Michelle A. Lowes

The tryptophan metabolism enzyme L-kynureninase is a novel inflammatory factor in psoriasis and other inflammatory diseases

BACKGROUND Many human diseases arise from or have pathogenic contributions from a dysregulated immune response. One pathway with immunomodulatory ability is the tryptophan metabolism pathway, which promotes immune suppression through the enzyme indoleamine 2,3-dioxygenase (IDO) and subsequent production of kynurenine. However, in patients with chronic inflammatory skin disease, such as psoriasis and atopic dermatitis (AD), another tryptophan metabolism enzyme downstream of IDO, L-kynureninase (KYNU), is heavily upregulated. The role of KYNU has not been explored in patients with these skin diseases or in general human immunology. OBJECTIVE We sought to explore the expression and potential immunologic function of the tryptophan metabolism enzyme KYNU in inflammatory skin disease and its potential contribution to general human immunology. METHODS Psoriatic skin biopsy specimens, as well as normal human skin, blood, and primary cells, were used to investigate the immunologic role of KYNU and tryptophan metabolites. RESULTS Here we show that KYNU(+) cells, predominantly of myeloid origin, infiltrate psoriatic lesional skin. KYNU expression positively correlates with disease severity and inflammation and is reduced on successful treatment of psoriasis or AD. Tryptophan metabolites downstream of KYNU upregulate several cytokines, chemokines, and cell adhesions. By mining data on several human diseases, we found that in patients with cancer, IDO is preferentially upregulated compared with KYNU, whereas in patients with inflammatory diseases, such as AD, KYNU is preferentially upregulated compared with IDO. CONCLUSION Our results suggest that tryptophan metabolism might dichotomously modulate immune responses, with KYNU as a switch between immunosuppressive versus inflammatory outcomes. Although tryptophan metabolism is increased in many human diseases, how tryptophan metabolism is proceeding might qualitatively affect the immune response in patients with that disease.

Molecular Phenotyping Small (Asian) versus Large (Western) Plaque Psoriasis Shows Common Activation of IL-17 Pathway Genes but Different Regulatory Gene Sets.

Psoriasis is present in all racial groups, but in varying frequencies and severity. Considering that small plaque psoriasis is specific to the Asian population and severe psoriasis is more predominant in the Western population, we defined Asian small and intermediate plaque psoriasis as psoriasis subtypes and compared their molecular signatures with the classic subtype of Western large plaque psoriasis. Two different characteristics of psoriatic spreading-vertical growth and radial expansion-were contrasted between subtypes, and genomic data were correlated to histologic and clinical measurements. Compared with Western large plaque psoriasis, Asian small plaque psoriasis revealed limited psoriasis spreading, but IL-17A and IL-17-regulated proinflammatory cytokines were highly expressed. Paradoxically, IL-17A and IL-17-regulated proinflammatory cytokines were lower in Western large plaque psoriasis, whereas T cells and dendritic cells in total psoriatic skin area were exponentially increased. Negative immune regulators, such as CD69 and FAS, were decreased in both Western large plaque psoriasis and psoriasis with accompanying arthritis or obesity, and their expression was correlated with psoriasis severity index. Based on the disease subtype comparisons, we propose that dysregulation of T-cell expansion enabled by downregulation of immune negative regulators is the main mechanism for development of large plaque psoriasis subtypes.

Deep Sequencing of the T-cell Receptor Repertoire Demonstrates Polyclonal T-cell Infiltrates in Psoriasis

It is well known that infiltration of pathogenic T-cells plays an important role in psoriasis pathogenesis. However, the antigen specificity of these activated T-cells is relatively unknown. Previous studies using T-cell receptor polymerase chain reaction technology (TCR-PCR) have suggested there are expanded T-cell receptor (TCR) clones in psoriatic skin, suggesting a response to an unknown psoriatic antigen. Here we describe the results of high-throughput deep sequencing of the entire αβ- and γδ- TCR repertoire in normal healthy skin and psoriatic lesional and non-lesional skin. From this study, we were able to determine that there is a significant increase in the abundance of unique β- and γ- TCR sequences in psoriatic lesional skin compared to non-lesional and normal skin, and that the entire T-cell repertoire in psoriasis is polyclonal, with similar diversity to normal and non-lesional skin. Comparison of the αβ- and γδ- TCR repertoire in paired non-lesional and lesional samples showed many common clones within a patient, and these close were often equally abundant in non-lesional and lesional skin, again suggesting a diverse T-cell repertoire. Although there were similar (and low) amounts of shared β-chain sequences between different patient samples, there was significantly increased sequence sharing of the γ-chain in psoriatic skin from different individuals compared to those without psoriasis. This suggests that although the T-cell response in psoriasis is highly polyclonal, particular γδ- T-cell subsets may be associated with this disease. Overall, our findings present the feasibility of this technology to determine the entire αβ- and γδ- T-cell repertoire in skin, and that psoriasis contains polyclonal and diverse αβ- and γδ- T-cell populations.

