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Papuloerythroderma (PEO) is a representative form of senile erythroderma with an unclear pathogenesis. This study aimed to characterize the T-cell phenotypes responsible for the pathogenesis of PEO. Cytokine profiles and cutaneous lymphocyte antigen (CLA) expression on circulating T lymphocytes in patients with PEO were simultaneously analyzed using flow cytometry. The patients with PEO showed significantly higher circulating interleukin (IL)-4-, IL-13-, IL-22-, and IL-31-producing CD4 + and CD8 + T-cell levels than healthy subjects. However, their levels significantly decreased after remission of PEO. No difference was observed in the proportions of circulating interferon (IFN)-γ- and IL-17-producing CD4 + and CD8 + T cells between the patients with PEO and healthy subjects. In particular, the proportion of circulating IL-4-, IL-13-, IL-22-, and IL-31-producing CD4 + and CD8 + T cells was much higher in the CLA + subset than in the CLA - subset. There was a positive correlation between IL-13-, IL-22-, and IL-31-producing CD4 + T cells and the disease severity score of PEO. Moreover, a positive correlation was also observed between the proportion of IL-22- or IL-31-producing cells and circulating IL-13-producing cells in both CD4 + and CD8 + T cells, and approximately 50% of both IL-22- and IL-31-producing CD4 + and CD8 + T cells coproduced IL-13. IL-13/IL-22/IL-31 skewing within the skin-homing T-cell population may be involved in the pathogenesis of PEO., (© 2021 Japanese Dermatological Association.)

Competing Interests: Competing interests: None declared.

Background: Cytotoxic T cells seem to be the main effector cells in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). However, recent data support a role of the innate immune system in the etiopathology of drug-induced cutaneous reactions. In this study, we analyzed the expression of α-defensins 1-3 in mononuclear cells from patients with SJS/TEN, drug-induced maculopapular exanthema (MPE), and healthy donors., Methods: DEFA1A3 gene expression was analyzed by quantitative and end-point RT-PCR. Intracellular flow cytometry, immunofluorescence and immunohistochemistry were carried out to verify α-defensin 1-3 protein expression in mononuclear cells from peripheral blood and skin infiltrates. α-Defensin 1-3 concentration was evaluated in plasma and blister fluid samples by ELISA., Results: We herein describe DEFA1A3 gene expression in peripheral blood mononuclear cells (PBMCs) from patients with drug-induced cutaneous diseases. Gene expression analysis unveiled transcription in CD4 and CD8 peripheral blood T cells. Protein expression was confirmed by intracellular flow cytometry in mononuclear cells from the patients, including monocytes, NK cells, and T cells from peripheral blood and blister fluid. Further analysis of protein content by flow cytometry revealed higher protein levels in CD56(+) CD3(+) lymphocytes from patients with SJS/TEN when compared to MPE and healthy donors. Immunohistological analysis was used to confirm expression in dermal infiltrates. α-Defensin levels were estimated by ELISA to be 3- to 175-fold higher in blister fluid when compared to simultaneously drawn plasma samples., Conclusion: Upregulation of innate immune molecules such as α-defensins 1-3 in T cells from patients with SJS/TEN may be involved in the etiopathology of these life-threatening diseases induced by medications., (© 2010 John Wiley & Sons A/S.)

Parapsoriasis is a chronic dermatosis whose biological distinction from early mycosis fungoides, the most frequent form of cutaneous T-cell lymphoma, is still not clearly defined. Two types of parapsoriasis have been delineated: large-plaque parapsoriasis and small-plaque parapsoriasis. The lack of clinical and histological features, which may allow distinguishing parapsoriasis from early mycosis fungoides has prompted several investigations to assess the role of immunohistochemistry in establishing a conclusive diagnosis of these conditions. However, the additional data obtained by immunohistochemical analysis concerning the CD4/CD8 ratio, the aberrant expression of T-cell antigens and the expression of proliferation markers has not generally helped establish a more definitive diagnosis. This review critically discusses these immunohistochemical markers and their use in diagnosis of parapsoriasis., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

