Apoptosis in fatal Ebola infection. Does the virus toll the bell for immune system?

In fatal Ebola virus hemorrhagic fever massive intravascular apoptosis develops rapidly following infection and progressing relentlessly until death. While data suggest that T lymphocytes are mainly deleted by apoptosis in PBMC of human fatal cases, experimental Ebola infection in animal models have shown some evidence of destruction of lymphocytes in spleen and lymph nodes probably involving both T and B cells. Nevertheless, we are able to conclude from the accumulated evidence that early interactions between Ebola virus and the immune system, probably via macrophages, main targets for viral replication, lead to massive destruction of immune cells in fatal cases.     

Is there a mucosal immune system associated with the mammalian oviduct?

The oviduct is a key component of the reproductive system where essential states such as spermatozoa capacitation, fertilization and early embryo development take place. Recently, an additional role for the entire female reproductive tract has emerged with important implications for our understanding and management of reproductive health, namely, its role in mounting local immune responses against microbial pathogens. Most of the evidence about mucosal immune responses in the female reproductive tract is related to the vagina, with less information available for the uterus. The less known segment in this regard is the oviduct, which prompted us to review and summarize the current state of knowledge on the immune system at the level of the mammalian oviduct. A comprehensive search was conducted in Medline and--for the last two years--also in Current Contents. Result demonstrate that the mammalian oviduct is endowed with many of the elements that characterize a mucosal immune system. However, there are gaps in our knowledge that, in addition to important interspecies differences, make it essential to explore further some fundamental questions regarding this system.     

Does the immune system of a mouse age faster than the immune system of a human?

One of the characteristics of all somatic cells is a finite life span. Cells may proliferate until they reach a point after which, although they are metabolically active, they can no longer produce daughter cells. This observation is central to the clonal exhaustion hypothesis, a mechanism cited to explain age-associated immune dysfunction. In this hypothesis, repeated division of lymphocytes leads to a replicative limit, after which they enter the senescent phase but are not lost from the pool of T cells. Advancing age would then be associated with an increase in the number of T cells that are unable to proliferate to a stimulus which induces a proliferative response in T cells from younger individuals. This hypothesis seems both logical and reasonable and is supported by data from both humans and mice with the demonstration of an age-related accumulation of senescent T cells in both species. However, there is an apparent paradox. The paradox arises because the onset of immunosenescence appears to be more closely linked to the life span of the animal rather than the life span of the lymphocyte. BioEssays 21:519–524, 1999. © 1999 John Wiley & Sons, Inc.     

Is an immune reaction required for malignant transformation and cancer growth?

Increasing evidence has shown that probably all malignant mouse cells, even those of spontaneous sporadic cancers, are endowed with tumor-specific antigens. Stimulation of cancer growth, rather than inhibition by the immune reaction, is seemingly the prevalent effect in the animal of origin (the autochthonous animal). Small initial dosages of even strong tumor antigens tend to produce stimulatory immune reactions rather than tumor inhibition in any animal. Thus, an immune response at a low level may be an essential growth-driving feature of nascent cancers, and this may be why all cancers apparently have tumor-specific antigens. Inasmuch as a low level of immunity is stimulatory to tumor growth while larger dosages are inhibitory, immuno-selection via this low response may tend to keep the antitumor immune reaction weak and at a nearly maximal stimulatory level throughout most of a tumor's existence. These facts suggest that both suppression of tumor immunity and a heightened immune reaction might each be therapeutic although very contrasting modalities.     

Is the renin-angiotensin system involved in urinary concentration mechanisms?

Renin release elicited by i.v. injection of loop-diuretics was used to study the effects of angiotensin II (AII) on intrarenal hemodynamics. The vasoconstrictive action of intrarenally synthesized AII predominates in the efferent glomerular arteriole. Such a vasoconstrictive effect could affect blood flow in the vasa recta which stem from efferent arterioles of juxtamedullary glomeruli. Renin secretion and renal inner medullary blood flow (tissue clearance of 133Xe) were simultaneously measured before and after frusemide-induced renin release. The relationship between renin secretion and renal inner medullary blood flow was inverse. Changes in renal medullary blood flow may be physiological determinants of medullary osmolality and renal concentration ability. The intrarenal role of AII in urinary concentration recovery after frusemide was examined. Inhibition of renin release by propranolol or AII-blockade (by saralasin or Hoe 409) delayed recovery of urinary osmolality. In the conscious rat, propranolol slowed down recovery of the cortico-papillary gradient for sodium. Its vasoconstrictive action on the efferent glomerular arteriole might enable the renin-angiotensin system to participate in the control of renal excretion of salt and water.     

Is immune cell activation the missing link in the pathogenesis of post-diarrhoeal HUS?

