CD56 highCD16 - NK cell involvement in cutaneous lichen planus

Lichen planus is an inflammatory disease of the skin and mucous membranes characterized by vacuolization of basal keratinocytes associated with a prominent junctional lymphocyte infiltrate which comprises T?lymphocytes, NK cells, myeloid and plasmacytoid dendritic cells. Basal keratinocyte damage is considered as being a consequence of a lymphocytic cytotoxic attack, mostly mediated by perforin+CD8+ T?lymphocytes. NK cells have been described to infiltrate inflamed skin and significantly contribute to the amplification of immune-mediated skin diseases, thanks to their cytotoxic activity and the release of pro-inflammatory cytokines. Here, we investigated the characteristics and functional properties of NK lymphocytes involved in lichen planus. Double staining immunohistochemistry showed a considerable number (6.42 ± 2.2% of the total cellular infiltrate) of CD3-CD56+ cells in early lichen planus lesions, mostly distributed in the papillary dermis and at the epidermal-dermal interface. Skin NK cells isolated from lichen planus lesions belong to the CD56highCD16- subset, are highly positive for perforin and natural cytotoxic receptors NKG2D and NKp44, and, in accordance with their phenotype, are negative for KIRs receptors CD158a and CD158b. Skin CD56highCD16- NK cells display a CCR6+CXCR3+CCR5+ChemR23+ chemokine receptor asset for homing into inflamed skin. In terms of cytokine release, skin CD56highCD16- NK cells are able to secrete IFN-γ, TNF-α and hardly release IL-22, IL-17 and IL-4. Overall, our data propose a pro-inflammatory role of NK lymphocytes in lichen planus.     

Intraepidermal lymphocytes in psoriatic lesions are activated GMP-17(TIA-1)+CD8+CD3+ CTLs as determined by phenotypic analysis

The onset and persistence of psoriatic lesions are linked to the presence of an inflammatory infiltrate of CD3+ lymphocytes that includes CD4+ and CD8+ subsets. Since a primary susceptibility factor for psoriasis is the Class I HLA-Cw6 molecule, we set out to learn more about the features of the epidermal CD8+ lymphocytes. The markers tested were GMP-17, a cytotoxic granule protein found in activated cytotoxic lymphocytes (CTLs), and the alpha chain of the IL-2 receptor (CD25), a plasma membrane molecule found on activated T cells. Lymphocytes in lesional skin expressed the GMP-17 protein, whereas lymphocytes in non-lesional skin, resolving lesional skin and normal skin had little or no GMP-17. By flow cytometry analysis, lesional epidermal GMP-17+ cells were CD8+CD3+, with a subpopulation expressing the activation marker CD25+. Due to the abundance of activated GMP-17+CD8+CD3+ lymphocytes (the phenotype of activated cytotoxic cells) in psoriatic lesions compared to non-lesional and normal skin, we hypothesize that they are contributing directly to the psoriatic phenotype.     

Eosinophil activation and in situ interleukin-5 production by mononuclear cells in skin lesions of patients with drug hypersensitivity.

In order to determine the inflammatory mechanisms of skin lesions in patients with drug hypersentivity, we examined eosinophil activation and interleukin-5 (IL-5) production in infiltrating lymphocytes. First, we showed that the number of peripheral eosinophils and the level of serum IL-5 at the eruption-active stage were both significantly higher than those in healed skin eruptions. Histological and immunohistological examination revealed that CD4+ T cells and eosinophils significantly more densely infiltrated drug eruptions than control skin lesions. The infiltrating eosinophils were also shown to be activated by immunostaining using anti-secreted formed eosinophilic cationic protein monoclonal antibody. The expression of mRNA for IL-5 in the infiltrating mononuclear cells at drug eruptions was shown by in situ hybridization. These results suggest that infiltrating CD4+ T cells might regulate both peripheral and tissue eosinophils and facilitate allergic inflammation at drug eruptions by means of IL-5 production.     

The interaction between Langerhans cells and CD4+ T cells.

