Eosinophil-Associated Dermatoses

Eosinophil Biology

The eosinophil is produced in the bone marrow and circulates transiently (8–18 hours) in the peripheral blood. Except for the bone marrow, gastrointestinal tract (distal to the esophagus), and lymphoid tissues (including spleen, thymus and lymph nodes), eosinophils found within tissues are classically associated with allergic inflammation or extra-gastrointestinal parasitic disease. In 1879, Paul Ehrlich named the “eosinophil” because of the intense staining of its distinctive cytoplasmic granules with the acidic dye, eosin. Ultrastructurally, membrane-bound, specific eosinophil granules have an electron-dense core and less dense matrix ( Fig. 25.1 ). The eosinophil produces multiple factors (e.g. toxic cationic proteins, oxidative products) that contribute to its role in inflammation . Surface molecule expression is important in activation and/or priming and further directs eosinophil involvement in inflammation (see Fig. 25.1 ) .

Eosinophils are attracted into tissues and activated by at least three interrelated signals: (1) chemokines; (2) other cytokines; and (3) adhesion molecules. Several members of the C-C chemokine gene superfamily are chemotactic for eosinophils, and these chemoattractants include the eotaxin family and RANTES ( r egulated on a ctivation, n ormal T cell e xpressed and s ecreted). Eosinophil-active chemokines signal primarily through C-C chemokine receptor (CCR)-3, which is expressed by eosinophils. Eotaxins 1–3 are specifically chemotactic for eosinophils, while RANTES is chemotactic not only for eosinophils but also for monocytes, T lymphocytes, natural killer cells, and basophils (but not neutrophils). In addition to their chemotactic properties, the eotaxins and RANTES induce production of reactive oxygen species by eosinophils, indicating that they have both chemotactic and functional activation effects. As eosinophil chemoattractants, the eotaxins are stronger than RANTES, and eotaxins 1 and 2 are also stronger in inducing reactive oxygen species by eosinophils than are eotaxin 3 and RANTES. Eotaxins 1, 2 and 3 and RANTES are produced by dermal fibroblasts, while RANTES is also produced by keratinocytes, positioning them well for participation in cutaneous inflammation .

Eosinophils enter tissues by traversing blood vessels. Similar to other leukocytes, selectin, integrin and immunoglobulin gene superfamily members (see Ch. 102 ) contribute to the signaling needed for eosinophil transmigration . In particular, eosinophils constitutively express the integrin very late antigen (VLA)-4, a ligand for vascular cell adhesion molecule (VCAM)-1, which is induced on endothelial cells by chemokines and cytokines. After entering the extracellular matrix, eosinophil activity is influenced by interactions between cell-surface integrins and fibrous proteins (in particular, fibronectin, laminin and collagen) and glycosaminoglycans (especially hyaluronic acid and chondroitin sulfate). Integrin expression, specifically CD11b/CD18 (MAC-1), is also critical for eosinophil effector functions, including degranulation.

Activating cytokines such as granulocyte–macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 are also important for the effector functions of eosinophils . Several lines of investigation indicate that eosinophils are recruited to and activated in tissues by cytokine activity from the Th2 subset of T cells, which produces IL-4, IL-5, IL-10 and IL-13, in addition to cytokines common to Th1 cells. Natural killer cells also produce IL-5, and mast cell-derived cytokines contribute indirectly to eosinophil activation via induction of IL-5 and GM-CSF. Eosinophils themselves elaborate important inflammatory and regulatory cytokines, including IL-1α, TGF-α and TGF-β ₁ , GM-CSF, IL-3, IL-5, IL-6, IL-8, TNF-α, and macrophage inflammatory protein 1α (see Fig. 25.1 ). As a result, eosinophil activation also occurs in an autocrine manner. In cytotoxicity assays, eosinophils are maximally activated by GM-CSF, followed by IL-3, IL-5, TNF-α and IL-4, in order of potency.