Background: It is unsettled whether small plaque parapsoriasis (SPP) represents an inflammatory dermatosis or has a potential to transform into mycosis fungoides (MF) or is, in fact, MF. The literature contains no fully documented example of progression of SPP into MF., Objective: The purpose of our study was to present a patient with clinical features of SPP who later developed plaque-stage MF, as seen both clinically and pathologically and to compare the clinicopathologic features of this unique case with 27 "nonprogressive" SPP cases., Methods: This study is a prospective and retrospective evaluation of 28 patients, using light microscopy, immunohistochemistry, and molecular biology., Results: A 56-year-old man with a 3-year history of persistent SPP with typical small (<5 cm), elongated and "digitate" lesions presented with newly developed larger patches and plaques. Whereas histologic examination of the patch lesion revealed relatively nonspecific features, a specimen of the crusted plaque showed a dense lymphoid infiltrate composed of small cerebriform lymphocytes, medium-sized lymphoid cells, and occasional large hyperchromatic cells that infiltrated the basal layer of the epidermis and formed small collections. There were atypical mitotic figures. Immunohistochemically, an aberrant immunophenotype with the loss of CD5 expression was found in the plaque specimen. T-cell receptor (TCR)-gamma gene rearrangement studies detected clones in the plaque and in the peripheral blood (biallelic in blood), while the patch tested polyclonal. The 27 SPP patients included 23 men and 4 women, ranging in age from 29 to 75 years. They were followed up and treated for 1.2 to 52 years (mean 10); no patient's SPP progressed into MF. All patients presented with small patch lesions measuring 3 to 6 cm lengthwise and 0.5 to 2 cm in width. Histologic features were nonspecific. Molecular genetic studies revealed the following results: two cases tested polyclonal, 3 cases demonstrated the oligoclonal pattern, whereas the remaining 13 specimens showed a pattern which can be interpreted as oligoclonal or pseudomonoclonal., Limitations: Oligoclonal and monoclonal patterns were overrepresented in the SPP group, which may be due to the low amount and, probably, suboptimal quality of DNA used in the TCR-gamma rearrangement studies., Conclusions: Occasionally patients with the clinical and pathologic presentation of SPP may develop typical features for MF. This event seems to be extremely rare; at present there appears to be no means to predict such a course. The vast majority of SPP patients will never have disease progression to MF.

Background: Abnormal cell proliferation, which results from deregulation of the cell cycle, is fundamental in tumorigenesis., Objectives: To investigate the expression of proliferation markers and cell cycle regulators in a range of T cell lymphoproliferative skin diseases., Methods: We studied skin specimens of 51 patients with parapsoriasis (PP), mycosis fungiodes (MF), or lymphomatoid papulosis (LyP). Immunohistochemistry was performed for Ki-67, proliferating cell nuclear antigen (PCNA), minichromosome maintenance protein 7 (MCM7), and p21., Results: MF with stage IIB-IV and LyP showed a significantly greater number of Ki-67-positive cells than PP (P=0.02 and 0.001) and MF I-IIA (P=0.019 and 0.003), respectively. MCM7 staining revealed significantly higher labeling indices for MF IIB-IV and LyP when compared to PP (P=0.002 and 0.04) and MF I-IIA (P=0.0005 and 0.01), respectively. Compared to PP and MF I-IIA, MF IIB-IV was associated with significantly higher labeling indices for PCNA (P=0.006 and 0.0004). p21 staining was significantly increased in MF IIB-IV and LyP when compared to PP (P=0.006 and 0.003) and MF I-IIA (P=0.003). However, p21 staining was all in all very weak., Conclusions: Ki-67 and PCNA seem to be useful immunohistological parameters for the correlation with the clinical stage of MF. In the differentiation and prognostication of T cell lymphoproliferative skin disorders, MCM7 may serve as a novel biomarker which is, in contrast to Ki-67 and PCNA, stable throughout the cell cycle.

