Prurigo Nodularis Is Characterized by Systemic and Cutaneous T Helper 22 Immune Polarization.

Prurigo nodularis (PN) is an understudied, chronic inflammatory skin disease that disproportionately affects African Americans and presents with intensely pruritic nodules of unknown etiology. To better characterize the immune dysregulation in PN, PBMCs and skin biopsies were obtained from patients with PN and healthy subjects (majority African American) matched by age, race, and sex. Flow cytometric analysis of functional T-cell response comparing patients with PN with healthy subjects identified increased γδT cells (CD3+CD4-CD8-γδTCR+) and Vδ2+ γδT enrichment. Activated T cells demonstrated uniquely increased IL-22 cytokine expression in patients with PN compared with healthy controls. CD4+ and CD8+ T cells were identified as the source of increased circulating IL-22. Consistent with these findings, RNA sequencing of lesional PN skin compared with nonlesional PN skin and biopsy site‒matched control skin demonstrated robust upregulation of T helper (Th) 22‒related genes and signaling networks implicated in impaired epidermal differentiation. Th22‒related cytokine upregulation remained significant, with stratifications by race and biopsy site. Importantly, the expression of the IL-22 receptors IL22RA1 and IL22RA2 was significantly elevated in lesional PN skin. These results indicate that both systemic and cutaneous immune responses in patients with PN are skewed toward a Th22/IL-22 profile. PN may benefit from immunomodulatory therapies directed at Th22‒mediated inflammation.

Prurigo nodularis: Epidemiology and clinical features.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by intensely pruritic, hyperkeratotic nodules that favor the extensor surfaces of the extremities and the trunk. In addition to its significant impact on quality of life, many patients with PN are recalcitrant to therapy because there are currently no therapies approved by the US Food and Drug Administration. In the first article of this 2-part continuing medical education series, we describe the broader epidemiology, patient demographics, physical examination findings, and symptoms to aid in the timely recognition and diagnosis of PN. Furthermore, we quantify the burden of comorbidities in PN by discussing the broad spectrum of systemic diseases and mental health conditions that have been associated with this condition. The second article of this 2-part series focuses on the pathogenesis of PN and provides detailed algorithms for comprehensive work-up and management.

Eosinophilic dermatoses.

Eosinophilic dermatoses are a heterogeneous group of diseases, characterized by an eosinophil-rich infiltrate and/or degranulation of eosinophils. Blood eosinophilia may be an associated feature. Typical, albeit not specific histological findings include 'flame figures', which are caused by the accumulation of cationic proteins released by eosinophils and subsequent collagen denaturation. "Classic" eosinophilic dermatoses include eosinophilic cellulitis (Wells syndrome), granuloma faciale, eosinophilic fasciitis (Shulman syndrome) and eosinophilic folliculitis (Ofuji disease). In addition, there is a multitude of skin diseases that present with varying degrees of eosinophilic infiltration. These include atopic dermatitis, bullous pemphigoid, urticaria, allergic contact dermatitis, prurigo nodularis, arthropod bite reaction, parasitic infections, and drug hypersensitivity. Even though these disorders share a common characteristic (tissue eosinophilia), they differ greatly in their clinical presentation.

Invasive dermatophyte infection with Trichophyton interdigitale is associated with prurigo-induced pseudoperforation and a signal transducer and activator of transcription 3 mutation.

Invasive dermatophyte infection, with extension beyond the dermis, in immunocompetent hosts is exceptionally rare. Dermatophytes are keratinophilic and are usually confined to the stratum corneum, hair and nails. Susceptibility to dermatophyte infections is incompletely understood, but inherited mutations in key signalling pathways of the innate immune system have been identified. We report the first case of an invasive dermatophyte infection associated with abrupt onset of a prurigo-induced pseudoperforation and a loss-of-function mutation in signal transducer and activator of transcription 3 (STAT3).

Immunoglobulin G4-related disease presenting with prurigo: Circulating T-helper 2 cells may be involved in the pathogenesis.

