Eosinophil infiltration is found in a broad spectrum of skin disorders ().3
It is a characteristic feature of allergic diseases or parasitic infestations, but it is also observed in autoimmune diseases, hematologic diseases, as well as in association with tumors, and bacterial or viral infections. Depending upon the disease, eosinophils can be the predominant cell infiltrate such as in eosinophilic cellulitis or can be part of a mixed inflammatory infiltrate in the dermis such as in eczematous reactions. Eosinophils may infiltrate the epidermis presenting as eosinophilic spongiosis in particular in autoimmune bullous diseases, insect bite reactions or acute contact dermatitis. Eosinophil infiltration of the deep dermis and subcutaneous fat tissue can be observed in eosinophilic cellulitis, parasitic infections, erythema nodosum, vasculitis, or lymphomas. Peripheral blood eosinophilia may be associated with tissue eosinophilia, e.g. in drug reactions with eosinophilia and systemic symptoms (DRESS), atopic dermatitis, or bullous pemphigoid.
A selection of diseases associated with skin eosinophilia
In hematoxylin and eosin stained skin specimens, eosinophils are noticeable as round shaped cells stuffed with coarse eosinophil granules. In subacute and chronic eczematous lesions, disrupted oval shaped eosinophils may also be found. Extracellular deposits of granular proteins can be detected in varying amounts either as separate little granules or as a thin coating on collagen bundles. The latter are called flame figures and can typically be seen in eosinophilic cellulitis. Immunofluorescence staining using antibodies directed against eosinophilic cationic protein (ECP) or major basic protein (MBP) allows a more sensitive detection of eosinophils and extracellular granular protein depositions compared with hematoxylin and eosin staining.
Eosinophils do not enter the skin under physiological states. Mechanistically, cutaneous eosinophilia can be from a primary problem internal to the eosinophil or may be caused by stimuli outside the cell.3
In either case, increased production, recruitment and/or survival of eosinophils is likely. Hematologic disorders affecting multipotent or pluripotent hematopoietic stem cells may involve the eosinophil lineage. In these diseases, mutations that represent intrinsic defects in eosinophils cause eosinophil proliferation and tissue infiltration including the skin. Cutaneous manifestations are described as multiple erythematous papules, plaques and nodules, or generalized erythematous maculopapular eruptions often associated with pruritus. By means of cytogenetic and molecular techniques, a number of diseases formerly defined as idiopathic hypereosinophilic syndrome (HES) can now be classified as separate entities. Clonal eosinophilia is often associated with rearrangements involving the genes of the platelet-derived growth factors A and B (PDGFRA, PDGFRB) resulting in increased tyrosine kinase activity.4
Notably, patients with HES due to the fusion of the PFGFRA and FIP1L1 genes respond to imatinib therapy.4
More commonly, extrinsic eosinophilic disorders are observed, in which skin eosinophilia is due to cytokine release by either T cells or tumor cells. Cytokines involved in the development of skin eosinophilia include interleukin (IL-)-3, IL-5 and granulocyte/macrophage colony-stimulating factor (GM-CSF). The expression of IL-5 in association with eosinophilic skin disorders has been reported in atopic dermatitis,5, 6
exanthematous drug reactions, 7
episodic angioedema with eosinophilia,9
cutaneous T cell lymphoma,13
and HES with skin involvement.15
IL-3 expression has been detected in blister fluids of bullous pemphigoid.16
In Langerhans cell histiocytosis17
as well as in atopic dermatitis, atopy patch test reactions and cutaneous late phase reactions, the expression of both IL-3 and GM-CSF has been shown.16, 18
Expression of the chemokine eotaxin has been observed in atopic dermatitis,19
autoimmune-blistering diseases like dermatitis herpetiformis and bullous pemphigoid,21
but also lymphomas, (e.g. cutaneous T cell lymphoma) and Hodgkin’s disease.23
The functional role of eosinophils in the pathogenesis of skin diseases remains largely unknown. Depending on the skin disease, a role in host defense, immunoregulation and/or remodeling and fibrosis can be assumed. Specific cutaneous eosinophilic disorders are described below.
Eosinophilic cellulitis (Wells syndrome) and HES
As the name implies, Wells syndrome is characterized by an intense infiltration of eosinophils, extracellular granule deposition and flame figures in the dermis. Patients present with recurrent episodes of acute pruritic dermatitis, seldom with blisters, painful edematous swellings or persistent urticarial eruptions.24
An increased expression of IL-5 has been reported in a number of cases. The cause is not known, but some patients developed eosinophilic cellulitis in association with hematological disorders, infections, or anti-TNF-alpha therapy. Corticosteroids are usually helpful in Wells syndrome. Eosinophilic cellulitis may also occur as a cutaneous manifestation of HES. Other skin manifestations of HES are erythematous macules, papules or nodules, blisters, necrosis, ulcerations, purpura, lichenoid eruptions or urticarial lesions, and pruritus. The skin is affected in 37% of HES patients.25
Anti-IL-5 antibody therapy was shown to improve skin symptoms in HES patients.26
In a subgroup of patients with HES, IL-5 producing clonal T cells has been identified. These T cells often exhibit an abnormal phenotype in as far as they have an either higher, lower or absent expression of lineage-associated markers. Those patients usually present with cutaneous symptoms.27
Eosinophilic pustular folliculitis (EPF)
EPF presents as annular clusters of sterile follicular papules and pustules predominantly on the face and trunk that heal with postinflammatory hyperpigmentation but tend to recur periodically.28
The histology shows a dense follicular and perifollicular infiltrate of eosinophils and scattered lymphocytes, and sometimes follicle destruction. The classic type of EPF affects immunocompetent subjects. Meanwhile two other subtypes of EPF have been identified. Infancy-associated EPF often involves the scalp. More commonly, EPF is seen in context with immunosuppression. EPF has been reported in association with infections, in particular AIDS, medications, autoimmune diseases, as well as autologous peripheral blood stem cell and allogeneic bone marrow transplantation. A pathogenic role for eosinophils in response to fungi (Malassezia), demodex mites and bacteria has been suggested.
