress responses in lactobacilli and other bacteria are compared.     

Critical role for activation of antigen-presenting cells in priming of cytotoxic T cell responses after vaccination with virus-like particles

Virus-like particles (VLPs) are known to induce strong Ab responses in the absence of adjuvants. In addition, VLPs are able to prime CTL responses in vivo. To study the efficiency of this latter process, we fused peptide p33 derived from lymphocytic choriomeningitis virus to the hepatitis B core Ag, which spontaneously assembles into VLPs (p33-VLPs). These p33-VLPs were efficiently processed in vitro and in vivo for MHC class I presentation. Nevertheless, p33-VLPs induced weak CTL responses that failed to mediate effective protection from viral challenge. However, if APCs were activated concomitantly in vivo using either anti-CD40 Abs or CpG oligonucleotides, the CTL responses induced were fully protective against infection with lymphocytic choriomeningitis virus or recombinant vaccinia virus. Moreover, these CTL responses were comparable to responses generally induced by live vaccines, because they could be measured in primary ex vivo (51)Cr release assays. Thus, while VLPs alone are inefficient at inducing CTL responses, they become very powerful vaccines if applied together with substances that activate APCs.     

Signal transduction and ligand-receptor dynamics in the human neutrophil. Transient responses and occupancy-response relations at the formyl peptide receptor

The responses of neutrophils to formyl peptides are initiated and in many cases achieve a maximal level prior to equilibrium receptor occupancy. In order to begin to understand the linkage between receptor occupancy and cell response we have used a pulsed binding procedure to analyze: 1) the number of receptors contributing to three potential signalling events and six functional responses and 2) the evolution of these responses once ligand binding is interrupted. We find that the half-optimal elevations of the potential signals are produced by less than 1% occupancy (Ca2+) or 1-3% occupancy (cAMP, membrane depolarization). In contrast, actin polymerization and a rapid light scatter response are elicited by less than 0.1% occupancy. Half-optimal elastase release and degranulation require approximately 3% occupancy. While half-optimal O2- production and aggregation require approximately 30% occupancy, the half-optimal rate of O2- production requires less than 10% occupancy. To resolve the apparent lack of correlation between the responses and the signals we examined their time courses following the pulse of stimulation. At least four responses and one signal are transient and decay while occupied receptors remain on the membrane surface. These include the Quin 2-Ca2+ signal, actin polymerization, the light scatter response, O2- generation, and aggregation. Ca2+ elevation is correlated with the responses in that: 1) each of these responses is transient unless new receptors are occupied; 2) occupancy of nearly all of the receptors contributes to the time course of these responses; 3) when binding is interrupted, the responses decay with a half-time of 15 s, following a latency of approximately 10 s or less (except for disaggregation where latency is 30-40 s). We discuss evidence in support of the hypothesis that transient cell responses arise from transient receptor activation.     

Song-selective auditory input to a forebrain vocal control nucleus in the zebra finch

Neurons in nuclei on the motor pathway for vocalizations in songbirds are known to responses in one such nucleus, robustus archistriatalis (RA), were characterized by making multi-unit recordings in awake and anesthetized adult male zebra finches and in birds that had received lesions of the input to RA from the lateral part of the magnocellular nucleus of the anterior neostriatum (LMAN) or the Higher Vocal Center (HVC). In awake birds, RA neurons have a high level of spontaneous activity and vigorous auditory responses to song stimuli. Significantly greater responses are seen to the bird's own song (BOS) than to BOS played in reverse (REV) or to the songs of conspecifics (CON). Under ketamine-xylazine anesthesia, spontaneous activity is reduced, response latency increases and responses to BOS, REV and CON are indistinguishable. Responses obtained under urethane anesthesia are similar to those seen in awake birds. Thus, the pattern and selectivity of auditory responses in RA depend on the animal's state. Auditory responses in RA are qualitatively unchanged following lesion of the input to RA from LMAN, indicating that this pathway is not required for the sensory processing that underlies the preference for BOS on the vocal production pathway. Our results show that an input other than that from LMAN must be primarily responsible for auditory responses in RA. The direct projection form HVC is the most likely pathway by which song selective auditory information arrives in RA, since lesioning HVC abolished auditory responses in RA. © 1993 John Wiley & Sons, Inc.     

