Phase separation in immune regulation and immune-related diseases

Journal of Molecular Medicine - Phase separation is an emerging paradigm for understanding the biochemical interactions between proteins, DNA, and RNA. Research over the past decade has provided...     

Evidence for the involvement of corticosterone in the ontogeny of the cellular immune apparatus of the mouse.

The effects of corticosterone deprivation in the cellular immune system of the mouse have been studied. Adrenalectomy was performed from three weeks after birth; at an earlier age oral administration of aminoglutethimide phosphate (AGP) had to be used. Three effects could be recognized: (1) Adrenalectomy or AGP treatment, at any age studied, resulted in an enhanced delayed hypersensitivity (DH) to sheep red blood cells (SRBC). This effect has previously been ascribed to monocytes. (2) An altered T lymphocyte distribution was observed as consequence of early adrenalectomy or continuous AGP administration. The lymph nodes were depleted whereas the thymus was increased in size and blood-leucocytes increased in number. This effect appeared reversible on restoration of adrenal function. (3) Irreversible damage to the cellular immune system following early AGP intake was observed in DH after recovery of the adrenal function. As corticosterone is the principal glucocorticoid produced by mice the effects described under (2) and (3) may be ascribed to this hormone. Our results suggest that thymic involution during life, is at least partially, under adrenal control.     

Attenuation of amnesia by hydrocortisone in the mouse

Effects of hydrocortisone on the retrograde amnesia produced by electroconvulsive shock (ECS) was studied in 228 mice. The animals were given ECS after one-trial training in a step-through apparatus, and tested for passive avoidance behavior 7 days later. The amnesic effect of ECS was absent in the animals that were injected with hydrocortisone SC prior to the administration of ECS. Hydrocortisone alone, without ECS, had no significant effect on passive avoidance. There was no indication that the hormone suppressed the ECS-induced seizure activity in the brain. The results suggest that hydrocortisone protected the animals from amnesia by acting on the brain before the onset of the disruptive action of ECS.     

Neuroendocrine regulation of immune processes: change in circulating corticosterone levels induced by the primary antibody response in mice

The induction of antibody formation mediated significant changes in circulating corticosterone (CS) levels in mice. On the day of the peak plaque-forming cell (PFC) response to sheep red blood cells (SRBC) or to the trinitrophenyl (TNP) hapten, the 0800 h serum CS concentration was increased. This hormonal elevation was not observed in SRBC-immunized low responder animals which did not give a significant PFC response, thus suggesting a direct correlation between immune responsiveness and hormonal changes. A change in the circadian rhythm of CS was evident in immune animals injected with SRBC. Control animals injected with saline showed a regular circadian pattern of low CS level at 0800 h followed by a high level at 1600 h. In contrast, responding animals injected with SRBC were found to have a reversed CS pattern, i.e. the hormonal concentration was high at 0800 h and low at 1600 h, on the day of the peak PFC response. This reversal of the circadian CS pattern may have important immunoregulatory significance. The immunization-induced CS response could be significantly blocked by the administration of diazepam (DZM), an effect which implies the involvement of central hypothalamic-pituitary control of the response.     

Effect of hydrocortisone on immune system of the lizard, II. Differential action on T and B lymphocytes

Lymphocytes of thymus, spleen, peripheral blood (PB) and bone marrow (BM) collected from adult lizards, were cultured for 24 hr in the presence of 10⁻³M hydrocortisone acetate (HC) in order to assess the effect of in vitro HC on lizard T and B cell viability. The results indicated that HC induced stepwise, time-dependent mortality of the majority of thymocytes carrying T cell specific antigen(s) (TSA), 30–50% of T cells of spleen, PB and BM, and of a proportion of splenic B lymphocytes. Administration of 1 mg/g body weight HC to adult . lead to depletion of all TSA⁺ thymocytes. In contrast, T lymphocytes in the peripheral lymphoid compartments revealed both sensitivity and resistance to HC; similarly, B lymphocytes constituted susceptible and resistant subpopulations.     

Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases

The gut microbiota has a critical role in the maintenance of immune homeostasis. Alterations in the intestinal microbiota and gut microbiota-derived metabolites have been recognized in many immune-related inflammatory disorders. These metabolites can be produced by gut microbiota from dietary components or by the host and can be modified by gut bacteria or synthesized de novo by gut bacteria. Gut microbiota-derived metabolites influence a plethora of immune cell responses, including T cells, B cells, dendritic cells, and macrophages. Some of these metabolites are involved in the pathogenesis of immune-related inflammatory diseases, such as inflammatory bowel diseases, diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Here, we review the role of microbiota-derived metabolites in regulating the functions of different immune cells and the pathogenesis of chronic immune-related inflammatory diseases.     