The human skin is increasingly exposed to haptens and environmental protein antigens. Because Langerhans cells represent the outermost network of MHC class II+ antigen presenting cells in mammalians, we investigated their interaction with CD4+ T cells. Hapten-modified Langerhans cells induced proliferation and IL-2 production in naive resting CD4+ T cells. T cells activated in this manner and subsequently cultured with IL-2 mediated contact sensitivity in vivo and produced IL-2 but no IL-4 upon restimulation in vitro. Thus they corresponded to Th1 cells. Repeated stimulation with Langerhans cells induced a modulation of the lymphokine pattern: IL-2- and IL-4-producing Th0-like cells were identified after 3 to 4 rounds of restimulation; after > 5 rounds, Th2-like cells with an IL-4+IL-2- pattern and the capacity for inducing IgE synthesis in B cells was identified. Th2 cells were also recently found to mediate inflammatory tissue lesions containing a cellular infiltrate. This demonstrates that Langerhans cells may activate resting CD4+ T cells, Th1-, Th0- and Th2-like cells. It further shows that Langerhans cells may promote the differentiation of postthymic CD4+ T cells into subsets with distinct immune functions: Th1 cells which have the potential to mediate inflammatory reactions such as allergic contact sensitivity and Th2 cells which may be responsible for abnormalities associated with atopic dermatitis, such as elevated IgE and inflammatory skin lesions containing a cellular infiltrate.     

CD8+ T cell granzyme B activates keratinocyte endogenous IL-18

IL-18 is a pro-inflammatory cytokine of the IL-1 family involved in Th1/Th2 polarization. IL-18 is produced and stored as an inactive precursor (proIL-18) in several cells including keratinocytes, and thus appropriate processing is required to release its active form. In a previous study using recombinant protein, we demonstrated that granzyme B (GrB) cleaves proIL-18 into its active forms in a similar fashion as caspase-1 and human mast cell chymase. GrB released from cytotoxic T lymphocyte (CTL) and NK cells has roles in apoptosis and cytotoxic activity. In certain inflammatory skin diseases with epidermal cell death, the epidermal keratinocytes are targets of CTL and NK cells. However, IL-18 activation during the direct interaction of CTL/NK with keratinocytes has not been described so far. We investigated the interaction between CTL and keratinocytes, and IL-18 processing by CTL-derived GrB using cultured CD8+ T cells and keratinocyte cell line HaCaT. GrB(+)/caspase-1(?) CD8+ T cells cultivated from healthy human PBMC were co-cultured with interferon(IFN)-γ-treated HaCaT cells. The expression of GrB and caspase-1 in HaCaT cells was analyzed by flow cytometry and PCR. The IL-18 concentration in the culture supernatant was measured by specific ELISA. The interaction between HaCaT cells and CTL co-culture increased the number of cytoplasmic GrB-positive HaCaT cells with limited endogenous GrB mRNA expression. The concentration of mature IL-18 levels increased in the co-culture supernatant. GrB from CTLs acts double roles to keratinocytes: a IL-18 converting enzyme and pro-apoptotic factor in the skin inflammatory diseases.     

Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses

The contribution of T helper (Th) and T cytotoxic (Tc) type 1 lymphocytes in the expression of allergic contact dermatitis to haptens has been amply documented. Conversely, the existence of T cell-based regulatory mechanisms has been poorly investigated. Here, we examined the properties of a subset of nickel-specific CD4+ T cells displaying the cytokine profile (IL-10 , IL-5 , IFN-gamma+/-, IL-4+/-) of T regulatory cells 1 (Tr1) and with the potential to down-modulate immune responses to nickel. Tr1 clones were isolated from skin challenged with NiSO4 and peripheral blood of nickel-allergic patients, and from the blood of healthy individuals. Tr1 clones expressed CD25, CD28, CD30, CD26, and the IL-12 receptor beta2 chain upon activation, whereas the lymphocyte activation antigen-3 was present on 50% of the clones. Monocytes precultured with Tr1 cells in the presence of nickel, or treated with Tr1-derived supernatant, exhibited a markedly diminished capacity to stimulate nickel-specific Th1 responses. Tr1 supernatants also blocked the differentiation of dendritic cells (DC) from monocytes, as well as DC maturation and IL-12 production induced by lipopolysaccharide. As a consequence, the ability of DC to stimulate nickel-specific Th1 and Tc1 responses was greatly impaired. These inhibitory effects were completely prevented by IL-10, but not IL-5, neutralization. In aggregate, the results indicate that Tr1 cells can potently regulate the expression of Th1-mediated allergic diseases via release of IL-10.     