An oscillator network exhibiting a long-lasting response to an external signal

This study proposes an oscillator network to model the long-lasting responses observed in neural circuits. The responses of the proposed network model are represented by the temporal synchronization of the oscillators. The response duration does not depend on the natural frequency of the oscillators, which allows the responses to last much longer than the oscillation period of the oscillators. We can control the response duration by tuning the connection strengths between the oscillators and the external signal that triggers the responses. It is possible to break and restart the responses regardless of the way in which the oscillators are connected.     

The conundrum of CD40 function: host protection or disease promotion?

T cells regulate the immune responses to pathogens and autoantigens. The immune responses are tolerizing or anti-inflammatory against autoantigens but are inflammatory against pathogens and allografts. Such contradictory immune responses have been attributed to two counteracting effector cell types or to two counterregulatory sets of molecules: cell-surface expressed or secreted. By contrast, recent reports suggest that CD40, a co-stimulatory molecule on antigen-presenting cells, is a crucial controller of these counteractive immune responses, and emphasize reciprocal inhibition as an essential feature of biological responses. The molecular mechanism of such reciprocity in CD40 functions is the basis of immunotherapy in many diseases.     

The generation of Th memory in neonates versus adults: prolonged primary Th2 effector function and impaired development of Th1 memory effector function in murine neonates

Immunization during the neonatal period often results in Th2-biased secondary responses. To understand the regulation of this phenomenon, we have examined all phases of Th development, from the generation of primary effectors to the duration of the primary effector stage to the production of memory effector function. First, we had previously reported that although primary responses in the neonatal lymph nodes are mature, mixed Th1/Th2-like, primary responses in the spleens of the same animals are exclusively Th2-like. To determine whether Th2-dominant secondary responses are due to the Th2-polarized primary function in the spleen, neonates were splenectomized before immunization. Even in the absence of primary neonatal splenic responses, the secondary responses of neonates were Th2 dominant. Thus, the overwhelmingly Th2 primary responses in the neonatal spleen are not required to generate Th2-dominant memory in the lymph nodes. Second, we have compared the kinetics of the primary response phase in neonates and adults. In adults, Ag-specific Th2 function disappeared rapidly from both the lymph nodes and spleen. In contrast, primary Th2 function persisted out to 5 wk in both neonatal organs. Third, the generation of Th memory responses was examined in animals initially immunized as neonates and in adults. These experiments demonstrated that neonates are selectively impaired in the development of Th1 memory effector function. Together, these results indicate that neonates are biased to Th2 function at all phases of an immune response.     

Full-breadth analysis of CD8+ T-cell responses in acute hepatitis C virus infection and early therapy

Multispecific CD8(+) T-cell responses are thought to be important for the control of acute hepatitis C virus (HCV) infection, but to date little information is actually available on the breadth of responses at early time points. Additionally, the influence of early therapy on these responses and their relationships to outcome are controversial. To investigate this issue, we performed comprehensive analysis of the breadth and frequencies of virus-specific CD8(+) T-cell responses on the single epitope level in eight acutely infected individuals who were all started on early therapy. During the acute phase, responses against up to five peptides were identified. During therapy, CD8(+) T-cell responses decreased rather than increased as virus was controlled, and no new specificities emerged. A sustained virological response following completion of treatment was independent of CD8(+) T-cell responses, as well as CD4(+) T-cell responses. Rapid recrudescence also occurred despite broad CD8(+) T-cell responses. Importantly, in vivo suppression of CD3(+) T cells using OKT3 in one subject did not result in recurrence of viremia. These data suggest that broad CD8(+) T-cell responses alone may be insufficient to contain HCV replication, and also that early therapy is effective independent of such responses.     

ABA-specific responses are I region restricted by the carriers used for immunization

Immunization of mice with ABA coupled to carriers to which they are nonresponders gives rise to ABA-specific proliferative responses in lymph node cells. When C3H/HeN and CBA/J nonresponder mice are immunized with ABA on (T,G)-A-L (an I-A-restricted carrier in responder mice), the responses to ABA-tyr and ABA coupled to a variety of unrelated carriers are solely I-A restricted as determined by inhibition with anti-IA and anti-I-E sera. When ABA on GLT (an I-E-restricted carrier in responder mice) is used for immunization, the responses are both I-A and I-E restricted. Thus, ABA-specific responses in nonresponder mice appear in part to be restricted by the carrier used for immunization. B10.S mice, lacking functional I-E molecules, channel their ABA-specific responses entirely through I-A when immunized with ABA-GLT. These results support the hypothesis that the failure in nonresponders lies in a functional deficit in the T cell repertoire rather than an inability of accessory cells to present antigen.