Background: Diagnosing mycosis fungoides (MF) can be challenging in the early stage of the disease because histopathological features may simulate a variety of benign inflammatory skin diseases. Assessment of T-cell clonality was found to be useful in diagnosis and follow-up of patients., Objective: In this study, PCR-based TCRgamma gene rearrangement analysis was performed in skin and peripheral blood samples of patients with MF treated at the two largest referral centers in Serbia, and the results obtained were correlated with clinical and follow-up data., Methods: Skin and peripheral blood samples were obtained with informed consent from 37 patients treated at the Department of Dermatology of the Military Medical Academy and the Medical Center of Serbia from 2001 to 2006. The median time of follow-up was 4 years. Multiplex PCR was used for TCRgamma gene rearrangement analysis in skin and peripheral blood samples. Clonality results were correlated with the clinical data and disease course data., Results: Monoclonality was detected in skin samples of 30/37 patients (81%), in 2/5 patients with large-plaque parapsoriasis (LPP), in 28/32 (88%) patients with histologically proven MF, and in 1/16 (6%) patients with benign inflammatory dermatoses. A monoclonal pattern in both skin and peripheral blood was detected in 7/16 (44%) patients in the late stage of the disease, and in 1/7 (14%) patients in the early stage of the disease. A dominant clone was found in both skin and peripheral blood in 1/4 patients in remission, 2/5 with a stable disease, and 4/9 (44%) with disease progression., Conclusion: TCR-gamma gene rearrangement analysis can be regarded as a useful adjunct to diagnosis of epidermotropic lymphoproliferative disorders. The presence of a dominant clone in both the skin and peripheral blood was more frequently detected in late stages and in patients with disease progression, confirming the usefulness of clonality detection by TCR-gamma gene rearrangement analysis in follow-up of patients with primary cutaneous T-cell lymphomas.

Background: In the non-immediate type of drug eruptions, the populations of circulating T cells may be altered as a consequence of T cell responses to a culprit drug., Objective: The aim of this study was to investigate differences among the types of drug eruptions in propagating T cell populations of the patients' peripheral blood., Methods: The type of eruptions were divided into three categories: (1) generalized maculopapular eruption (MPE), (2) erythema multiforme (EM)/Stevens-Johnson syndrome (SJS), and (3) drug-induced hypersensitivity syndrome (DIHS) or drug rash with eosinophilia and systemic symptoms (DRESS). T cell populations were phenotypically analyzed by flow cytometry in the percentage of T helper (Th) 1 (CXCR3+CD4+), Th2 (CCR4+CD4+), Tc1 (CXCR3+CD8+), and Tc2 (CCR4+CD8+) subsets and their activation states as assessed by CD69, CD25 or HLA-DR positivity., Results: Upon occurrence of both MPE and EM/SJS, Th2 cells outnumbered Th1 cells, whereas Tc1 and Tc2 cells differentially predominated in EM/SJS and MPE, respectively. An increase of HLA-DR+CD8+ cells in EM/SJS type provided another supportive evidence for Tc1 stimulation. In DIHS, during the development of the second wave of eruption and/or liver dysfunction associated with anti-HHV6 antibody elevation, CD4+ cells were gradually decreased, but CD8+ cells were inversely increased. Tc1 cells were increased as well as Th1 cells. Finally, in all the three groups, there existed a considerable number of CD25+CTLA-4-CD4+ T cells., Conclusion: Our study suggests that Th2/Tc2 and Th2/Tc1 cells mediate MPE and EM/SJS, respectively, and Tc1 cells are involved in the pathogenesis of DIHS at the late stage.

