Spike-Train Responses of a Pair of Hodgkin-Huxley Neurons with Time-Delayed Couplings

Model calculations have been performed on the spike-train response of a pair of Hodgkin-Huxley (HH) neurons coupled by recurrent excitatory-excitatory couplings with time delay. The coupled, excitable HH neurons are assumed to receive the two kinds of spike-train inputs: the transient input consisting of $M$ impulses for the finite duration ($M$: integer) and the sequential input with the constant interspike interval (ISI). The distribution of the output ISI $T_{\rm o}$ shows a rich of variety depending on the coupling strength and the time delay. The comparison is made between the dependence of the output ISI for the transient inputs and that for the sequential inputs.Comment: 19 pages, 4 figure

Ligand-Receptor Interactions

The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the interest of biologists to the kinetic and mechanical properties of cell membrane receptors. The aim of this review is to give a description of these advances that benefitted from a largely multidisciplinar approach

Toll-like receptors in cellular subsets of human tonsil T cells: altered expression during recurrent tonsillitis

BACKGROUND: The palatine tonsils have a pivotal role in immunological detection of airborne and ingested antigens like bacteria and viruses. They have recently been demonstrated to express Toll-like receptors (TLRs), known to recognize molecular structures on such microbes and activate innate immune responses. Their activation might also provide a link between innate and adaptive immunity. In the present study, the expression profile of TLR1-TLR10 was characterized in human tonsil T cells, focusing on differences between subsets of CD4(+ )T helper (Th) cells and CD8(+ )cytotoxic T lymphocytes (CTL). The study was also designed to compare the TLR expression in T cells from patients with recurrent tonsillitis and tonsillar hyperplasia. METHODS: Tonsils were obtained from children undergoing tonsillectomy, and classified according to the clinical diagnoses and the outcome of tonsillar core culture tests. Two groups were defined; recurrently infected tonsils and hyperplastic tonsils that served as controls. Subsets of T cells were isolated using magnetic beads. The expression of TLR transcripts in purified cells was assessed using quantitative real-time RT-PCR. The corresponding protein expression was investigated using flow cytometry and immunohistochemistry. RESULTS: T cells expressed a broad repertoire of TLRs, in which TLR1, TLR2, TLR5, TLR9 and TLR10 predominated. Also, a differential expression of TLRs in CD4(+ )and CD8(+ )T cells was obtained. TLR1 and TLR9 mRNA was expressed to a greater extent in CD4(+ )cells, whereas expression of TLR3 mRNA and protein and TLR4 protein was higher in CD8(+ )cells. CD8(+ )cells from infected tonsils expressed higher levels of TLR2, TLR3 and TLR5 compared to control. In contrast, CD4(+ )cells exhibited a down-regulated TLR9 as a consequence of infection. CONCLUSION: The present study demonstrates the presence of a broad repertoire of TLRs in T cells, a differential expression in CD4(+ )and CD8(+ )cells, along with infection-dependent alterations in TLR expression. Collectively, these results support the idea that TLRs are of importance to adaptive immune cells. It might be that TLRs have a direct role in adaptive immune reactions against infections. Thus, further functional studies of the relevance of TLR stimulation on T cells will be of importance

Normalization of the Lymph Node T Cell Stromal Microenvironment in lpr/lpr Mice Is Associated with SU5416-Induced Reduction in Autoantibodies

The vascular-stromal elements of lymph nodes can play important roles in regulating the activities of the lymphocytes within. During model immune responses, the vascular-stromal compartment has been shown to undergo proliferative expansion and functional alterations. The state of the vascular-stromal compartment and the potential importance of this compartment in a spontaneous, chronic model of autoimmunity have not been well studied. Here, we characterize the vascular expansion in MRL-lpr/lpr lymph nodes and attempt to ask whether inhibiting this expansion can interfere with autoantibody generation. We show that characteristics of vascular expansion in enlarging MRL-lpr/lpr lymph nodes resemble that of the VEGF-dependent expansion that occurs in wild-type mice after model immunization. Surprisingly, treatment with SU5416, an inhibitor of VEGF and other receptor tyrosine kinases, did not have sustained effects in inhibiting vascular growth, but attenuated the anti-dsDNA response and altered the phenotype of the double negative T cells that are expanded in these mice. In examining for anatomic correlates of these immunologic changes, we found that the double negative T cells are localized within ectopic follicles around a central B cell patch and that these T cell-rich areas lack the T zone stromal protein ER-TR7 as well as other elements of a normal T zone microenvironment. SU5416 treatment disrupted these follicles and normalized the association between T zone microenvironmental elements and T cell-rich areas. Recent studies have shown a regulatory role for T zone stromal elements. Thus, our findings of the association of anti-dsDNA responses, double negative T cell phenotype, and altered lymphocyte microenvironment suggest the possibility that lymphocyte localization in ectopic follicles protects them from regulation by T zone stromal elements and functions to maintain autoimmune responses. Potentially, altering the lymphocyte microenvironment that is set up by the vascular-stromal compartment can be a means by which to control undesired autoimmune responses