We report a case of immunoglobulin G4-related disease (IgG4-RD) which presented with prurigo on the trunk and extremities. A 66-year-old man had a 2-month history of itchy erythematous papules on his trunk and extremities. Bilateral eyelid swelling and enlargement of the submandibular and parotid glands were also observed. Computed tomography revealed pleural thickening and diffuse pancreatic enlargement. Serum levels of IgG4 were markedly increased. A biopsy specimen obtained from an erythematous papule showed a perivascular inflammatory infiltrate of lymphocytes with eosinophils in the dermis, whereas a parotid gland biopsy revealed an infiltrate of abundant IgG4-positive plasma cells. Treatment with prednisolone resulted in improvement of the skin and other lesions along with a decrease in IgG4 serum levels. A flow cytometric assay revealed that percentages of interleukin (IL)-4- and IL-13-producing CD4(+) T cells were markedly higher in the circulation of the IgG4-RD patient than in that of healthy subjects. Moreover, those populations dramatically decreased after treatment. Thus, prurigo may be a skin manifestation of IgG4-RD and T-helper 2 cells may contribute to the pathogenesis.

Protective Role of STAT6 in Basophil-Dependent Prurigo-like Allergic Skin Inflammation.

Prurigo is a common, but treatment-resistant, skin disease characterized by persistent papules/nodules and severe itching. Prurigo occurs in association with various underlying diseases, such as diabetes, chronic renal failure, and internal malignancies. Atopic dermatitis is occasionally complicated by prurigo lesions. However, the pathology of prurigo is completely undefined. We demonstrate that repeated intradermal administration of Ag to IgE-transgenic mice causes persistent and pruritic papulonodular skin lesions mimicking prurigo. Skin lesions were histopathologically characterized by irregular acanthosis and dermal cellular infiltrates comprising eosinophils, mononuclear cells, and basophils, with epidermal nerve fiber sprouting. In vivo depletion of basophils alleviated skin reactions, indicating that the inflammation is basophil dependent. Unexpectedly, STAT6 signaling was unnecessary for skin lesion development if IgE was present. Moreover, the absence of STAT6 signaling exacerbated the inflammation, apparently as the result of impaired generation of an M2-type anti-inflammatory macrophage response. These results provide novel insights into the pathologic mechanisms underlying prurigo. Although basophils are indispensable for prurigo-like inflammation, Th2 immunity mediated by STAT6 appears to play a protective role, and therapies targeting Th2-type cytokines may risk aggravating the inflammation.

Immunophenotyping of inflammatory cells in subacute prurigo.

BACKGROUND: Subacute prurigo (SP) is a relatively common disease of papular cutaneous lesions that itch intensely. However, there is a lack of systematic clinical and histological studies on SP. OBJECTIVES: We aimed to immunophenotype inflammatory cells in SP using immunohistochemistry and flow cytometry. METHODS: Lesional and non-lesional skin of 21 patients with SP was investigated. Immunohistochemical staining for CD1a, CD3, CD4, CD8, CD15, CD34, CD68, and anti-human tryptase (AHT) was performed. In order to evaluate the absolute counts and percentages of CD4+ and CD8+ lymphocytes in the peripheral blood of SP patients, flow cytometric methods were used. RESULTS: Compared to non-lesional skin, there was a significant increase of the median percentage of CD3+, CD4+, and CD8+ cells in the lesional dermis (12.6% vs. 19.7%, P=0.044; 0.8% vs. 3.7%, P=0.016; and 1% vs. 15.6%, P=0.0039, respectively). The mean ± SD CD4+/CD8+ ratio was 0.58 ± 0.6. Median percentage of CD15+ cells was significantly increased in lesional skin as compared to non-lesional skin (11.7 vs. 1%, P=0.027). Median percentage immunoreactivity of CD68+ cells was significantly increased in lesional dermis as compared to non-lesional skin (32.5% vs. 9.4%, P=0.0005). CD1a, CD34, and AHT positive cells did not significantly differ between lesional and non-lesional skin. T lymphocyte subsets in the peripheral blood of SP patients did not show significant pathologies. CONCLUSIONS: We observed that the inflammatory cell infiltrate in SP mainly consists of T lymphocytes, particularly CD8+ cells, CD15+ neutrophils, and CD68+ macrophages.

Atypical presentation of adult T-cell leukaemia/lymphoma due to HTLV-1: prurigo nodularis lasting twelve years followed by an acute micropapular eruption.

