Philip L. Tong

Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells

Type 2 immunity is critical for defense against cutaneous infections but also underlies the development of allergic skin diseases. We report the identification in normal mouse dermis of an abundant, phenotypically unique group 2 innate lymphoid cell (ILC2) subset that depended on interleukin 7 (IL-7) and constitutively produced IL-13. Intravital multiphoton microscopy showed that dermal ILC2 cells specifically interacted with mast cells, whose function was suppressed by IL-13. Treatment of mice deficient in recombination-activating gene 1 (Rag1−/−) with IL-2 resulted in the population expansion of activated, IL-5-producing dermal ILC2 cells, which led to spontaneous dermatitis characterized by eosinophil infiltrates and activated mast cells. Our data show that ILC2 cells have both pro- and anti-inflammatory properties and identify a previously unknown interactive pathway between two innate populations of cells of the immune system linked to type 2 immunity and allergic diseases.

The Skin-Resident Immune Network

The skin provides an effective physical and biological barrier against environmental and pathogenic insults whilst ensuring tolerance against commensal microbes. This protection is afforded by the unique anatomy and cellular composition of the skin, particularly the vast network of skin-associated immune cells. These include the long-appreciated tissue-resident macrophages, dendritic cells, and mast cells, as well as the more recently described dermal γδ T cells and innate lymphoid cells. Collectively, these cells orchestrate the defense against a wide range of pathogens and environmental challenges, but also perform a number of homeostatic functions. Here, we review recent developments in our understanding of the various roles that leukocyte subsets play in cutaneous immunobiology, and introduce the newer members of the skin immune system. Implications for human disease are discussed.

IL-2 is a critical regulator of group 2 innate lymphoid cell function during pulmonary inflammation

BACKGROUND Group 2 innate lymphoid cells (ILC2) have been implicated in the pathogenesis of allergic lung diseases. However, the upstream signals that regulate ILC2 function during pulmonary inflammation remain poorly understood. ILC2s have been shown to respond to exogenous IL-2, but the importance of endogenous IL-2 in ILC2 function in vivo remains unclear. OBJECTIVE We sought to understand the role of IL-2 in the regulation of ILC2 function in the lung. METHODS We used histology, flow cytometry, immunohistochemistry, ELISA, and quantitative PCR with knockout and reporter mice to dissect pulmonary ILC2 function in vivo. We examined the role of ILC2s in eosinophilic crystalline pneumonia, an idiopathic type 2 inflammatory lung condition of mice, and the effect of IL-2 deficiency on this disease. We determined the effect of IL-2 administration on pulmonary ILC2 numbers and function in mice in the steady state and after challenge with IL-33. RESULTS We discovered an unexpected role for innate cell-derived IL-2 as a major cofactor of ILC2 function during pulmonary inflammation. Specifically, we found that IL-2 was essential for the development of eosinophilic crystalline pneumonia, a type 2 disease characterized by increased numbers of activated ILC2s. We show that IL-2 signaling serves 2 distinct functions in lung ILC2s, namely promoting cell survival/proliferation and serving as a cofactor for the production of type 2 cytokines. We further demonstrate that group 3 innate lymphoid cells are an innate immune source of IL-2 in the lung. CONCLUSION Innate cell-derived IL-2 is a critical cofactor in regulating ILC2 function in pulmonary type 2 pathology.

The Skin Immune Atlas: Three-Dimensional Analysis of Cutaneous Leukocyte Subsets by Multiphoton Microscopy

Site-specific differences in skin response to pathogens and in the course of cutaneous inflammatory diseases are well appreciated. The composition and localization of cutaneous leukocytes has been studied extensively using histology and flow cytometry. However, the precise three-dimensional (3D) distribution of distinct immune cell subsets within skin at different body sites requires visualization of intact living skin. We used intravital multiphoton microscopy in transgenic reporter mice in combination with quantitative flow cytometry to generate a 3D immune cell atlas of mouse skin. The 3D location of innate and adaptive immune cells and site-specific differences in the densities of macrophages, T cells and mast cells at four defined sites (ear, back, footpad, tail) is presented. The combinatorial approach further demonstrates an as yet unreported age-dependent expansion of dermal gamma-delta T cells. Localization of dermal immune cells relative to anatomical structures was also determined. While dendritic cells were dispersed homogeneously within the dermis, mast cells preferentially localized to the perivascular space. Finally, we show the functional relevance of site-specific mast cell disparities using the passive cutaneous anaphylaxis model. These approaches are applicable to assessing immune cell variations and potential functional consequences in the setting of infection as well as the pathogenesis of inflammatory skin conditions.

A quantitative approach to histopathological dissection of elastin-related disorders using multiphoton microscopy

Multiphoton microscopy (MPM) is a novel imaging technology that has recently become applicable for diagnostic purposes. The use of (near) infrared light in MPM allows for deep tissue imaging. In addition, this modality exploits the autofluorescent nature of extracellular matrix fibres within the skin.

