Interleukin (IL) 25 (IL-17E), a distinct member of the IL-17 cytokine family, plays important roles in evoking T helper type 2 (Th2) cell–mediated inflammation that features the infiltrations of eosinophils and Th2 memory cells. However, the cellular sources, target cells, and underlying mechanisms remain elusive in humans. We demonstrate that human Th2 memory cells expressing distinctive levels of IL-25 receptor (R) are one of the responding cell types. IL-25 promotes cell expansion and Th2 cytokine production when Th2 central memory cells are stimulated with thymic stromal lymphopoietin (TSLP)–activated dendritic cells (DCs), homeostatic cytokines, or T cell receptor for antigen triggering. The enhanced functions of Th2 memory cells induced by IL-25 are associated with sustained expression of GATA-3, c-MAF, and JunB in an IL-4–independent manner. Although keratinocytes, mast cells, eosinophils, and basophils express IL-25 transcripts, activated eosinophils and basophils from normal and atopic subjects were found to secrete bioactive IL-25 protein, which augments the functions of Th2 memory cells. Elevated expression of IL-25 and IL-25R transcripts was observed in asthmatic lung tissues and atopic dermatitis skin lesions, linking their possible roles with exacerbated allergic disorders. Our results provide a plausible explanation that IL-25 produced by innate effector eosinophils and basophils may augment the allergic inflammation by enhancing the maintenance and functions of adaptive Th2 memory cells.

Memory CD4+ T cells that produce both Th2 and Th17 cytokines are increased in the blood of patients with atopic asthma and in the lungs of asthmatic mice, where they contribute to inflammation.

Urticarial vasculitis is a clinico-pathologic entity typified by recurrent episodes of urticaria that have the histopathologic features of leukocytoclastic vasculitis. The cutaneous features may include painful, burning or pruritic skin lesions, the persistence of individual lesions greater than 24 hours, palpable purpura, pronounced central clearing of lesions, and residual hyperpigmentation following resolution. However, because clinical characteristics of urticarial vasculitis may overlap with those of allergic urticaria, confirmation of the diagnosis requires a lesional skin biopsy. This condition is idiopathic in many patients but can also occur in the context of autoimmune disorders, infections, drug reactions, or as a paraneoplastic syndrome. In idiopathic urticarial vasculitis common laboratory findings are an elevation of erythrocyte sedimentation rate and reduction of serum complement. An association between urticarial vasculitis and systemic lupus erythematosus has been hypothesized as some clinical manifestations of disease overlap and C1q autoantibodies may be present in both diseases. Normo-complementemic patients usually have minimal or no systemic involvement and often have a better prognosis. On-the-other-hand, hypocomplementemic patients have the propensity to have more severe multi-organ involvement. Response to treatment is variable and a wide variety of therapeutic agents may be efficacious. Initial recommendations for treatment of urticarial vasculitis manifest only as non-necrotizing skin lesions include antihistamines, dapsone, colchicine, hydroxychloroquine or indomethacin, but corticosteroids are often required. With necrotizing skin lesions or visceral involvement, corticosteroids are regularly indicated. Cases of severe corticosteroid resistant urticarial vasculitis or where corticosteroid morbidity is evident [table: see text] may require treatment with other immunosuppressive agents such as azathioprine, cyclophosphamide, or cyclosporine.

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. The importance of granulocyte/macrophage colony-stimulating factor (GM-CSF) in the pathogenesis of PAP has been confirmed in humans and mice, wherein GM-CSF signaling is required for pulmonary alveolar macrophage catabolism of surfactant. PAP is caused by disruption of GM-CSF signaling in these cells, and is usually caused by neutralizing autoantibodies to GM-CSF or is secondary to other underlying diseases. Rarely, genetic defects in surfactant proteins or the common β chain for the GM-CSF receptor (GM-CSFR) are causal. Using a combination of cellular, molecular, and genomic approaches, we provide the first evidence that PAP can result from a genetic deficiency of the GM-CSFR α chain, encoded in the X-chromosome pseudoautosomal region 1.

We conclude that GM-CSF, IL-5 and RANTES are produced in increased amounts in both allergic and non-allergic NP. Distinguishing features of non-allergic NP include fewer numbers of CD3 T lymphocytes, fewer IL-5+/CD3+ T lymphocytes and greater numbers of IL-5+ eosinophils. These differences may suggest different mechanisms of eosinophil accumulation and activation in allergic vs non-allergic NP.