Making a differential diagnosis between early mycosis fungoides and parapsoriasis is often difficult at the clinical and histological level. The aim of this study was to explore markers that could help in this process. A total of 88 patients were included in 2 categories: large plaque parapsoriasis and digitiform parapsoriasis. A histological examination was performed for each patient, and expression of the antigen My7 (CD13), which is lacking in cutaneous T-lymphomas (but not in inflammatory lesions) and rearrangement of the T-cell receptor gene were analysed. A histological aspect of epidermotropic cutaneous T-cell lymphoma was observed in 23.5% of cases of large plaque parapsoriasis and 15% of cases of digitiform parapsoriasis. A disappearance of My7 antigen was noted in the 2 forms of parapsoriasis, more frequently when there was cutaneous T-cell lymphoma histology. A cutaneous clone was observed in 10.3% of cases of large plaque parapsoriasis, but not of digitiform parapsoriasis. For 3 patients, a cutaneous clone and a disappearance of My7 were associated with a non-specific histology. Considering these histological, immunological and molecular biological data, it appears that My7 antigen combined with T-cell clone may help the dermatologist to confirm the diagnosis of early mycosis fungoides. Moreover, further studies will determine whether CD13 is an early prognostic marker of evolution of a parapsoriasis to mycosis fungoides. Finally, these results demonstrate that digitiform parapsoriasis can be an early stage of MF.

We have investigated the HECA-452 expression in large plaque parapsoriasis (PP) and mycosis fungoides (MF) patients, evaluating the potential role of this biomarker in both cutaneous disorders. Skin specimens from 72 PP and 61 MF patients were selected in this study. We compared their actual histological diagnosis with their previous diagnosis and we found that all 72 PP patients had the same diagnosis as before (stable PP), while 26 out of 61 MF had a previous PP histological diagnosis (evolving PP). Our results show an increased expression of HECA-452 in MF compared to PP (p<0.01). Furthermore, evolving PP showed a significantly higher level of HECA-452 than stable PP (p<0.05). We conclude that HECA-452 expression increases during the natural history of Mycosis Fungoides. HECA-452 could be used as a biomarker for MF and predict which PP evolves to MF.

Background: The number of identified tumour-associated antigens for cutaneous lymphoma is still very restricted, which limits the elucidation of the tumour immunology of these malignancies and the development of specific immunotherapies and immunodiagnostics., Objectives: To identify new serologically defined antigens associated with cutaneous lymphoma., Methods: A phage expression library of the human testis transcriptom was established and immunoscreened with sera from 100 patients with cutaneous lymphoma and nine with parapsoriasis, and 81 age-matched control donors. Positive expression clones were sequenced to identify the respective antigen., Results: The testis-specific protein 10 (TSGA10) was identified as an antigen recognized by sera of two patients with Mycosis fungoides but not by sera from healthy donors. By reverse transcription-polymerase chain reaction analysis, TSGA10 was found expressed in all cutaneous lymphoma samples tested, various tumour cell lines, testis, peripheral blood mononuclear cells, skin, isolated lymphocytes, keratinocytes and fibroblasts. TSGA10 overexpression had previously been reported for other cancers., Conclusions: TSGA10 is a new tumour-associated antigen of cutaneous lymphoma.

CD7, a molecule normally expressed on 90% of CD4+ T cells, is often deficient on the malignant T cells of cutaneous T cell lymphoma. Therefore deletion of CD7 is considered a specific marker for the diagnosis of cutaneous T cell lymphomas. Because an expansion of CD4+CD7- cells may also be observed in benign lymphocyte-mediated dermatoses, we present our experience concerning CD7 expression in both cutaneous T cell lymphomas and a broad variety of T cell-mediated inflammatory dermatoses using an immunohistochemical approach on frozen sections from 45 patients. No, or at most scarce, expression of CD7 was detectable in the inflammatory skin conditions investigated as compared to CD3-positive cells. In cutaneous T cell lymphomas, a striking reduction of CD7 reactive cells was found in either reactive or malignant T cell components. Our findings indicate that CD7-negative T cells are more common within both benign and neoplastic T cell infiltrates than was previously demonstrated and suggest that, using a conventional immunoenzymatic technical approach on fresh-frozen sections, CD7 deletion is an unreliable criterion for the immunohistological diagnosis of T cell-mediated skin infiltrates.