Suppurative cribriform ulcers in one leg

Department of Dermatology, Westmead Hospital, Sydney, NSW, Australia, Department of Anatomical Pathology, Sydney South West Pathology, Liverpool Hospital, Sydney, NSW, Australia, School of Medical Sciences, Faculty of Medicine, University of New South Wales, NSW, Australia, School of Medicine, University of Western Sydney, NSW, Australia, Department of Dermatology, Liverpool Hospital, Sydney, NSW, Australia, Centenary Institute, Newtown, NSW, Australia, and Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia

Oral supplementation with bovine whey-derived Ig-rich fraction and lactoferrin improves SCORAD and DLQI in atopic dermatitis

Atopic dermatitis (AD) is a chronic but relapsing skin condition, which has a substantial impact on quality of life [1]. Concerns regarding side effects of medications have led to interest in non-pharmacological interventions [2]. While the cellular and molecular mechanisms of AD continue to be elucidated, the immune – skin microbiota aberrations associated with AD [3] are progressively being utilised as a basis for novel treatments for this inflammatory disease. Bovine-derived immune proteins with immunomodulatory properties, such as lactoferrin and the Ig-rich fraction from whey [4], are being investigated for their effectiveness in AD. Immunoglobulins are key effector molecules produced by plasma cells as part of the adaptive immune response. Lactoferrin is a constitutive component of mucosal secretions and limits bacterial colonisation through iron scavenging. More recently, evidence of a role for lactoferrin in limiting chronic inflammation by linking innate and adaptive immune processes [5] suggests that there may be promise in the use of bovine whey-derived immune proteins in chronic inflammatory diseases

Isopropyl myristate contact allergy: could your moisturizer be the culprit?

Isopropyl myristate (IPM), an ester of isopropyl alcohol and myristic acid, is a solvent with emollient and lubricating properties, and is found in a number of creams, lotions, and oils. It improves the texture of consumer products with a high oil content, and increases transdermal penetration – a desirable property in topical medicaments and emollients used in the management of dermatitis. We report 2 instructive cases with IPM, an under-appreciated allergen in atopic patients, as a cause of allergic contact dermatitis resulting from the use of moisturizers.

Lichenoid keratosis as a cause of localised alopecia areata.

The association of alopecia areata with other autoimmune diseases is well known; however its co-localisation with other inflammatory skin diseases is rare. Concomitant anatomical presentations have been described with vitiligo and lichen planus in the past, suggesting a common aetiological pathway with alopecia areata. To our knowledge, lichenoid keratosis as a cause for localised alopecia areata has yet to be reported after an extensive database search of PubMed MEDLINE (1946–present), Web of Science, Embase (1966–present), CINAHL (1982– present) and Google, using the search terms ‘lichenoid’, ‘areata’, ‘lichenoid keratosis’ and ‘lichen-planus-like keratosis’. We present a 38-year-old Caucasian man who described a 2-year history of a raised irritated warty lesion on the left parietal scalp. The clinical appearance was typical of a seborrhoeic keratosis and was left untreated. One year later he presented again for the same lesion but on this occasion the lesion was smaller in size and was surrounded by a patch of non-scarring alopecia associated with a positive hair pull test at the periphery (Fig. 1a). He had no evidence of hair loss elsewhere, no nail changes and no previous history of alopecia areata. The central lesion was excised and histopathological examination revealed a lichenoid seborrhoeic keratosis (Fig. 1b). At the margins of the biopsy there was a patchy but pronounced peribulbar lymphocytic infiltrate associated with terminal hairs and increased numbers of miniaturised hairs, consistent with alopecia areata (Fig. 1c). Subsequent topical treatment with betamethasone dipropionate ointment resulted in complete hair regrowth after 4 months without any further recurrence on regular routine follow up. Lichenoid keratoses are believed to be caused by a cellmediated immune rejection of various epidermal lesions such as solar lentigo, seborrhoeic keratosis, large cell acanthoma or viral warts, with this mechanism proposed to be mediated by CD8 cytotoxic T-cells. In our patient we speculate that a cell-mediated immune system process attacking the pre-existing seborrhoeic keratosis had caused a bystander effect on the surrounding hair follicles in the area, thus leading to a localised patch of alopecia areata. In genetically susceptible individuals, alopecia areata is postulated to result from a breakdown in MHC class I-based immune privilege of the anagen hair follicles, resulting in the presentation of hair follicle autoantigens to CD8 T-cells in the anagen hair bulb. The trigger is thought to be interferon-γ, leading to secondary pro-inflammatory events with other Th1 cytokines involved. Alopecia has also been reported secondary to a number of other lichenoid processes, such as lichenoid drug reaction, lichenoid red tattoo reaction and also frontal fibrosing alopecia, a variant of lichen planopilaris. In summary we present the first reported case to our knowledge of localised alopecia areata triggered by a lichenoid keratosis. These findings are useful in generating hypotheses to further clarify the pathogenesis of alopecia areata.