Haemolytic uraemic syndrome (HUS), which is caused by Shiga toxin (Stx)-producing Escherichia coli, is the commonest cause of acute renal failure in childhood. It is widely believed that HUS develops following the release of Stx, an AB5 toxin that inhibits protein synthesis and has a direct toxic effect on the kidney endothelium. There remains, however, a mismatch between the current understanding of the pathogenesis of HUS and the evolution of the clinical signs of the disease. Our hypothesis is that Stx-mediated immune cell activation in the gut is the missing link in the pathogenesis of this condition, initiating the characteristic renal pathology of HUS either alone or in synergy with Stx. Validation of this hypothesis could lead to a targeted anti-inflammatory approach aimed at modulating immune cell function in HUS.     

Can the immune system be harnessed to repair the CNS?

Experimental and clinical data have demonstrated that activating the immune system in the CNS can be destructive. However, other studies have shown that enhancing an immune response can be therapeutic, and several clinical trials have been initiated with the aim of boosting immune responses in the CNS of individuals with spinal cord injury, multiple sclerosis and Alzheimer's disease. Here, we evaluate the controversies in the field and discuss the remaining scientific challenges that are associated with enhancing immune function in the CNS to treat neurological diseases.     

Evolution of the mammary gland from the innate immune system?

The mammary gland is a skin gland unique to the class Mammalia. Despite a growing molecular and histological understanding of the development and physiology of the mammary gland, its functional and morphological origins have remained speculative. Numerous theories on the origin of the mammary gland and lactation exist. The purpose of the mammary gland is to provide the newborn with copious amounts of milk, a unique body fluid that has a dual role of nutrition and immunological protection. Interestingly, antimicrobial enzymes, such as xanthine oxidoreductase or lysozyme, are directly involved in the evolution of the nutritional aspect of milk. We outline that xanthine oxidoreductase evolved a dual role in the mammary gland and hence provide new evidence supporting the hypothesis that the nutritional function of the milk evolved subsequent to its protective function. Therefore, we postulate that the mammary gland evolved from the innate immune system. In addition, we suggest that lactation partly evolved as an inflammatory response to tissue damage and infection, and discuss the observation that the two signaling pathways, NF-kB and Jak/Stat, play central roles in inflammation as well as in lactation.     

Is maximum stimulation intensity required in the assessment of muscle activation capacity?

Voluntary activation assessment using the interpolation twitch technique (ITT) has almost invariably been done using maximal stimulation intensity, i.e., an intensity beyond which no additional joint moment or external force is produced by increasing further the intensity of stimulation. The aim of the study was to identify the minimum stimulation intensity at which percutaneous ITT yields valid results. Maximal stimulation intensity and the force produced at that intensity were identified for the quadriceps muscle using percutaneous electrodes in eight active men. The stimulation intensities producing 10–90% (in 10% increments) of that force were determined and subsequently applied during isometric contractions at 90% of maximum voluntary contraction (MVC) via twitch doublets. Muscle activation was calculated with the ITT and pain scores were obtained for each stimulation intensity and compared to the respective values at maximum stimulation intensity. Muscle activation at maximal stimulation intensity was 91.6 (2.5)%. The lowest stimulation intensity yielding comparable muscle activation results to maximal stimulation was 50% (88.8 (3.9)%, p < 0.05). Pain score at maximal stimulation intensity was 6.6 (1.5) cm and it was significantly reduced at 60% stimulation intensity (3.7 (1.5) cm, p < 0.05) compared to maximal stimulation intensity. Submaximal stimulation can produce valid ITT results while reducing the discomfort obtained by the subjects, widening the assessment of ITT to situations where discomfort may otherwise impede maximal electrostimulation.     

Alpha,beta-elimination reaction of O-acetylserine sulfhydrylase. Is the pyridine ring required?

O-Acetylserine sulfhydrylase (OASS) catalyzes the elimination of acetate from O-acetyl-L-serine (OAS) followed by addition of bisulfide to give L-cysteine. Site-directed mutagenesis has been used to replace the active site serine, S272, which forms a hydrogen bond to N1 of pyridoxal 5'-phosphate (PLP) with alanine and aspartate. Based on UV-visible spectral and steady-state kinetic studies, both mutant enzymes catalyze the elimination reaction with an efficiency equal to that of the wild-type enzyme. Data are consistent with an anti-E(2) reaction proposed for the elimination reaction.     

Is there anything "autonomous" in the nervous system?