Pain, Psychological Comorbidities, Disability, and Impaired Qualify of Life in Hidradenitis Suppurativa

Purpose of ReviewHidradenitis suppurativa (HS) is a chronic, painful dermatologic disease characterized by recurrent inflammatory nodules and abscesses of intertriginous areas such as the axilla and groin. People with HS suffer from greater pain and associated psychological comorbidities, including depression, anxiety, disability, and impairments in quality of life (QoL), compared to those with other dermatologic conditions. Our review focuses on the occurrence of pain and these relationships.Recent FindingsThe existing literature indicates that acute and chronic pain, depression, anxiety, and disability all contribute to poor quality of life in individuals with HS. Despite the central role of pain and distress in the presentation of HS, few studies have empirically evaluated the impact of pain and gaps remain in the existing psychosocial literature. There are no formal guidelines for treating HS-specific pain or psychological comorbidities.SummaryThe results of this review show a clear and pressing need to develop treatment recommendations and effective interventions for addressing acute and chronic pain, psychological comorbidities, disability, and impaired quality of life among people with HS. This review outlines a multidisciplinary approach to treating and managing pain and psychological comorbidities.

Isotretinoin treatment in a patient with known peanut allergy and positive IgE test results for soybean

Isotretinoin is a retinoid that is approved by the US Food and Drug Administration for the treatment of acne vulgaris and used off label for other dermatologic conditions, including hidradenitis suppurativa (HS). Isotretinoin decreases comedones and sebum production, influences cell-cycle progression, and reduces inflammation.1 Prescribing information leaflets state that oral isotretinoin is contraindicated in patients with known allergy to isotretinoin, peanut, or soya.2 Soybean oil is found within the capsules; thus, patients with peanut allergy might be considered at risk because of the known cross-reactivity between soybean and peanut.3 Currently, all isotretinoin products on the market contain soybean derivatives; therefore, patients with known allergy to soybean or peanut could be at risk of developing an allergic response if they are treated with oral isotretinoin. Peanut and soybean are derived from the same plant family of legumes. These legumes contain allergenic protein fractions, specifically, Ara h 1, Ara h 2, and Ara h 3 in peanuts and Gly m 1 and G2 glycinin in soy, that exhibit in vitro and in vivo cross-reaction.4,5 However, clinical observations have revealed a low rate of crossreactivity between peanut and soy.5 In addition, it has been documented that proteins present in the oil of soybean have little clinical significance with regard to soybean allergy.6 Two prior case reports by Pierret et al7 and Hulstaert et al8 reported successful isotretinoin treatment in 2 patients with documented peanut allergy who had negative allergy test results to soybean. We present the case of HS, a history of peanut allergy, and positive test results for soy allergy in a 23-year-old man whose treatment of choice was isotretinoin. A 23-year-old man with history of longstanding eczema, acne, asthma, and peanut allergy was referred to the allergy clinic by a dermatologist who recommended treatment of the patient’s acne and HSwith isotretinoin. On the basis of the results of an IgE test for peanut of more than 18.00 kUA/L (class 5) performed when the patient as a child, the patient was advised to avoid peanuts and prescribed an epinephrine autoinjector. The patient has been avoiding peanuts ever since and has never had an allergic reaction. The patient denied a prior history of allergic reactions to soy and reported that he was not avoiding soy in his diet. Physical examination findings were remarkable for eczema, xerosis, and hidradenitis lesions in his axillae and right groin. In addition, his face had some scarring and scattered inflammatory papules on his cheeks. The results of skin prick tests for peanut and soybean were positive at 4þ and 1þ, respectively. Laboratory tests revealed elevated

Polyclonal hyperglobulinaemia and elevated acute-phase reactants in hidradenitis suppurativa

DEAR EDITOR, Hidradenitis suppurativa (HS) is a chronic, painful, inflammatory skin disease characterized by recurrent nodules and abscesses affecting intertriginous areas including the axillae and inframammary and anogenital regions. Hurley staging (I–III) is commonly used to classify patients, with mild disease limited to inflammatory cystic nodules (stage I), which may be connected by isolated tunnels or sinuses (stage II), or form a network of bridging tunnels or sinuses (stage III) associated with odoriferous, purulent drainage. The cause of HS is unknown, but it is generally considered to be multifactorial. It appears that an aberrant innate immune response initiates cutaneous inflammation in early lesions, and recruitment of the adaptive immune system may be involved in maintaining HS chronicity. Only a few published studies have focused on the humoral immune system in HS. The sera of patients with advanced HS revealed elevations of tumour necrosis factor-a, interleukin-6 and IgE. Significantly increased levels of C-reactive protein (CRP) have been found across all three Hurley stages. We recently established a multispecialty HS Treatment Center at Montefiore Medical Center in the Bronx, NY. Our team was interested in further characterizing the humoral immune system in the sera of patients with HS by measuring immunoglobulin levels and acute-phase reactants (CRP and erythrocyte sedimentation rate, ESR), under an institutional review board-approved protocol. The diagnosis of HS was made by history and clinical examination in patients who attended the HS Treatment Center.

Correction to: Pain, Psychological Comorbidities, Disability, and Impaired Quality of Life in Hidradenitis Suppurativa

The original version of this article contains an error in the spelling of the title. The title should read: Pain, Psychological Comorbidities, Disability, and Impaired Quality of Life in Hidradenitis Suppurativa.