Effect of hydrocortisone on immune system of the lizard,Chalcidesocellatus II. Differential action on T and B lymphocytes

Lymphocytes of thymus, spleen, peripheral blood (PB) and bone marrow (BM) collected from adult lizards, $\text{Chalcides}$$\text{ocellatus}$ were cultured for 24 hr in the presence of 10^?3M hydrocortisone acetate (HC) in order to assess the effect of in vitro HC on lizard T and B cell viability. The results indicated that HC induced stepwise, time-dependent mortality of the majority of thymocytes carrying T cell specific antigen(s) (TSA), 30–50% of T cells of spleen, PB and BM, and of a proportion of splenic B lymphocytes. Administration of 1 mg/g body weight HC to adult $\text{Ch}$. $\text{ocellatus}$ lead to depletion of all TSA⁺ thymocytes. In contrast, T lymphocytes in the peripheral lymphoid compartments revealed both sensitivity and resistance to HC; similarly, B lymphocytes constituted susceptible and resistant subpopulations.     

Differential acquired immune responsiveness to bacterial lipoproteins in Lyme disease-resistant and -susceptible mouse strains

We investigated the effect of Borrelia burgdorferi lipoproteins (outer surface protein A) and the synthetic lipohexapeptide tripalmitoyl-S-glyceryl-Cys-Ser-4(Lys) (Pam3-Cys) on isolated lymph node (LN) cells from Lyme disease-susceptible (C3H/HeJ) and -resistant (C57BL/6J) mice. Mice were either infected with B. burgdorferi for 1 week or left uninfected. Lipoprotein-stimulated LN cells from infected C3H/HeJ mice produced significantly higher levels of the inflammatory cytokines IL-6 and IFN-gamma than did cells from C57BL/6J mice. Cells from uninfected mice did not respond. No TNF-alpha or IL-1beta were produced by LN cells from infected mice of either strain in response to lipoprotein or B. burgdorferi spirochetes. Unlike with IL-6 or IFN-gamma, LN cells from either strain failed to produce IL-10 in response to lipoproteins. However, the LN cells were able to produce this cytokine in response to B. burgdorferi spirochetes or after incubation with phorbol-12-myristate-13-acetate/ionomycin, anti-CD3 antibody alone or anti-CD3 combined with anti-CD28 antibodies. Addition of exogenous IL-10 to lipopeptide-stimulated cultures significantly reduced IFN-gamma and IL-6 production in a dose-dependent fashion. This inhibition was more effective with cells from disease-resistant C57BL/6J mice than with cells from disease-susceptible C3H/HeJ mice. The proclivity to disease of the C3H/HeJ mouse could be simultaneously based on the phenomena of enhanced inflammatory responsiveness to lipoproteins and diminished ability to respond to IL-10. An investigation of the determinants of these two phenomena could be used as a blueprint to elucidate the pathogenesis of Lyme disease in humans.     

ACTH effects on response suppression and plasma corticosterone in the mouse.

The effects of adrenocorticotropin (ACTH) on behavioral and adrenocortical responses in the mouse were investigated. In Experiment 1 ACTH facilitated the suppression of activity in a situation where this activity was punished by footshock. In Experiment 2 repeated injections with ACTH resulted in an increase in adrenocortical responsiveness. The data demonstrate the cross-species generality of effects on aversively motivated behavior.     

Effect of hydrocortisone on immune system of the lizard,Chalcidesocellatus I. Response of lymphoid tissues and cells to in vivo and in vitro hydrocortisone

A single dose of 1 mg/g body weight of hydrocortisone acetate (HC) administered intraperitoneally to adult lizards, $\text{Chalcides}$$\text{ocellatus}$ induced rapidly a reduction of about 85% of thymic lymphocytes. Histological evidence indicated that cortical, as well as, medullary thymocytes are sensitive to HC exposure. Around 40–50% of lymphocytes in peripheral blood (PB) and spleen were depleted at 3–7 days post-HC injection; such depletion durated about 4 weeks for PB but was rather temporary in spleen. Increase in number of bone marrow (BM) lymphocytes was negligible and transient and could by no way account for the dramatic cell losses in the different lymphoid tissues. The findings thus suggested that HC-mediated lymphocyte depletion in lizards is not attributable to redistribution between the different lymphoid compartments but rather to destruction. In direct conformation, lymphocytes were readily lysed in vitro by 10^?3M HC, thymocytes being more vulnerable > PB> spleen >BM lymphocytes.     

