The immune system as the sixth sense BLALOCK, J. E.
Journal of internal medicine,
February 2005, Letnik:
257, Številka:
2
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
.
One of the truly remarkable discoveries in modern biology is the finding that the nervous system and immune system use a common chemical language for intra‐ and inter‐system communication. This ...review will discuss some of the pivotal results that deciphered this chemical language. Specifically the nervous and immune systems produce a common set of peptide and nonpeptide neurotransmitters and cytokines that act on a common repertoire of receptors in the two systems. The paper will also review more recent studies that have delineated hardwired and humoral pathways for such bidirectional communication. This is discussed in the context of the idea that the sharing of ligands and receptors allows the immune system to serve as the sixth sense that notifies the nervous system of the presence of entities, such as viruses and bacteria, that are imperceptible to the classic senses. Lastly, this review will suggest ways to apply the newfound knowledge of the sixth sense to understand a placebo effect and to treate human disease.
Neutrophil influx and activation contributes to organ damage in several major lung diseases. This inflammatory influx is initiated and propagated by both classical chemokines such as interleukin-8 ...and by downstream mediators such as the collagen fragment cum neutrophil chemokine Pro-Gly-Pro (PGP), which share use of the ELR + CXC receptor family. Benzyloxycarbonyl-proline-prolinal (ZPP) is known to suppress the PGP pathway via inhibition of prolyl endopeptidase (PE), the terminal enzyme in the generation of PGP from collagen. However, the structural homology of ZPP and PGP suggests that ZPP might also directly affect classical glutamate-leucine-arginine positive (ELR+) CXC chemokine signaling. In this investigation, we confirm that ZPP inhibits PE in vitro, demonstrate that ZPP inhibits both ELR + CXC and PGP-mediated chemotaxis in human and murine neutrophils, abrogates neutrophil influx induced by murine intratracheal challenge with LPS, and attenuates human neutrophil chemotaxis to sputum samples of human subjects with cystic fibrosis. Cumulatively, these data demonstrate that ZPP has dual, complementary inhibitory effects upon neutrophil chemokine/matrikine signaling which make it an attractive compound for clinical study of neutrophil inhibition in conditions (such as cystic fibrosis and chronic obstructive pulmonary disease) which evidence concurrent harmful increases of both chemokine and matrikine signaling.
•Canonical and non-canonical CXCR signaling both contribute to PMN recruitment.•ZPP inhibits PE, reducing the production of the non-canonical CXCR ligand PGP.•ZPP also inhibits canonical (ELR+ CXC) CXCR signaling.•ZPP suppresses cystic fibrosis sputum-induced PMN chemotaxis via both mechanisms.
P-type point contact (PPC) HPGe detectors are a leading technology for rare event searches due to their excellent energy resolution, low thresholds, and multi-site event rejection capabilities. We ...have characterized a PPC detector’s response to
α
particles incident on the sensitive passivated and p
+
surfaces, a previously poorly-understood source of background. The detector studied is identical to those in the
Majorana
Demonstrator
experiment, a search for neutrinoless double-beta decay (
0
ν
β
β
) in
76
Ge.
α
decays on most of the passivated surface exhibit significant energy loss due to charge trapping, with waveforms exhibiting a delayed charge recovery (DCR) signature caused by the slow collection of a fraction of the trapped charge. The DCR is found to be complementary to existing methods of
α
identification, reliably identifying
α
background events on the passivated surface of the detector. We demonstrate effective rejection of all surface
α
events (to within statistical uncertainty) with a loss of only 0.2% of bulk events by combining the DCR discriminator with previously-used methods. The DCR discriminator has been used to reduce the background rate in the
0
ν
β
β
region of interest window by an order of magnitude in the
Majorana
Demonstrator
and will be used in the upcoming LEGEND-200 experiment.
It has been recognized for some time that the Ca2+-dependent slow afterhyperpolarization (sAHP) is larger in hippocampal neurons of aged compared with young animals. In addition, extensive studies ...since have shown that other Ca2+-mediated electrophysiological responses are increased in hippocampus with aging, including Ca2+ transients, L-type voltage-gated Ca2+ channel activity, Ca2+ spike duration and action potential accommodation. Elevated Ca2+-induced Ca2+ release from ryanodine receptors (RyRs) appears to drive amplification of the Ca2+ responses. Components of this Ca2+ dysregulation phenotype correlate with deficits in cognitive function and plasticity, indicating they may play critical roles in aging-related impairment of brain function. However, the molecular mechanisms underlying aging-related Ca2+ dysregulation are not well understood. FK506-binding proteins 1a and 1b (FKBP1a/1b, also known as FKBP12/12.6) are immunophilin proteins that bind the immunosuppressant drugs FK506 and rapamycin. In muscle cells, FKBP1a/1b also bind RyRs and inhibits Ca2+-induced Ca2+ release, but it is not clear whether FKBPs act similarly in brain cells. Recently, we found that selectively disrupting hippocampal FKBP1b function in young rats, either by microinjecting adeno-associated viral vectors expressing siRNA, or by treatment with rapamycin, increases the sAHP and recapitulates much of the hippocampal Ca2+ dysregulation phenotype. Moreover, in microarray studies, we found FKBP1b gene expression was downregulated in hippocampus of aging rats and early-stage Alzheimer's disease subjects. These results suggest the novel hypothesis that declining FKBP function is a key factor in aging-related Ca2+ dysregulation in the brain and point to potential new therapeutic targets for counteracting unhealthy brain aging.
The pathogenesis of incipient Alzheimer's disease (AD) has been resistant to analysis because of the complexity of AD and the overlap of its early-stage markers with normal aging. Gene microarrays ...provide new tools for addressing complexity because they allow overviews of the simultaneous activity of multiple cellular pathways. However, microarray data interpretation is often hindered by low statistical power, high false positives or false negatives, and by uncertain relevance to functional endpoints. Here, we analyzed hippocampal gene expression of nine control and 22 AD subjects of varying severity on 31 separate microarrays. We then tested the correlation of each gene's expression with MiniMental Status Examination (MMSE) and neurofibrillary tangle (NFT) scores across all 31 subjects regardless of diagnosis. These well powered tests revealed a major transcriptional response comprising thousands of genes significantly correlated with AD markers. Several hundred of these genes were also correlated with AD markers across only control and incipient AD subjects (MMSE > 20). Biological process categories associated with incipient AD-correlated genes were identified statistically (EASE program) and revealed up-regulation of many transcription factor/signaling genes regulating proliferation and differentiation, including tumor suppressors, oligodendrocyte growth factors, and protein kinase A modulators. In addition, up-regulation of adhesion, apoptosis, lipid metabolism, and initial inflammation processes occurred, and down-regulation of protein folding/metabolism/transport and some energy metabolism and signaling pathways took place. These findings suggest a new model of AD pathogenesis in which a genomically orchestrated up-regulation of tumor suppressor-mediated differentiation and involution processes induces the spread of pathology along myelinated axons.
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