Plasma concentrations of interleukin-10 (IL-10) were examined in 126 patients with drug-induced cutaneous reactions: maculopapular eruptions (ME), erythema multiforme (EM), erythema multiforme coexisting with erythema nodosum (EMN), drug-induced urticaria (DU), hyperergic vasculitis (HV), Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). Activity of the cytokine was measured using the immunoenzymatic ELISA method: a) in the acute stage of disease before treatment was administered, and b) after clearing of skin lesions, after treatment. In the acute stage of disease highly elevated mean concentrations of IL-10 in all 6 groups of patients were found (p<0.001) in comparison with the control. After clearing of clinical symptoms IL-10 concentrations were decreased highly significantly (ME, EM, DU, HV) or significantly (EMN, SJS/TEN) in comparison with the values before treatment, but remained still considerably elevated (p<0.001; p<0.01) when compared with the healthy control. Results of this study indicate that the compensatory antiinflammatory response, expressed as elevated IL-10 activity, is induced as early as in the acute stage of skin lesions and lasts longer than clinical symptoms of drug-induced cutaneous reactions.

Background: Cytokines are of potential importance in the pathogenesis of cutaneous T-cell mediated disorders, including cutaneous T-cell lymphoma (CTCL)., Objectives: To compare interleukin (IL)-15 expression in certain inflammatory cutaneous diseases, with that in CTCL (mycosis fungoides and Sézary syndrome)., Methods: IL-15 mRNA and protein expression were examined by in situ hybridization and immunohistochemistry, respectively, on formalin-fixed, paraffin-embedded biopsies of normal human skin, atopic dermatitis, psoriasis, parapsoriasis and CTCL., Results: Despite similar expression of IL-15 mRNA, we found differences in IL-15 protein expression between normal human skin, atopic dermatitis and psoriasis on the one hand, and parapsoriasis and CTCL on the other. IL-15 protein expression was not detected in normal human skin, atopic dermatitis or psoriasis, but was detected, mainly at low levels but in a few patients at higher levels, in epidermal keratinocytes in parapsoriasis, mycosis fungoides and Sézary syndrome., Conclusions: Induction of keratinocyte IL-15 expression appears to be a feature of CTCL. The factors stimulating such an expression remain unknown.

Clinical, immunohistological, and molecular biological data suggest the chronic dermatosis small plaque parapsoriasis (SPP) to be a precursor of mycosis fungoides (MF). However, most data are contradictory and confusing due to inexact definition of SPP. Recently, clonal T cells were detected in skin and blood samples of early MF. Because demonstration of identical T-cell clones in skin and blood of SPP patients would indicate a close relationship of SPP to MF, we investigated the clonality of skin and blood specimens from 14 well-defined SPP patients. By a polymerase chain reaction (PCR) amplifying T-cell receptor gamma rearrangements and subsequent high-resolution electrophoresis, clonal T cells were detected in 9 of 14 initial and 32 of 49 follow-up blood samples, but in 0 of 14 initial skin specimens. Even a clone-specific PCR showing the persistence of the initial blood T-cell clone in 20 of 20 follow-up samples, failed to detect the T-cell clone in the skin. In 2 patients, the clonal T cells were shown to be CD4(+). For the first time, the majority of SPP patients was shown to carry a T-cell clone in the peripheral blood. Although a relation between circulating clonal T cells and SPP cannot directly be proven by the applied techniques, our results indicate blood T-cell clonality to be a characteristic feature of SPP and CTCL because analysis of multiple controls and clinical workup of our SPP patients excluded other factors simulating or causing a clonal T-cell proliferation. A sufficient cutaneous antitumor response but also an extracutaneous origin of the T-cell clones might explain the failure to detect skin infiltrating clonal T cells.