Prurigo nodularis is a pruritic dermatosis of unknown origin. Human T-cell lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukaemia/lymphoma. HTLV-1 is not considered to be a cause of prurigo nodularis. A 52-year-old black man, from the French West Indies, who had had prurigo nodularis for 12 years, presented with a distinct micropapular eruption with the typical pathological picture of epidermotropic T-cell lymphoma. Based on HTLV-1-positive serology and monoclonal integration of HTLV-1 we diagnosed smouldering adult T-cell leukaemia/lymphoma. Re-examination of previous skin biopsies revealed that the disease had been evolving for 12 years. Treatment with alpha-interferon, 3 x 106 units three times a week, associated with zidovudine, 1 g daily, resulted in complete remission within 4 months. When investigating a prurigo nodularis, we therefore recommend: (i) performing HTLV-1 serology if the patient comes from an endemic area; (ii) if positive, performing CD25 staining and looking for a HTLV-1 clonal integration; and (iii) if positive, using a treatment targeting HTLV-1.

Immune responses to isolated human skin antigens in actinic prurigo.

BACKGROUND: Actinic prurigo (AP) is a frequent photodermatosis among Amerindians, with a high incidence among women and children below ten years of age. Neither the cause of actinic prurigo nor its etiological agent have been described. Not much is known about the pathogenic mechanisms of the disease, although associations with the human leucocitary antigens (HLA) and local immune responses seem to play an important role in its expression, as is the case in other skin autoimmune disorders, such as pemphigus and psoriasis. MATERIAL/METHODS: In this paper we compare cellular and humoral immunity through in vitro proliferation studies, ELISA and immunofluorescence tests in actinic prurigo patients and healthy controls. RESULTS: Autoantibody reactivities on the skin and also proliferative responses to isolated autologous skin antigens were higher in patients than in controls. The polyclonal cellular immune response against T cell mitogens and against allogeneic stimuli was found to be diminished in patients. CONCLUSIONS: We found autoimmune reactivity in patients suffering from actinic prurigo. We postulate that AP patients may have one or more skin antigens that stimulate an autoimmune response, which causes the observed skin lesions. As AP is a pathology that affects mainly the skin, any immune response should be localized and the observed infiltrating lymphocytes in skin biopsies should be activated by these hypothetical antigens.

Evidence that thalidomide modifies the immune response of patients suffering from actinic prurigo.

BACKGROUND: Actinic prurigo (AP) is a photodermatosis with a restricted ethnic distribution, mainly affecting Mestizo women (mixed Indian and European). The lesions are polymorphic and include macules, papules, crusts, hyperpigmentation and lichenification. Thalidomide, an effective immunomodulatory drug, was first used successfully to treat AP in 1973. In this work we describe the effect that thalidomide had on TNF-alpha sera levels and on IL-4- and IFN gamma (IFNgamma)-producing lymphocytes of actinic prurigo (AP) patients. METHODS: Actinic prurigo patients were analyzed before and after thalidomide treatment. The percentage of IL-4+ or IFNgamma+ CD3+ lymphocytes was analyzed in eight of them by flow cytometry. TNFalpha in sera was measured by ELISA in 11 patients. RESULTS: A direct correlation was observed between resolution of AP lesions and an increase in IFNgamma+ CD3+ peripheral blood mononuclear cells (P < or = 0.001) and a decrease in TNFalpha serum levels (no statistical difference). No IL-4+ CD3+ cells were detected. CONCLUSIONS: Our findings confirm that AP is a disease that has an immunological component and that thalidomide clinical efficacy is exerted not only through inhibition of TNFalpha synthesis, but also through modulation of INFgamma-producing CD3+ cells. These cells could be used as clinical markers for recovery.

Lymphocyte subtypes and adhesion molecules in actinic prurigo: observations with cyclosporin A.

BACKGROUND: Actinic prurigo is a photodermatitis in which UV light is implicated by an unknown mechanism. METHODS: Skin biopsies of 19 patients with actinic prurigo and 11 controls were analyzed by immunohistochemistry. RESULTS: In actinic prurigo patients, there was a significant increase in the number of CD3, CD4, CD8, CD45RA, CD45RO, and CD45RB lymphocytes and Langerhans cells, as well as in the level of human leukocyte antigen-DR (HLA-DR) expression and cell adhesion molecules lymphocyte functional antigen-1 (LFA-1), intercellular adhesion molecule-1 (ICAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1). Actinic prurigo patients were treated with cyclosporin A (CsA), and a final skin biopsy was taken after 6 months of treatment. All the cell populations and markers studied, except for the CD4 lymphocytes, Langerhans cells, and HLA-DR expression, returned to normal levels. CONCLUSIONS: CsA was found to be effective in relieving the clinical symptoms of actinic prurigo.

