Interferon gamma constrains type 2 lymphocyte niche boundaries during mixed inflammation.

Allergic immunity is orchestrated by group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells prominently arrayed at epithelial- and microbial-rich barriers. However, ILC2s and Th2 cells are also present in fibroblast-rich niches within the adventitial layer of larger vessels and similar boundary structures in sterile deep tissues, and it remains unclear whether they undergo dynamic repositioning during immune perturbations. Here, we used thick-section quantitative imaging to show that allergic inflammation drives invasion of lung and liver non-adventitial parenchyma by ILC2s and Th2 cells. However, during concurrent type 1 and type 2 mixed inflammation, IFNγ from broadly distributed type 1 lymphocytes directly blocked both ILC2 parenchymal trafficking and subsequent cell survival. ILC2 and Th2 cell confinement to adventitia limited mortality by the type 1 pathogen Listeria monocytogenes. Our results suggest that the topography of tissue lymphocyte subsets is tightly regulated to promote appropriately timed and balanced immunity.

MS4A4A Regulates Arginase 1 Induction during Macrophage Polarization and Lung Inflammation in Mice.

MS4A4A regulates the expression of arginase 1 in macrophages under IL4 stimulation. Also, MS4A4A regulates eosinophil infiltration during lung allergic inflammation induced by intranasal administration of house dust mite.

Lessons in Innate and Allergic Immunity From Dust Mite Feces and Tick Bites.

Allergic diseases represent a major cause of morbidity in modern industrialized and developing countries. The origins and development of allergic immune responses have proven difficult to unravel and remain an important scientific objective. House dust mites (HDM) and ticks represent two important causes of allergic disease. Investigations into HDM fecal particles and tick bites have revealed insights which have and will continue to shape our understanding of allergic immunity. In the present review, focus is given to the role of innate immunity in shaping the respective responses to HDM and ticks. The HDM fecal particle represents a rich milieu of molecules that can be recognized by pathogen-recognition receptors of the innate immune system. Factors in tick saliva and/or tissue damage resultant from tick feeding are thought to activate innate immune signaling that promotes allergic pathways. Recent evidence indicates that innate sensing involves not only the direct recognition of allergenic agents/organisms, but also indirect sensing of epithelial barrier disruption. Although fecal particles from HDM and bites from ticks represent two distinct causes of sensitization, both involve a complex array of molecules that contribute to an innate response. Identification of specific molecules will inform our understanding of the mechanisms that contribute to allergic immunity, however the key may lie in the combination of molecules delivered to specific sites in the body.

Mechanism(s) of prolonged attenuation of allergic responses after modulation of idiotypic regulatory network.

BACKGROUND: We showed previously that allergic reactivity to ovalbumin (OVA) could be regulated in mice following perturbation of immune networks using combinations of an immune Ig along with anti-idiotypic Ig. We have explored features of this regulation including: its persistence after cessation of administration of combined Igs; the ability of heterologous Igs to produce immunoregulation; a role for Treg induction in regulation; and the ability to attenuate responses in mice pre-sensitized to an allergic stimulus. METHODS: BALB/c mice were sensitized to OVA. Mice also received 5 weekly injections of immune Ig or anti-idiotype Ig (at separate sites) from either homologous (mouse) or heterologous (human) sources. In the latter case pooled IVIG (given IM, hence hereafter IMIG) was used as a source of anti-idiotype Ig, and human anti-Tet as immune Ig. Injections of the Ig were given from the time of OVA sensitization (to attenuate development of immunity), or after pre-sensitization of mice (to attenuate existing allergic responses). All mice were assayed for development of OVA-specific serum IgE and IgG, as well as the production of OVA-induced IL-2, IL-4, IL-13, IL-31 and IL-33 in splenocytes cultured for 72 h. In studies examining possible mechanism(s) responsible for inhibition of immunity mice received, in addition to the Ig treatments described, infusion of depleting anti-CD4, and/or anti-CD8 antibodies, or a mAb to TNFSFR25, known to expand Tregs implicated in regulation of Allo immunity. RESULTS: Combinations of both heterologous and homologous immune Igs and anti-idiotype Igs attenuated OVA allergic responses in both naïve and pre-sensitized mice. This attenuation persisted in mice greater than 14 weeks after cessation of treatment with the Igs used. Finally, depletion of either CD4 or CD8 cells ameliorated the suppressive effect seen, while the combination of anti-CD4 and anti-CD8 essentially abolished suppression. Suppression was further enhanced by anti-TNFSFR25 mAb. CONCLUSIONS: We conclude that the combine Ig treatment protocols used produced a long-lasting suppression of allergic immunity, even in pre-sensitized animals. The effects seem to depend upon induction and expansion of Tregs and represents a novel approach to treatment of allergic disease in humans and other animals.

A Fungal Protease Model to Interrogate Allergic Lung Immunity.

Allergic airway diseases (asthma and chronic rhinosinusitis) are among the most common of all human diseases in heavily industrialized societies. Animal models of asthma have provided remarkable insight into allergic disease pathogenesis and will continue to drive the discovery of new therapeutic insights. We provide in this chapter a detailed protocol for inducing allergic immunity in the lungs of mice using a purified fungal protease and include related protocols for assessing immune endpoints.