Parakeratosis variegata is a rare disorder with unknown aetiology. In a few cases it arises from benign skin diseases such as pityriasis lichenoides et varioliformis acuta (Mucha Habermann disease) or pityriasis lichenoides chronica. However, transformation into malignant diseases such as cutaneous T-cell lymphoma has been observed. We report an 11-year-old girl with a 10-year history of pityriasis lichenoides chronica now presenting with parakeratosis variegata. Analysis of skin infiltrating T cells showed clonally rearranged T-cell receptor gamma chains occurring with a frequency of more than 2%. This finding is compatible with the clinical observation of parakeratosis variegata transforming into a malignant T-cell disorder. We therefore suggest that patients suffering from parakeratosis variegata and other diseases such as pityriasis lichenoides et varioliformis acuta or pityriasis lichenoides chronica should be continuously monitored.

Background: Small plaque parapsoriasis is an idiopathic chronic dermatosis characterized by patches on the trunk and extremities that are often smaller than 5 cm in diameter and that sometimes have a digitate contour. These latter cases are often referred to as digitate dermatosis. Histopathologic examination reveals a mild superficial perivascular lymphocytic infiltrate associated with mild spongiosis and parakeratosis. To characterize this disease more completely, we analyzed the differentiation and clonality of lesional lymphocytes using immunohistologic and molecular biologic methods., Observations: We studied five cases using a frozen-section immunoperoxidase technique. In each case, there was a predominantly CD4+ T-cell infiltrate admixed with CD8+ T cells, Langerhans cells/indeterminate cells, and macrophages. In three cases, the clonality of lesional T cells was studied by denaturing gradient gel electrophoresis of polymerase chain reaction-amplified T-cell receptor-gamma gene rearrangements. Two cases showed a dominant clonal pattern, while one case exhibited a polyclonal pattern. Clinical follow-up disclosed persistent disease in one of the two clonal cases, while lesions in the other clonal case and the polyclonal case gradually resolved., Conclusions: Our findings indicate that small plaque parapsoriasis is a clinically indolent, histopathologically nonspecific, predominantly CD4+ T-cell-mediated disease that, at least in some cases, contains a dominant T-cell clone. These features put small plaque parapsoriasis into a category with certain other members of the parapsoriasis group, namely, pityriasis lichenoides and lymphomatoid papulosis, which have been shown to be clonal T-cell disorders despite their clinically benign course. It remains to be determined if the dominant T-cell clones identified in some cases of small plaque parapsoriasis can ever be the direct precursors of overt cutaneous T-cell lymphomas.

Parapsoriasis has been described rarely in childhood; a few reports mention this condition as preceding early mycosis fungoides. We report a boy age 15 and a girl age 8 years with different clinical features of parapsoriasis who were followed clinically and histologically for about four years. Immunophenotyping of the skin infiltrate and a T cell receptor gene rearrangement analysis were performed on each. The infiltrate was composed mainly of CD4+ and CD45+ lymphocytes in the first patient and of CD8+ and CD45+ in the second. No T cell receptor gene rearrangements were found. The paucity of knowledge about the evolution of this entity in childhood and its relationship to mycosis fungoides makes follow-up critical. The importance of immunophenotyping and immunogenotyping is particularly stressed.

The paper deals with the origin of parapsoriasis nodularis, which in its micronodular variant belongs to chronic dermatosis and has a clear-cut clinical and histological appearance. The disease arises most frequently after stress and occurs for the most part in middle-aged males. The leading role in pathogenesis of parapsoriasis nodularis is played by cellular immunity as indicated by reduced count of T-lymphocytes, active T-lymphocytes as well as the emergence of delayed hypersensitivity.