A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells

Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-γ producing CD4 T-cells. By contrast, mucosal exposure to ultraviolet light (UV)-inactivated Ct (UV-Ct) generated regulatory T-cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAP) elicited long-lived protection in conventional and humanized mice. UV-Ct-cSAP targeted immunogenic uterine CD11b+CD103− dendritic cells (DCs), whereas UV-Ct accumulated in tolerogenic CD11b−CD103+ DCs. Regardless of vaccination route, UV-Ct-cSAP induced systemic memory T-cells, but only mucosal vaccination induced effector T-cells that rapidly seeded uterine mucosa with resident memory T-cells (TRM). Optimal Ct clearance required both TRM seeding and subsequent infection-induced recruitment of circulating memory T-cells. Thus, UV-Ct-cSAP vaccination generated two synergistic memory T-cell subsets with distinct migratory properties

RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm

Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 minute injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 minute unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury blood flow was decreased in the inner cortex of wild type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 hours after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMC) to secrete the macrophage chemoattractant, RANTES; a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared to transgenic and non-transgenic mice after the 10 minute injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation

Kupffer Cells Hasten Resolution of Liver Immunopathology in Mouse Models of Viral Hepatitis

Kupffer cells (KCs) are widely considered important contributors to liver injury during viral hepatitis due to their pro-inflammatory activity. Herein we utilized hepatitis B virus (HBV)-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus-specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1) protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Acanthus montanus: An experimental evaluation of the antimicrobial, anti-inflammatory and immunological properties of a traditional remedy for furuncles

<p>Abstract</p> <p>Background</p> <p><it>Acanthus montanus </it>(Nees) T. Anderson (Acanthaceae) is a shrub widespread in Africa, the Balkans, Romania, Greece and Eastern Mediterranean. It is used in African traditional medicine for the treatment of urogenital infections, urethral pain, endometritis, urinary disease, cystitis, leucorrhoea, aches and pains. In southeastern Nigeria, the root is popular and acclaimed highly effective in the treatment of furuncles. This study was undertaken to experimentally evaluate the antimicrobial and anti-inflammatory properties of the root extract as well as its effect on phagocytosis and specific cell-mediated immune response which may underlie the usefulness of the roots in treatment of furuncles.</p> <p>Methods</p> <p>The aqueous root extract (obtained by hot water maceration of the root powder) was studied for effects on the growth of clinically isolated strains of <it>Pseudomonas aeruginosa </it>and <it>Staphylococcus aureus</it>. The anti-inflammatory activity was investigated using acute topical edema of the mouse ear induced by xylene, acute paw edema induced by agar in rats, formaldehyde arthritis in rats, vascular permeability induced by acetic acid in mice and heat- and hypotonicity-induced haemolysis of ox red blood cells (RBCs). Also evaluated were the effects on <it>in vivo </it>leukocyte migration induced by agar, phagocytic activity of macrophages on <it>Candida albicans </it>and specific cell-mediated immune responses (delayed type hypersensitivity reaction (DTHR) induced by sheep red blood cell (SRBC)). The acute toxicity and lethality (LD₅₀) in mice and phytochemical constituents of the extract were also determined.</p> <p>Results</p> <p>The extract moderately inhibited the growth of the test organisms and significantly (<it>P </it>< 0.05) inhibited (57%) topical acute edema in the mouse ear. It significantly (<it>P </it>< 0.05) suppressed the development of acute edema of the rat paw in a non-dose-related manner and was not effective in inhibiting the global edematous response to formaldehyde arthritis. It also inhibited vascular permeability induced by acetic acid in mice and the haemolysis of ox RBCs induced by heat- and hypotonicity. The extract increased total leukocyte and neutrophil counts and caused a significant (<it>P </it>< 0.05) dose-related increase in the total number of macrophages at the 800 mg/kg dose. On phagocytic activity, the extract evoked a significant (<it>P </it>< 0.05) increase in the number of macrophages with ingested <it>C. albicans </it>at 800 mg/kg dose, and significantly (<it>P </it>< 0.05) inhibited DTHR in a dose-related manner. Phytochemical tests on the extract revealed an abundant presence of alkaloids and carbohydrates while saponins, glycosides, and terpenoids occurred in trace amounts. Acute toxicity test established an oral and intraperitoneal LD₅₀greater than 5,000 mg/kg.</p> <p>Conclusion</p> <p>The effectiveness of the root of <it>A. montanus </it>in the treatment of furuncles may largely derive from mobilization of leukocytes to the site of the infection and activation of phagocytic activity as well as suppression of exacerbated immune responses by its constituents. Antimicrobial and anti-inflammatory activities are likely contributory mechanisms. Phytochemical constituents such as alkaloids and carbohydrates may be responsible for these pharmacological activities.</p