Similarities and differences in peripheral itch and pain pathways in atopic dermatitis.

Atopic dermatitis (AD) is predominantly characterized by intense itching, but concomitant skin pain is experienced by more than 40% of patients. Patients with AD display considerable somatosensory aberrations, including increased nerve sensitivity to itch stimuli (hyperknesis), perception of itch from innocuous stimuli (alloknesis), or perception of pain from innocuous stimuli (allodynia). This review summarizes the current understanding of the similarities and differences in the peripheral mechanisms underlying itch and pain in AD. These distinct yet reciprocal sensations share many similarities in the peripheral nervous system, including common mediators (such as serotonin, endothelin-1, IL-33, and thymic stromal lymphopoietin), receptors (such as members of the G protein-coupled receptor family and Toll-like receptors), and ion channels for signal transduction (such as certain members of the transient receptor potential [TRP] cation channels). Itch-responding neurons are also sensitive to pain stimuli. However, there are distinct differences between itch and pain signaling. For example, specific immune responses are associated with pain (type 1 and/or type 3 cytokines and certain chemokine C-C [CCL2, CCL5] and C-X-C [CXCL] motif ligands) and itch (type 2 cytokines, including IL-31, and periostin). The TRP melastatin channels TRPM2 and TRPM3 have a role in pain but no known role in itch. Activation of µ-opioid receptors is known to alleviate pain but exacerbate itch. Understanding the connection between itch and pain mechanisms may offer new insights into the treatment of chronic pain and itch in AD.

Cutaneous Components Leading to Pruritus, Pain, and Neurosensitivity in Atopic Dermatitis: A Narrative Review.

Atopic dermatitis (AD) is a chronic, relapsing immunoinflammatory skin condition characterized by sensations such as pruritis, pain, and neuronal hypersensitivity. The mechanisms underlying these sensations are multifactorial and involve complex crosstalk among several cutaneous components. This review explores the role these components play in the pathophysiology of atopic dermatitis. In the skin intercellular spaces, sensory nerves interact with keratinocytes and immune cells via myriad mediators and receptors. These interactions generate action potentials that transmit pruritis and pain signals from the peripheral nervous system to the brain. Keratinocytes, the most abundant cell type in the epidermis, are key effector cells, triggering crosstalk with immune cells and sensory neurons to elicit pruritis, pain, and inflammation. Filaggrin expression by keratinocytes is reduced in atopic dermatitis, causing a weakened skin barrier and elevated skin pH. Fibroblasts are the main cell type in the dermis and, in atopic dermatitis, appear to reduce keratinocyte differentiation, further weakening the skin barrier. Fibroblasts and mast cells promote inflammation while dermal dendritic cells appear to attenuate inflammation. Inflammatory cytokines and chemokines play a major role in AD pathogenesis. Type 2 immune responses typically generate pruritis, and the type 1 and type 3 responses generate pain. Type 2 responses and increased skin pH contribute to barrier dysfunction and promote dysbiosis of the skin microbiome, causing the proliferation of Staphyloccocus aureus. In conclusion, understanding the dynamic interactions between cutaneous components in AD could drive the development of therapies to improve the quality of life for patients with AD.

Maxadilan-simile expression in Nyssomyia neivai, a sandfly vector in an endemic region of Brazil, and its immunogenicity in patients with American tegumentary leishmaniasis

BACKGROUND Maxadilan (Max) is a salivary component in the sandfly Lutzomyia longipalpis (Lutz & Neiva 1912), a vector of visceral leishmaniasis. Max has a powerful vasodilatory effect and is a candidate vaccine that has been tested in experimental leishmaniasis. Nyssomyia neivai (Pinto 1926) is a vector of the pathogen responsible for American tegumentary leishmaniasis (ATL) in Brazil. OBJECTIVE We searched for Max expression in Ny. neivai and for antibodies against Max in ATL patients. METHODS cDNA and protein were extracted from the cephalic segment, including salivary glands, of Ny. neivai and analysed by polymerase chain reaction, DNA sequencing, and blotting assays. The results were compared with data obtained from Lu. longipalpis samples. We quantified antibodies against Max in serum samples from 41 patients with ATL (31 and 10 with the cutaneous and mucocutaneous forms, respectively) and 63 controls from the endemic northeastern region of São Paulo state, using enzyme-linked immunosorbent assay. FINDINGS Recognition of a Max-simile peptide by specific antibodies confirmed expression of a Max sequence in Ny. neivai (GenBank EF601123.1). Compared to controls, patients with ATL presented higher levels of antibodies against Max (p = 0.004); 24.4% of the patients with ATL and 3.2% of the controls presented anti-Max levels above the cutoff index (p = 0.014). The anti-Max levels were not associated with the specific clinical form of ATL, leishmanin skin test response, absence or presence of amastigotes in histopathologic exam, results of indirect immunofluorescence testing for leishmaniasis, or duration of cutaneous form disease. MAIN CONCLUSION High serum anti-Max levels did not protect patients against ATL, but confirmed previous natural exposure to Ny. neivai bites in this ATL endemic region.