Tissue Effects and Innate Immunity

The presence of eosinophils in certain normal organs (see above) suggests a role in homeostasis. In addition, eosinophil infiltration is associated with tissue remodeling and fibrosis. Although cytokines, including IL-5 and eotaxins, are known to mediate eosinophil development and survival, mechanisms underlying the basal regulation of eosinophils, including their circadian cycling, remained largely unknown until the identification of innate lymphoid cells (ILCs). Long-lived type 2 ILCs, also known as ILC2s, are resident in peripheral tissues and regulate basal eosinophilopoiesis and tissue eosinophil accumulation via constitutive and stimulated cytokine expression . ILC2s secrete IL-5 constitutively and are induced to coexpress IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation.

Studies of the interactions of skin ILCs with other cell types demonstrated that dermal ILCs interact selectively and strongly with mast cells . Type 2 innate lymphocytes have been designated part of the “Th2 franchise” , and a broad role for ILC2s is emerging for both eosinophils and metabolic homeostasis, e.g. in atopic dermatitis , in glucose metabolism within adipose tissue , and in allergic respiratory disease , including associated tissue remodeling . Interactions of eosinophils with nerves may in part explain pruritus and other neurophysiological changes (e.g. white dermographism) observed in eosinophil-infiltrated tissues .

Eosinophils may act as antigen-presenting cells for microbial (including staphylococcal superantigens), viral and parasitic antigens, promoting T-cell proliferation, and they play a role in the regulation of mast cell function. Activation of eosinophils via toll-like receptors (TLR) 7 and TLR9 affects several eosinophil functions, with the overall response influenced by a Th2-like cytokine milieu . In addition, eosinophils can generate mitochondrial DNA traps that contain ECP and eMBP1 and display antimicrobial activity and can promote thrombosis. In summary, eosinophils participate in innate and acquired immunity and their functional diversity has numerous ramifications for both homeostasis and disease pathogenesis .

Eosinophil-Associated Dermatoses

“Eosinophil-associated dermatoses” encompass a wide range of diseases characterized by the presence of a few to many eosinophils and/or evidence of eosinophil degranulation in skin and/or mucous membranes. Disorders traditionally associated with eosinophil infiltration include arthropod bite reactions and ectoparasite infestations (see Chs 84 & 85 ), drug eruptions, helminth infections (see Ch. 83 ), and Wells syndrome ( Fig. 25.2 ). In addition, there are a number of other skin diseases in which tissue eosinophilia is often present, including bullous pemphigoid, urticarial dermatitis, and eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) ( Table 25.1 ). However, it must be emphasized that tissue eosinophilia can be observed in a plethora of skin disorders, from inflammatory and infectious to neoplastic. Lastly, mild to moderate eosinophil infiltration is a key feature of IgG4-related disease (IgG4-RD), in which fibrosis can also be a major finding . Initially described as a pancreatic disorder with increased serum IgG4 levels and numerous IgG4-positive plasma cells in affected tissues, the spectrum of IgG4-RD has been expanded to include any organ, including the skin. Proposed cutaneous manifestations are granuloma faciale and lesions that resemble angiolymphoid hyperplasia with eosinophilia ( Table 25.2 ).

Granuloma Faciale

Clinical Features

Granuloma faciale usually presents as a solitary, asymptomatic, red–brown plaque on the face, with a predilection for the forehead, cheek, and preauricular area ( Fig. 25.3A,B ) . Less often, multiple papules or plaques may be present ( Fig. 25.3C ) ; in one retrospective analysis of 66 patients, one-third had more than one lesion . Uncommon locations for granuloma faciale include the ears, scalp, and trunk or extremities ; in the previously cited retrospective study, 7% of the patients had extrafacial involvement . The individual lesions tend to persist and only occasionally resolve spontaneously. Granuloma faciale has not been associated with systemic disease.

Pathology

In the dermis, there are perivascular and interstitial infiltrates of neutrophils, lymphocytes and plasma cells, admixed with numerous eosinophils. Characteristically, the inflammation spares the upper papillary dermis, creating a “grenz zone” ( Fig. 25.4 ). Features of leukocytoclastic vasculitis are most prominent early on, with older lesions tending to have fewer neutrophils and more eosinophils and plasma cells as well as fibrosis. Because of the presence of eosinophils, IgG4-bearing plasma cells and lamellar fibrosis, it has been proposed that at least a proportion of cases of granuloma faciale may represent a cutaneous manifestation of IgG4-RD (see Table 25.2 ) .

Papuloerythroderma of Ofuji