CD4+ CD8+ (thymocyte-like) T lymphocytes present in blood and skin from patients with atopic dermatitis suggest immune dysregulation

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease expressed early in life. Disease development is primarily determined by as yet unknown genetic factors, leading to the accumulation of activated T lymphocytes in the skin. OBJECTIVES: To investigate the nature of these T cells. METHODS: T-cell lines could be established from AD skin biopsies, but not from normal skin or AD peripheral blood, when placed in RPMI 1640 medium with 10% human AB serum, antibiotics, and the T-lymphocyte growth factors interleukins 2 and 4. The cell lines were subjected to phenotypic analysis using a fluorescence-activated cell sorter and compared with lymphocytes from AD and normal control peripheral blood. RESULTS: T-cell lines from 22 of 24 consecutive skin biopsies taken from 24 adult patients with AD were established. All cells were T lymphocytes expressing several activation markers. A significant proportion of the lymphocytes had stable expression of a CD4+ CD8+ phenotype (26% +/- 6%; mean +/- SEM). Such double-positive T lymphocytes are normally only seen in the thymus and not in the peripheral immune system. CD4+ CD8+ cells in peripheral blood of the patients (12.5% +/- 3.3%) were also detected. CONCLUSIONS: We suggest that a basic pathophysiological change in AD may be a faulty maturation of the T-lymphocyte system, leading to skin inflammation with CD4+ CD8+ T lymphocytes resembling immature T cells. This is likely to lead to skewing of many immune reactions in the patients.     

Mycosis fungoides skin lesions contain CD8+ tumor-infiltrating lymphocytes expressing an activated, MHC-restricted cytotoxic T-lymphocyte phenotype

In prior studies, we showed that most CD8⁺ cells infiltrating skin lesions of CD3⁺CD4⁺ mycosis fungoides were CD3⁺ T-line-age tumor-infiltrating lymphocytes (TIL) whose overall phenotype was suggestive of MHC-restricted cytotoxic T lymphocytes (CTL). However, their lack of cytotoxic-associated granzyme A mRNA suggested that they might be inactivated CTL precursors. In this study, we used single- and double-label immunohistologic techniques to assess the expression of TlA-1-reactive protein and HLA-DR by these CD8⁺TIL. Monoclonal antibody TIA-1 recognises a novel family of proteins expressed preferentially by cytotoxic cells, including some that lack grauzyme A. HLA-DR is a marker of T-cell activation. Single-label studies of 32 cases showed that CD8⁺TIL and TIA-1⁺ cells constituted a variable minority of the total cellular infiltrate and had a similar distribution. Double-label studies of 14 cases showed that in most instances the aggregate phenotype of the majority of CD8⁺TIL was CD3⁺TIA-1⁺HLA-DR⁺CD56⁻CD57⁻. These findings suggest that many of the CD8⁺TIL within skin lesions of CD3⁺CD4⁺ mycosis fungoides are activated, MHC-restricted CTL.     

Cytokine production of CD4+ and CD8+ peripheral T lymphocytes in patients with chronic idiopathic urticaria

The aim of this study was to investigate the characteristic cytokine pattern of patients with chronic idiopathic urticaria. Using flow cytometry, we examined the frequency of IL4, IL-10, IL-13 and IFN-gamma producing CD4+ and CD8+ T cells in the peripheral blood mononuclear cells at a single cell level. In patients with chronic idiopathic urticaria, the frequency of IL-10 producing CD4+ and CD8 + T cells was significantly higher than that of control subjects, while the frequency of IFN-y producing helper and cytotoxic T cells was significantly lower. The proportion of IL-4 producing CD4 + T cells from patients with urticaria was significantly lower. The ratio of IL-4 producing CD8 + T cells and the proportion of IL-13 producing CD4 + and CD8 + T lymphocytes did not show any significant difference between patients and controls. In our study, we could observe neither a dominant Th1 nor a dominant Th2 type cytokine pattern. We found a significant elevation in the intracellular IL-10 level which may be the cause of the down-regulated Th1 and Tc1 and partly Th2 lymphocyte functions.     

T lymphocytes bearing the γ/δ T-cell receptor in cutaneous lesions of dermatitis herpetiformis

T lymphocytes bearing the γ/δ T-cell receptor are a rare component of normal human GI epithelium and skin. Recently, however, an unusually high percentage of T lymphocytes with γ/δ receptors has been described in gastrointestinal biopsies from patients with dermatitis herpetiformis, implicating the γ/δ T cell subset in the pathogenesis of this disease. We investigated a possible role for this subset of lymphocytes in the pathogenesis of the cutaneous lesions of dermatitis herpetiformis. Using a standard immunoperoxidase technique, we labelled perilesional skin biopsies from patients with dermatitis herpetiformis and other inflammatory dermatoses with monoclonal antibodies to CDS, CD4, CDS, α/β T cell receptor, γ/δ T cell receptor, and IL-2 receptor. We found no differences in the percentage of γ/δ positive T lymphocytes in skin lesions of dermatitis herpetiformis as compared to other selected in-flammatory conditions. These findings suggest that die pathogenesis of the cutaneous lesions of dermatitis herpetiformis is not mediated through γ/δ T cells, and that the cutaneous lesions may develop through mechanisms different from those operative in the gastrointestinal tract.     

Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA

BACKGROUND: Infiltrating T lymphocytes are considered to play a major pathological role in skin lesions of cutaneous lupus erythematosus (CLE), a cutaneous autoimmune disease of unknown aetiology. Earlier histological studies revealed that the inflammatory infiltrate in CLE skin lesions is predominantly composed of T lymphocytes, with a slight predominance of CD4+ over CD8+ T cells, but failed to explain the development of scarring skin lesions, characteristic for chronic discoid lupus erythematosus (CDLE). Because recent investigations have highlighted the relevance of cytotoxic lymphocytes in autoimmune tissue destruction, we hypothesized that the scarring CDLE lesions might be caused by cytotoxic T lymphocytes. OBJECTIVES: To analyse skin biopsies of 15 patients with CLE [10 female, five male; localized CDLE (lCDLE), n = 5; disseminated CDLE (dCDLE), n = 5, subacute CLE (SCLE), n = 5] and five control biopsies taken from healthy controls and to characterize the inflammatory infiltrate. Methods We used immunohistochemistry, including staining for the cytotoxic molecule granzyme B, the skin-homing molecule cutaneous lymphocyte antigen (CLA) and the protein MxA, which is specifically induced by type I interferons (IFNs). RESULTS: We found a strong coexpression of granzyme B and CLA on lesional lymphocytes of patients with scarring lCDLE and dCDLE, which was significantly enhanced when compared with nonscarring SCLE and healthy controls. The increased expression of granzyme B was closely associated with the lesional expression of the type I IFN-induced protein MxA. CONCLUSIONS: Our results provide evidence that type I IFNs and potentially autoreactive cytotoxic lymphocytes targeting adnexal structures are highly associated with scarring lupus erythematosus lesions and might be responsible for their scarring character.     

Interleukin-4 promotes the expansion of skin-infiltrating lymphocytes from atopic dermatitis in vitro

Functional studies of lymphocytes in atopic dermatitis (AD) have so far focused on peripheral blood mononuclear cells (PBMC), whereas cells at the involved site, the skin, have not been examined. Accordingly, we have developed methods to generate lymphocyte cultures from biopsies of inflammatory skin areas. Skin-infiltrating lymphocytes (SIL) were isolated from skin biopsies of 6 patients with severe AD and expanded in vitro in the presence of interleukin-2 (IL-2) without additional antigens. After 6-10 d in culture, outgrowth of mononuclear cells from biopsy tissue was observed in all cases. Phenotypic analysis of skin-derived cells revealed the predominance of CD4+ T-helper/inducer phenotype in SIL populations. Parallel cultures of SIL and PBMC showed an increase and expansion of CD8+ T cells in cultured PBMC, whereas the CD4+ phenotype was predominant in SIL cultures. As indicated by their expression of HLA-DR and CD25 antigens, most of the SIL were activated and the cells mainly expressed T-cell receptors (TCR) composed of alpha and beta chains. Different strategies for expansion of SIL in vitro were examined. High levels of IL-4 (1,000 U/ml) in combination with IL-2 (50 U/ml or 1,000 U/ml) preferentially promoted growth of SIL derived from AD and were much more effective than IL-2 alone. No cells expanded in cultures with IL-4 alone. SIL grown with high concentrations of IL-4 contained a significant proportion of double-positive CD4+8+ cells. No other marked differences were observed in the distribution of T cell subsets in cultures propagated under different conditions for 21 d. Our results demonstrate the feasibility of growing infiltrating T lymphocytes from inflammatory skin of AD patients. The use of high concentrations of IL-2 in combination with high levels of IL-4 allows a large expansion of these cells and thus represents a useful strategy to expand cells for further functional and molecular biologic studies.     

