MYD88 L265P mutation in neurologic autoimmunity without evidence of malignancy.

MYD88 mutation status is assessed in the evaluation of CNS lymphoma since the mutation MYD88 L265P is highly predictive of this disease. However, whether the MYD88 L265P mutation may lead to other diseases outside of malignancy is not well understood. Here we describe two patients with the MYD88 L265P mutation in the CSF with no additional evidence of neoplastic disease but were found to have two distinct neurologic autoimmune conditions (anti-GFAP astrocytopathy and multiple sclerosis). These cases suggest this activating mutation may predispose certain patients to autoimmune conditions and may have future therapeutic implications.

IL-33 signaling in sensory neurons promotes dry skin itch.

BACKGROUND: Chronic pruritus, or itch, is common and debilitating, but the neuroimmune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron-restricted activity of IL-33 is necessary for chronic itch remains poorly understood. OBJECTIVES: We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models. METHODS: Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively. RESULTS: IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology. CONCLUSIONS: These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight into future therapeutic strategies targeting the IL-33 pathway for chronic itch.

Kallikrein 7 Promotes Atopic Dermatitis-Associated Itch Independently of Skin Inflammation.

Atopic dermatitis (AD) is a highly prevalent, itchy inflammatory skin disorder that is thought to arise from a combination of skin barrier defect and immune dysregulation. Kallikreins (KLK), a family of serine proteases with a diverse array of homeostatic functions, including skin desquamation and innate immunity, are hypothesized to contribute to AD pathogenesis. However, their precise role in AD has not been clearly defined. In this study, RNA sequencing analyses identified KLK7 as the most abundant and differentially expressed KLK in both human AD and murine AD-like skin. Further, in mice, Klk7 expression was localized to the epidermis in both steady state and inflammation. Unexpectedly, KLK7 was dispensable for the development of AD-associated skin inflammation. Instead, KLK7 was selectively required for AD-associated chronic itch. Even without the alleviation of skin inflammation, KLK7-deficient mice exhibited significantly attenuated scratching, compared with littermate controls, after AD-like disease induction. Collectively, our findings indicate that KLK7 promotes AD-associated itch independently from skin inflammation and reveal a previously unrecognized epidermal-neural mechanism of AD associated itch.

Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch.

Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

TRPV4 Channel Signaling in Macrophages Promotes Gastrointestinal Motility via Direct Effects on Smooth Muscle Cells.

Intestinal macrophages are critical for gastrointestinal (GI) homeostasis, but our understanding of their role in regulating intestinal motility is incomplete. Here, we report that CX3C chemokine receptor 1-expressing muscularis macrophages (MMs) were required to maintain normal GI motility. MMs expressed the transient receptor potential vanilloid 4 (TRPV4) channel, which senses thermal, mechanical, and chemical cues. Selective pharmacologic inhibition of TRPV4 or conditional deletion of TRPV4 from macrophages decreased intestinal motility and was sufficient to reverse the GI hypermotility that is associated with chemotherapy treatment. Mechanistically, stimulation of MMs via TRPV4 promoted the release of prostaglandin E2 and elicited colon contraction in a paracrine manner via prostaglandin E receptor signaling in intestinal smooth muscle cells without input from the enteric nervous system. Collectively, our data identify TRPV4-expressing MMs as an essential component required for maintaining normal GI motility and provide potential drug targets for GI motility disorders.

MicroRNA signature of central nervous system-infiltrating dendritic cells in an animal model of multiple sclerosis.

Innate immune cells are integral to the pathogenesis of several diseases of the central nervous system (CNS), including multiple sclerosis (MS). Dendritic cells (DCs) are potent CD11c+ antigen-presenting cells that are critical regulators of adaptive immune responses, particularly in autoimmune diseases such as MS. The regulation of DC function in both the periphery and CNS compartment has not been fully elucidated. One limitation to studying the role of CD11c+ DCs in the CNS is that microglia can upregulate CD11c during inflammation, making it challenging to distinguish bone marrow-derived DCs (BMDCs) from microglia. Selective expression of microRNAs (miRNAs) has been shown to distinguish populations of innate cells and regulate their function within the CNS during neuro-inflammation. Using the experimental autoimmune encephalomyelitis (EAE) murine model of MS, we characterized the expression of miRNAs in CD11c+ cells using a non-biased murine array. Several miRNAs, including miR-31, were enriched in CD11c+ cells within the CNS during EAE, but not LysM+ microglia. Moreover, to distinguish CD11c+ DCs from microglia that upregulate CD11c, we generated bone marrow chimeras and found that miR-31 expression was specific to BMDCs. Interestingly, miR-31-binding sites were enriched in mRNAs downregulated in BMDCs that migrated into the CNS, and a subset was confirmed to be regulated by miR-31. Finally, miR-31 was elevated in DCs migrating through an in vitro blood-brain barrier. Our findings suggest miRNAs, including miR-31, may regulate entry of DCs into the CNS during EAE, and could potentially represent therapeutic targets for CNS autoimmune diseases such as MS.

Interactions of the immune and sensory nervous systems in atopy.

A striking feature underlying all atopic disorders, such as asthma, atopic dermatitis, and food allergy, is the presence of pathologic sensory responses, reflexes, and behaviors. These symptoms, exemplified by chronic airway irritation and cough, chronic itch and scratching, as well as gastrointestinal discomfort and dysfunction, are often cited as the most debilitating aspects of atopic disorders. Emerging studies have highlighted how the immune system shapes the scope and intensity of sensory responses by directly modulating the sensory nervous system. Additionally, factors produced by neurons have demonstrated novel functions in propagating atopic inflammation at barrier surfaces. In this review, we highlight new studies that have changed our understanding of atopy through advances in characterizing the reciprocal interactions between the immune and sensory nervous systems.

PXR: A New Player in Atopic Dermatitis.

Epidemiological evidence suggests that environmental pollutants contribute to atopic dermatitis, but mechanistic details are currently lacking. Elentner et al. show that PXR, a key transcription factor involved in pollutant metabolism, drives features of subclinical atopic dermatitis. These observations provide new insight into how environmental insults may predispose individuals to atopic dermatitis.

Sensory TRP channels contribute differentially to skin inflammation and persistent itch.

Although both persistent itch and inflammation are commonly associated with allergic contact dermatitis (ACD), it is not known if they are mediated by shared or distinct signaling pathways. Here we show that both TRPA1 and TRPV1 channels are required for generating spontaneous scratching in a mouse model of ACD induced by squaric acid dibutylester (SADBE), a small molecule hapten, through directly promoting the excitability of pruriceptors. TRPV1 but not TRPA1 channels protect the skin inflammation, as genetic ablation of TRPV1 function or pharmacological ablation of TRPV1-positive sensory nerves promotes cutaneous inflammation in the SADBE-induced ACD. Our results demonstrate that persistent itch and inflammation are mediated by distinct cellular and molecular mechanisms in a mouse model of ACD. Identification of distinct roles of TRPA1 and TRPV1 in regulating itch and inflammation may provide new insights into the pathophysiology and treatment of chronic itch and inflammation in ACD patients.

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch.

Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.

CD164 identifies CD4+ T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214.

Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

New insights into basophil heterogeneity.

Basophils have become increasingly recognized as important innate immune cells that mediate antihelminth immunity and barrier inflammation. Recent discoveries have uncovered previously unrecognized heterogeneity in basophil populations. However, how diversity in basophil regulation and function impacts human disease remains poorly defined. The goal of the present review is to highlight how new insights into basophil heterogeneity can help us to better understand disease pathogenesis and inform the development of new therapeutics.