Despite various cutaneous and histopathological presentations of drug reactions (e.g. maculopapular rashes, erythema multiforme, acute generalized exanthematous pustulosis, pseudolymphomatous and granulomatous drug reactions), the presence of eosinophils in the skin is a quite striking finding.29
DRESS, also named hypersensitivity syndrome, presents with an acute, severe skin eruption that may develop from a maculopapular rash into erythroderma, as well as with fever, lymphadenopathy, hepatitis, blood eosinophilia, and other organ involvement due to hypereosinophilia.30
Eosinophils accompanied by other inflammatory cells are found in the skin and the lymph nodes. Severe hepatitis, in which eosinophilic infiltration or granulomas as well as hepatocyte necrosis and cholestasis are striking features, may result in liver failure accounting for the high mortality rate of 10%. The treatment is based on high-dose corticosteroids. Drugs known to cause DRESS are anticonvulsants, sulfa drugs, antimicrobial agents, anticancer drugs, nonsteroidal anti-inflammatory drugs and anti-diabetic agents.
Atopic dermatitis (AD)
Tissue eosinophilia is a typical feature of AD. The numbers of eosinophils in the skin are usually modest (2.8 cells/mm2
[range 0 to 90.3]) and correlate with disease severity, as well as the degree of spongiosis in acute exacerbations and marked epidermal hyperplasia in chronic stages.31
Besides eosinophils, eosinophil-derived products such as ECP, EDN (also abbreviated as EDX), and MBP are present in increased amounts in the blood and the skin of AD patients. The measurement of ECP in serum is frequently used as a tool for monitoring AD activity and response to therapy.32
Immunostaining with antibodies to MBP and ECP has demonstrated that eosinophil granule proteins are not only present inside eosinophils but also in the extracellular spaces, suggesting eosinophil degranulation. In biopsies obtained from chronic AD lesions, intact eosinophils are located predominantly within the perivascular mononuclear cell infiltrate. In contrast, in the upper dermis extensive extracellular MBP deposition are observed in the near absence of intact eosinophils.33
The presence of mostly disrupted eosinophils has been confirmed by electron-microscopy studies, which revealed various degrees of eosinophil degeneration ranging from intact eosinophils with granule abnormalities, to intact eosinophils with abnormal granules and pseudopod-like extensions, to eosinophils with degenerated cell and/or nuclear membranes to free eosinophil granules.34
Improvement of AD upon both systemic and topical therapy is usually associated with a decrease of eosinophils and other inflammatory cells in the skin. However, the administration of an anti-IL-5 antibody showed only moderate effects on clinical symptoms although blood eosinophils were almost completely depleted.35
Autoimmune bullous diseases
(BP) is due to an autoimmune response to structural components of junctional adhesion complexes leading to damage of the dermal-epidermal junction with subepidermal blister formation.36
Autoreactive B and T cell responses against the hemidesmosomal antigens BP180 and BP230 have been identified. IL-5 as well as eotaxin are abundant in blister fluids and the production of IL-5 is associated with blood eosinophilia and significant eosinophil infiltration in the skin of BP patients.37
Eosinophils are thought to be implicated in blister formation by releasing toxic granule proteins (ECP, MBP) and proteolytic enzymes, however, the molecular mechanisms are not well understood. In dermatitis herpetiformis
, a specific cutaneous manifestation of gluten-sensitive enteropathy due to anti-tissue transglutaminase antibodies, a neutrophilic infiltrate undermingled with eosinophils is found in the papillary dermis. The expression of eotaxin in lesional skin and increased levels of serum ECP suggest a role for eosinophils in disease pathology.21
In Langerhans cell histiocytosis
, among the infiltrate of Langerhans cells, scattered or clusters of eosinophils can be found in the papillary and deeper dermis, respectively.38
Langerhans cells produce a broad spectrum of proinflammatory cytokines, e.g. GM-CSF, and chemokines, and are thus likely to recruit and activate eosinophils directly or via stimulation of other cell types. Predominant T helper 2 type cytokine production by cutaneous T cell lymphoma
results in eosinophilia, extracellular granule protein depositions as well as increased IL-5 levels in the skin and/or peripheral blood.39
Currently, it is not known whether the eosinophils modulate the proliferation of the malignant cells.