The terms "autonomous" or "vegetative" are currently used to identify one part of the nervous system composed of sympathetic, parasympathetic, and gastrointestinal divisions. However, the concepts that are under the literal meaning of these words can lead to misconceptions about the actual nervous organization. Some clear-cut examples indicate that no element shows "autonomy" in an integrated body. Nor are they solely "passive" or generated "without mental elaboration." In addition, to be "not consciously controlled" is not a unique attribute of these components. Another term that could be proposed is "homeostatic nervous system" for providing conditions to the execution of behaviors and maintenance of the internal milieu within normal ranges. But, not all homeostatic conditions are under the direct influence of these groups of neurons, and some situations clearly impose different ranges for some variables that are adaptative (or hazardous) in the tentative of successfully coping with challenging situations. Finally, the name "nervous system for visceral control" emerges as another possibility. Unfortunately, it is not only "viscera" that represent end targets for this specific innervation. Therefore, it is commented that no quite adequate term for the sympathetic, parasympathetic, and gastrointestinal divisions has already been coined. The basic condition for a new term is that it should clearly imply the whole integrated and collaborative functions that the components have in an indivisible organism, including the neuroendocrine, immunological, and respiratory systems. Until that, we can call these parts simply by their own names and avoid terms that are more "convenient" than appropriate.     

Is the food‐entrainable circadian oscillator in the digestive system?

Food-anticipatory activity (FAA) is the increase in locomotion and core body temperature that precedes a daily scheduled meal. It is driven by a circadian oscillator but is independent of the suprachiasmatic nuclei. Recent results that reveal meal-entrained clock gene expression in rat and mouse peripheral organs raise the intriguing possibility that the digestive system is the site of the feeding-entrained oscillator (FEO) that underlies FAA. We tested this possibility by comparing FAA and Per1 rhythmicity in the digestive system of the Per 1-luciferase transgenic rat. First, rats were entrained to daytime restricted feeding (RF, 10 days), then fed ad libitum (AL, 10 days), then food deprived (FD, 2 days). As expected FAA was evident during RF and disappeared during subsequent AL feeding, but returned at the correct phase during deprivation. The phase of Per1 in liver, stomach and colon shifted from a nocturnal to a diurnal peak during RF, but shifted back to nocturnal phase during the subsequent AL and remained nocturnal during food deprivation periods. Second, rats were entrained to two daily meals at zeitgeber time (ZT) 0400 and ZT 1600. FAA to both meals emerged after about 10 days of dual RF. However, all tissues studied (all five liver lobes, esophagus, antral stomach, body of stomach, colon) showed entrainment consistent with only the night-time meal. These two results are inconsistent with the hypothesis that FAA arises as an output of rhythms in the gastrointestinal (GI) system. The results also highlight an interesting diversity among peripheral oscillators in their ability to entrain to meals and the direction of the phase shift after RF ends.     

In vitro effect of biogenic amines on the hormone content of immune cells of the peritoneal fluid and thymus. Is there a hormonal network inside the immune system?

Immune cells contain different hormones and hormone-like molecules, such as insulin, endorphin, triiodothyronine (T3) histamine, serotonin. In earlier in vitro experiments insulin down-regulated histamine, serotonin and T3 content of thymus cells. Now we studied the effect of biogenic amines on the endorphin, T3, serotonin and histamine content of rat peritoneal and thymic cells. Cells were obtained from male rats of 100g body weight. 100 ng/ml serotonin or 300 ng/ml histamine was added for 30 min. After that the cells were prepared for flow cytometric analysis with antibodies to endorphin, T3, histamine and serotonin as primary antibodies and anti-rabbit IgG as secondary antibody. Finishing the measurements the cells were also studied by confocal microscopy. T3 concentration (binding of anti-T3 antibody) increased in peritoneal mast cells after serotonin treatment and in the monocyte-macrophage-granulocyte group after histamine treatment. Thymocytes' T3 content radically decreased after both treatments. Serotonin and histamine treatment also radically reduced the amine content of each other. Endorphin level was resistant to hormonal treatments. The results call attention to a possible hormonal network inside the immune system in which hormones produced by the immune cells themselves can influence each other.     

The liver: an organ of the immune system?

The liver stands in a unique position between the gastrointestinal tract and systemic venous system. Its constant exposure to food antigens, bacterial products and potential pathogens through the mesenteric circulation, requires the liver to maintain tolerogenic capabilities while preserving the means to mount effective immune responses. The liver has the unique ability amongst solid organs, to activate na?ve CD8+ T lymphocytes in an antigen-specific manner. However, this activation can be inefficient and lead to apoptosis. This phenomenon is believed to be involved in both, the development of oral tolerance and the induction of tolerance in liver allografts. The liver is the target of both autoimmune diseases and of chronic viral infections and its unique tolerogenic environment has frequently been suggested as a factor in the development of these diseases. A better grasp of the liver's unique immunological processes would lead to a better understanding of immune tolerance mechanisms and their role in the development of autoimmune diseases and chronic viral infections.