Future Needs in Mast Cell Biology.

The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct "subpopulations" of mast cells based on a relatively small number of biochemical characteristics. More recently, "subtypes" of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease

Immune Sensitization in the Skin Is Enhanced by Antigen-Independent Effects of IgE

AbstractContact sensitivity responses require both effective immune sensitization following cutaneous exposure to chemical haptens and antigen-specific elicitation of inflammation upon subsequent hapten challenge. We report that antigen-independent effects of IgE antibodies can promote immune sensitization to haptens in the skin. Contact sensitivity was markedly impaired in IgE−/− mice but was restored by either transfer of sensitized cells from wild-type mice or administration of hapten-irrelevant IgE before sensitization. Moreover, IgE−/− mice exhibited impairment in the reduction of dendritic cell numbers in the epidermis after hapten exposure. Monomeric IgE has been reported to influence mast cell function. We observed diminished contact sensitivity in mice lacking FcϵRI or mast cells, and mRNA for several mast cell-associated genes was reduced in IgE−/− versus wild-type skin after hapten exposure. We speculate that levels of IgE normally present in mice favor immune sensitization via antigen-independent but FcϵRI-dependent effects on mast cells

Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus

BACKGROUND: Insulin dependent (i.e., "type 1") diabetes mellitus (T1DM) is considered to be a T cell mediated disease in which T(H)1 and T(c )autoreactive cells attack the pancreatic islets. Among the beta-cell antigens implicated in T1DM, glutamic acid decarboxylase (GAD) 65 appears to play a key role in the development of T1DM in humans as well as in non-obese diabetic (NOD) mice, the experimental model for this disease. It has been shown that shifting the immune response to this antigen from T(H)1 towards T(H)2, via the administration of GAD65 peptides to young NOD mice, can suppress the progression to overt T1DM. Accordingly, various protocols of "peptide immunotherapy" of T1DM are under investigation. However, in mice with experimental autoimmune encephalomyelitis (EAE), another autoimmune T(H)1 mediated disease that mimics human multiple sclerosis, anaphylactic shock can occur when the mice are challenged with certain myelin self peptides that initially were administered with adjuvant to induce the disease. RESULTS: Here we show that NOD mice, that spontaneously develop T1DM, can develop fatal anaphylactic reactions upon challenge with preparations of immunodominant GAD65 self peptides after immunization with these peptides to modify the development of T1DM. CONCLUSIONS: These findings document severe anaphylaxis to self peptide preparations used in an attempt to devise immunotherapy for a spontaneous autoimmune disease. Taken together with the findings in EAE, these results suggest that peptide therapies designed to induce a T(H)1 to T(H)2 shift carry a risk for the development of anaphylactic reactivity to the therapeutic peptides

Interstellar neutral helium in the heliosphere from IBEX observations. V. Observations in IBEX-Lo ESA steps 1, 2, & 3

Direct-sampling observations of interstellar neutral (ISN) He by Interstellar Boundary Explorer (IBEX) provide valuable insight into the physical state of and processes operating in the interstellar medium ahead of the heliosphere. The ISN He atom signals are observed at the four lowest ESA steps of the IBEX-Lo sensor. The observed signal is a mixture of the primary and secondary components of ISN He and H. Previously, only data from one of the ESA steps have been used. Here, we extended the analysis to data collected in the three lowest ESA steps with the strongest ISN He signal, for the observation seasons 2009-2015. The instrument sensitivity is modeled as a linear function of the atom impact speed onto the sensor's conversion surface separately for each ESA step of the instrument. We found that the sensitivity increases from lower to higher ESA steps, but within each of the ESA steps it is a decreasing function of the atom impact speed. This result may be influenced by the hydrogen contribution, which was not included in the adopted model, but seems to exist in the signal. We conclude that the currently accepted temperature of ISN He and velocity of the Sun through the interstellar medium do not need a revision, and we sketch a plan of further data analysis aiming at investigating ISN H and a better understanding of the population of ISN He originating in the outer heliosheath.Comment: 20 pages, 5 figures, 5 tables, accepted for publication in the The Astrophysical Journa

The c-kit Ligand, Stem Cell Factor, Can Enhance Innate Immunity Through Effects on Mast Cells

Mast cells are thought to contribute significantly to the pathology and mortality associated with anaphylaxis and other allergic disorders. However, studies using genetically mast cell–deficient WBB6F1-KitW/KitW-v and congenic wild-type (WBB6F1-+/+) mice indicate that mast cells can also promote health, by participating in natural immune responses to bacterial infection. We previously reported that repetitive administration of the c-kit ligand, stem cell factor (SCF), can increase mast cell numbers in normal mice in vivo. In vitro studies have indicated that SCF can also modulate mast cell effector function. We now report that treatment with SCF can significantly improve the survival of normal C57BL/6 mice in a model of acute bacterial peritonitis, cecal ligation and puncture (CLP). Experiments in mast cell–reconstituted WBB6F1-KitW/KitW-v mice indicate that this effect of SCF treatment reflects, at least in part, the actions of SCF on mast cells. Repetitive administration of SCF also can enhance survival in mice that genetically lack tumor necrosis factor (TNF)-α, demonstrating that the ability of SCF treatment to improve survival after CLP does not solely reflect effects of SCF on mast cell– dependent (or –independent) production of TNF-α. These findings identify c-kit and mast cells as potential therapeutic targets for enhancing innate immune responses

Meningeal Mast Cells as Key Effectors of Stroke Pathology

Stroke is the leading cause of adult disability in the United States. Because post-stroke inflammation is a critical determinant of damage and recovery after stroke, understanding the interplay between the immune system and the brain after stroke holds much promise for therapeutic intervention. An understudied, but important aspect of this interplay is the role of meninges that surround the brain. All blood vessels travel through the meningeal space before entering the brain parenchyma, making the meninges ideally located to act as an immune gatekeeper for the underlying parenchyma. Emerging evidence suggests that the actions of immune cells resident in the meninges are essential for executing this gatekeeper function. Mast cells (MCs), best known as proinflammatory effector cells, are one of the long-term resident immune cells in the meninges. Here, we discuss recent findings in the literature regarding the role of MCs located in the meningeal space and stroke pathology. We review the latest advances in mouse models to investigate the roles of MCs and MC-derived products in vivo, and the importance of using these mouse models. We examine the concept of the meninges playing a critical role in brain and immune interactions, reevaluate the perspectives on the key effectors of stroke pathology, and discuss the opportunities and challenges for therapeutic development