Fc epsilon receptor II/CD23 positive lymphocytes in atopic dermatitis: II. Infiltration of Fc epsilon R II(+) T cells in the skin lesion

Cells expressing Fc receptors for IgE (Fc epsilon R II) were identified in skin from patients with atopic dermatitis (AD), eczematous dermatitis (ED), and in skin from normal nonatopic subjects, with the use of monoclonal antibodies to human lymphocyte Fc epsilon R II, H107, and to lymphoid cell-surface antigens by double immunofluorescence staining. Two to four percent of infiltrating mononuclear cells expressed Fc epsilon R II, and more than half of these cells were T epsilon cells in both acute and chronic AD lesions. Fc epsilon R II(+) T cells (T epsilon cells) bearing CD8 infiltrated preferentially acute lesions, whereas chronic lesions contained either CD8(+) or CD4(+) T epsilon cells, or both. Fc epsilon R II(+) cells rarely were present in ED lesions. There was no significant correlation between % Fc epsilon R II(+) peripheral blood mononuclear cells and the proportion of lesional Fc epsilon R II(+) cells, extent of skin lesions, or serum IgE levels, implying the selective accumulation of Fc epsilon R II(+) cells in the inflammatory infiltrate of AD. These observations suggest that the increased generation of Fc epsilon R II(+) cells in skin lesions, including CD8 (+) T epsilon cells, is involved in the pathogenesis of AD.     

Cutaneous T-cell lymphoma lesional epidermal cells activate autologous CD4+ T lymphocytes: involvement of both CD1+OKM5+ and CD1+OKM5- antigen-presenting cells

Cutaneous T-cell lymphoma is characterized by infiltration of the skin by activated CD4+ T lymphocytes. The mechanism by which these T lymphocytes achieve and maintain their activated state is unknown. Antigen-specific activation of T lymphocytes is dependent upon antigen-presenting cells which express HLA-DR class II major histocompatibility complex molecules, such as epidermal Langerhans cells. In addition to CD1+DR+ Langerhans cells, cutaneous T-cell lymphoma lesional epidermis contains major histocompatibility complex class II positive non-Langerhans cell populations, including CD1+OKM5+ bone-marrow-derived cells and DR+ keratinocytes. We asked whether any of these epidermal cell populations demonstrate capacity to activate T lymphocytes. Various numbers of epidermal cells from uninvolved and involved cutaneous T-cell lymphoma plaques were therefore used to stimulate autologous CD4+ and CD8+ T lymphocytes in the absence of exogenous antigen. Involved epidermal cells potently induced proliferation of CD4+ T lymphocytes (S.I. +/- SEM = 466 +/- 45). In contrast, uninvolved epidermal cells only induced background levels of proliferation (S.I. +/- SEM = 2 +/- 0.5, N = 8, p less than 0.01). Neither involved nor uninvolved epidermal cells were able directly to activate CD8+ lymphocytes. The capability of involved epidermal cells to activate CD4+ T lymphocytes was dependent upon CD1+DR+ leukocytes and not DR+ keratinocytes, because depletion of either HLA-DR+, CD1+ or HLe1+ epidermal cells totally abrogated the T-lymphocyte proliferation. Interestingly, on a cell per cell basis CD1+DR+ cells obtained from involved skin, demonstrated relative to CD1+DR+ cells from uninvolved skin, enhanced capacity to activate CD4+ T lymphocytes. Furthermore, CD1+OKM5+ cells from involved epidermis stimulated autologous CD4+ T lymphocytes. This indicates that a unique hitherto undescribed CD1+OKM5+ epidermal antigen-presenting cell population may participate in T-lymphocyte activation. These findings provide support for the concept that the epidermal cells in cutaneous T-cell lymphoma patients, particularly the antigen-presenting cells, may contribute significantly to the activation of CD4+ malignant and/or non-malignant inflammatory T lymphocytes within the skin.     

Primary cutaneous CD8+ cytotoxic T‐cell lymphoma involving the epidermis and subcutis in a young child

CD8+ cytotoxic T‐cell lymphoma involving the skin represents a heterogeneous group of diseases that include subcutaneous panniculitis‐like T‐cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T‐cell lymphoma, and ‘type D’ lymphomatoid papulosis. In this report, we describe a case of CD8+ cytotoxic T‐cell lymphoma involving both the epidermis and subcutis. The patient was a 6‐year‐old girl who presented with a 3‐year history of multiple plaques on her trunk and legs. The lesions had relapsed twice but responded well to prednisone. Histopathologic examination showed the proliferation of atypical lymphocytes in the epidermis, dermis and subcutaneous tissue. On immunohistochemical analysis, the atypical lymphocytes were positive for βF1, CD3, CD8, perforin, granzyme B and TIA‐1, but negative for T‐cell receptor (TCR) γ, CD4, CD30 and CD56. It was difficult to classify this tumor in terms of the known types of cutaneous lymphoma, and this case should be differentiated with subcutaneous panniculitis‐like T‐cell lymphoma and primary cutaneous aggressive epidermotropic CD8+ T‐cell lymphoma.     