Tumour necrosis factor alpha promoter polymorphism at position -308 is not associated with actinic prurigo.

Actinic prurigo (AP) has been found to be strongly associated with HLA DR4 and in particular with the DR4 subtype DRB1*0407. However, AP may occur in the absence of HLA-DR4. Furthermore, it has been shown that HLA-DR4 and DRB1*0407, even in association with polymorphic light eruption (PLE), are insufficient for the expression of the AP phenotype. It seems likely, therefore, that other genes in the HLA DR or adjacent regions may contribute to AP susceptibility. One possible predisposing factor in AP may be tumour necrosis factor (TNF)alpha as suggested by the good response of AP to the TNFalpha inhibitor thalidomide, and by the involvement of this cytokine in many immune responses. The aim of this study was to explore the relationship between AP and TNFalpha by examining the frequency of TNF2 in patients with AP, PLE and in normal controls. TNF1 and TNF2 are biallelic polymorphisms at position -308 of the TNFalpha gene promoter and are known to affect transcription of TNFalpha. TNF2 is the rarer of the two alleles and is associated with high functional levels of TNFalpha. This study confirms the positive linkage disequilibrium that has been described between HLA DR3 and TNF2, but fails to show an association between TNF2 and AP.

Effectors of inflammation in actinic prurigo.

BACKGROUND: Actinic prurigo is a specific familial photodermatosis of uncertain pathogenesis. OBJECTIVE: Our purpose was to investigate the immunohistologic presentation of actinic prurigo to explore the involved pathomechanisms. METHODS: The present immunohistochemical study was performed on biopsy specimens from 20 Mexican patients presenting with a severe and perennial form of the disease. RESULTS: The dense inflammatory infiltrate was composed predominantly of helper T type 1 lymphocytes admixed with scattered B-cell lymphoid follicles and numerous dermal dendrocytes. Keratinocytes contained abundant tumor necrosis factor-alpha and calprotectin. CONCLUSION: In subjects genetically predisposed to actinic prurigo, ultraviolet light may trigger excessive tumor necrosis factor-alpha production by keratinocytes whose sustained release in turn exerts its proinflammatory activity and deleterious epidermal effects. Such a cascade of events is in line with the therapeutic benefit already reported when thalidomide is used to treat actinic prurigo.

[T and B clonal populations in actinic prurigo, a photodermatosis]. / Poblaciones clonales de células T y B en prurigo actínico, una fotodermatosis.

Actinic prurigo (AP) is a chronic photodermatosis in which genetic and immunological factors has been implicated in the pathogenesis of the disease. This work was designed to investigate the existence of clonal populations of T and B lymphocytes in lesions of the labial mucosa and conjunctiva of patients with actinic prurigo. Genomic DNA of three patients with actinic prurigo and controls were analyzed in Southern blots using DNA molecular probes for the b subunit of the T-cell receptor for antigen (TCR beta) and for the heavy chain of immunoglobulin genes (lg-JH). Clonal rearrangements of T-cell receptor genes were detected in biopsy samples taken from the labial mucosa of two patients and of immunoglobulin genes in DNA extracted from the conjunctiva of a different patient. The presence of distinct clonal T or B lymphocyte populations in patients with actinic prurigo indicates that the immune system may play a relevant role in the pathogenesis of the disease.

Estudio inmunohistoquímico para demostrar la presencia de linfocitos T y B en el infiltrado inflamatorio de las biopsias de piel, labio y conjuntiva de pacientes con prurigo actínico / Immunohistochemistry study to demostrate the presence of T and B lymphocytes in skin, lip and conjunctival biopsies of actinic prurigo patients

Se reportan los resultados de un estudio inmunohistoquímico del infiltrado inflamatorio de biopsias de la piel, el labio y la conjuntiva de pacientes con prurigo actínico (PA), donde se aplicaron anticuerpos monoclonales contra vimentina (para saber si el tejido necesitaba recuperación antigénica), contra antígeno común leucocitario (CD45), UCHL-1 (anti-CD45RO) marcador de linfocitos T, L-26 (anti-CD20) marcador de linfocitos B. Se demostró la presencia de linfocitos B y T en los infiltrados inflamatorios; cuando éstos se disponen en folículos linfoides los linfocitos B se encuentran al centro y los T en la periferia