Differential corticosterone responses to stress in the lung in two strains of Flinders rats

Background Acute stress affects a variety of organs and cellular systems. These include the hypothalamic–pituitary–adrenal (HPA) axis, corticotropin‐releasing factor (CRF), mast cells and nerves. Flinders‐sensitive (FSL) rat strains have hypercholinergic responses and are more sensitive than Flinders‐resistant rats (FRL) to anaphylaxis. Objective To investigate the effects of acute water avoidance stress (1 h) on FSL and FRL tracheal epithelial tissue. Methods We measured short circuit current (I_sc) as a measure of tracheal response, and the effect of substance P (SP) on tracheal epithelium in Ussing chambers. Electron microscopy was performed to assess mast cell activation. Results Both strains showed increased I_sc responses to stress, inhibited by prior injection of the CRF receptor 1 and 2 antagonist, α‐helical CRF‐(9–41). No increases in conductance were seen. Stress responses were accompanied by electron microscopic morphologic evidence for mast cell degranulation, which was not completely inhibited by α‐helical CRF‐(9–41) pre‐treatment. Stress primed the epithelium for an enhanced response to SP in FSL, but this again was not inhibited by α‐helical CRF‐(9–41). FRL had 2.5 times the corticosterone response of FSL. Conclusion Acute stress affects the tracheal epithelium, not accompanied by changes in ion permeability, but associated with mast cell degranulation. Because blunted HPA axis responses are associated with vulnerability to inflammation, this may partially explain the findings. These stress effects on the lung have a genetic basis associated with relative corticosterone responses, are complex and only in part mediated by CRF.     

The two simultaneously occurring processes in one immune response: the positive immune reaction and immune tolerance

The immune response is tightly shaped by both positive and negative signals on different levels. Based on the accumulating data, we hypothesize that, both immune reaction and immune tolerance processes were potentially and simultaneously triggered after antigen challenging. The actual outcome of immune response is dependent on the sum of these two reactions. The hypothesis, if proved to be correct, will significantly improve our understanding the immunity and its related pathological effects. It will influence our choice on immunosuppressive drugs for patients with transplant grafts, autoimmune diseases. As the immunosuppressive drugs may also block the potential immune tolerance process which is beneficial to the patients. Therefore, we should try to develop novel immunosuppressive medicines that selectively inhibit immune reaction but no effects on immune tolerance for patients with allo-grafts or autoimmune diseases. On the other hand, it will impact the immunotherapy for tumors and the development of vaccines.     

Effect of defensins on the blood level of corticosterone and the immune response during stress

Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 115, N ^o 6, pp. 646–649, June, 1993     

Differential PsaA-, PspA-, PspC-, and PdB-specific immune responses in a mouse model of pneumococcal carriage

Larger numbers of pneumococci were detected in the nasal tract compared to the lung, cervical lymph nodes, and spleen 1, 2, 4, 7, 14, and 21 days after nasal challenge with Streptococcus pneumoniae strain EF3030. In this mouse model of pneumococcal carriage, peripheral S. pneumoniae pneumococcal surface adhesin A (PsaA)-specific humoral responses (immunoglobulin G2a [IgG2a] > IgG1 = IgG2b > IgG3) were significantly higher than pneumococcal surface protein A (PspA)-specific, genetic toxoid derivative of pneumolysin (PdB)-specific, or pneumococcal surface protein C (PspC)-specific serum antibody levels. However, PspA-specific mucosal IgA antibody levels were significantly higher than those against PsaA, PdB, and PspC. In general, both PsaA- and PspA-specific lung-, cervical lymph node-, nasal tract-, and spleen-derived CD4(+) T-cell cytokine (interleukin-4, interleukin-6, granulocyte-macrophage colony-stimulating factor, gamma interferon, and tumor necrosis factor alpha) and proliferative responses were higher than those for either PspC or PdB. Taken together, these findings suggest that PsaA- and PspA-specific mucosal responses as well as systemic humoral and T helper cell cytokine responses are predominantly yet differentially induced during pneumococcal carriage.