CD69 expression and tumour necrosis factor-α immunoreactivity in the inflammatory cell infiltrate of halo naevi

It has been suggested that the involution of the pigmented lesions of halo naevus (HN) is mediated by an immune response, with the involvement of specific cytotoxic T lymphocytes. To explore further the pathogenesis of HN. skin biopsies from six patients with this condition were obtained and the characteristics of the infiltrating inflammatory ceils were studied by immunostaining techniques. We found that the cell infiltrate of HN is mainly composed by CD8⁺ T lymphocytes that express the activation molecule CD69. Tumour necrosis factor-α (TNF-α) immunoreactivity was detected on the inflammatory cells, a finding that suggests that the infiltrating T cells of HN are actively synthesizing this cytokine. Our results indicate that the infiltrating cells of HN predominantly have an activated cytotoxic phenotype, and suggest that these cells are indeed involved in the regression of the naevomelanocytic naevus of HN.     

Seborrhoeic dermatitis and Pityrosporum (Malassezia) folliculitis: characterization of inflammatory cells and mediators in the skin by immunohistochemistry

BACKGROUND: The fact that Pityrosporum ovale plays a part in seborrhoeic dermatitis is well established but the mechanism of this relationship has not been established. OBJECTIVES: To compare the number and type of inflammatory cells and mediators in skin biopsies from normal and lesional skin from the trunk and scalp in patients with seborrhoeic dermatitis, Pityrosporum (Malassezia) folliculitis and in normal skin from healthy controls. METHODS: The skin biopsies were stained using the labelled Streptavidin-biotin METHOD: The following markers were studied: CD4, CD8, CD68, HLA-DR, NK1, CD16, C1q, C3c, IgG, CD54 (ICAM-1), interleukin (IL) -1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, tumour necrosis factor-alpha and interferon-gamma. RESULTS: HLA-DR+ cells were seen in the highest number, and were higher in lesional skin compared with normal skin from both patients and healthy volunteers. ICAM-1 expression was also increased in lesional skin. C1q and the interleukins showed an increased cellular and intercellular staining in patients compared with healthy controls and the intercellular staining was often more intense in lesions compared with non-lesional skin. Staining was often more intense when Malassezia (Pityrosporum ovale) yeast cells were present. CONCLUSIONS: An increase in NK1+ and CD16+ cells in combination with complement activation indicates that an irritant non-immunogenic stimulation of the immune system is important. The result with the interleukins showed both an increase in the production of inflammatory interleukins as well as in the regulatory interleukins for both TH1 and TH2 cells. Similarities to the immune response described for Candida albicans infections indicate the role of Malassezia in the skin response in seborrhoeic dermatitis and Pityrosporum folliculitis.     

Possible involvement of CD14+ CD16+ monocyte lineage cells in the epidermal damage of Stevens-Johnson syndrome and toxic epidermal necrolysis

Background Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are characterized by keratinocyte apoptosis and necrosis, resulting in epidermal detachment. Although monocytes abundantly infiltrate the epidermis in SJS/TEN skin lesions, the properties and functions of these cells have not been fully examined. Objectives To determine the properties of monocytes infiltrating into the epidermis in SJS/TEN. Methods Immunostaining of skin sections was performed to examine the membrane markers of monocytes infiltrating into skin lesions. Results Immunostaining of cryosections from 11 SJS/TEN skin lesions revealed numerous CD14+ monocytes located along the dermoepidermal junction and throughout the epidermis. The cells coexpressed CD16, CD11c and HLA‐DR. CD14+ CD16+ cells were identified in very early lesions without epidermal damage, suggesting that their infiltration is a cause, rather than a result, of epidermal damage. Moreover, these cells expressed CD80, CD86 and CD137 ligand, indicative of their ability to facilitate the proliferation and cytotoxicity of CD8+ T cells. CD16+ cells infiltrating the epidermis and detected at the dermoepidermal junction were immunostained and counted in paraffin‐embedded skin sections obtained from 47 patients with drug rash manifested as TEN, SJS, maculopapular‐type rash or erythema multiform‐type rash. The number of CD16+ monocytes infiltrating the epidermis increased significantly, depending on the grade of epidermal damage. Conclusions These findings suggest that the appearance of CD14+ CD16+ cells of monocyte lineage plays an important role in the epidermal damage associated with SJS/TEN, most probably by enhancing the cytotoxicity of CD8+ T cells.