Immune-mediated reactions to NSAIDs are unusual. We have observed two cases of maculopapular eruptions occurring 48-72 h after administration of diclofenac sodium. Patch tests performed with diclofenac were positive. The histopathologic findings resembled those of contact dermatitis with different degrees of dermal involvement. Clinical, allergologic, and histopathologic patterns strongly suggest a type IV mechanism of hypersensitivity. Patch tests play an important role in the assessment of possible immunologic mechanisms underlying cutaneous reactions to drugs.

Activity of acid non-specific esterase (ANAE) in infiltrating lymphocytes in nine patients with mycosis fungoides and four patients with parapsoriasis en plaques was examined in frozen tissue sections. Within the dermal infiltrate 81.7 +/- 6.1% of all lymphocytes contain this enzyme in mycosis fungoides, 74.7 +/- 3.3% in parapsoriasis en plaques. These results correlate well with the percentage of T lymphocytes determined by immunological techniques. Mycosis fungoides may be regarded as an ANAE-positive cutaneous T-cell lymphoma. Because of its simplicity this technique may be of value in further investigations of mycosis fungoides.

Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica are idiopathic, papular eruptions that exhibit certain clinicopathologic similarities to each other and to lymphomatoid papulosis. In order to determine if these disorders are also similar immunologically, we studied the immunopathology of five biopsy specimens from three cases of pityriasis lichenoides et varioliformis acuta and three biopsy specimens from three cases of pityriasis lichenoides chronica. We then compared them to our prior immunohistologic study of nine cases of lymphomatoid papulosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica both exhibited a dermal and epidermal infiltrate of CD4+ and CD8+ T cells expressing activation antigens. These were admixed with numerous macrophages. The lesional epidermis was diffusely human lymphocyte antigen (HLA)-DR+ and contained decreased CD1+ dendritic cells. Endothelial cells were also HLA-DR+. Cells bearing the phenotypes of B cells, follicular dendritic cells, or natural killer/killer cells were essentially absent. Except for the lack of large atypical cells, the results resembled those described previously for lymphomatoid papulosis. These findings indicate that pityriasis lichenoides chronica, pityriasis lichenoides et varioliformis acuta, and lymphomatoid papulosis share several immunohistologic features. Together with certain clinicopathologic similarities, they are consistent with the hypothesis that these three disorders are interrelated.

A monoclonal antibody, OKT 6, has been developed against an antigen which is expressed by immature T cells as part of their normal intrathymic differentiation, but not by mature peripheral T cells. It was though that a search for the expression of such an antigen might be worthwhile in prelymphomatous conditions. This communication describes the investigation of lymphocytic infiltrates of atropic parapsoriasis, lymphomatoid papulosis, and a small group of miscellaneous skin conditions with OKT 6 and the immunoperoxidase technic. OKT 6-positive cells were identified in the dermis in varying numbers in four cases of atrophic parapsoriasis and in one case of lymphomatoid papulosis, but not in any of the other disorders. Positive epidermal staining was noted in all tissues examined. The pattern obtained suggested that epidermal dendritic cells may react with OKT 6. The findings indicate that OKT 6-positive cells may be found outside the thymus in certain conditions. The observations in epidermis cast doubt on the exact nature of the positively reacting cells observed in dermis, suggesting that may either be immature thymocytes or possibly Langerhans cells.

The development of a monoclonal antibody directed against HLA DR (Ia-like) antigens of B cells and monocytes but not against normal peripheral human T cells suggested that this antibody might be used as a marker of B cells and monocytes in tissue sections. The T cell nature of large plaque (atrophic) parapsoriasis has recently been demonstrated by the immunoperoxidase technic. Immunoperoxidase examination of serial sections of tissues from two cases of large plaque parapsoriasis with one T cell antiserum, two monoclonal T cell antibodies, and one monoclonal reagent directed against HLA DR indicated that T cells in the cutaneous infiltrates were also HLA DR-positive. Evidence is accumulating that HLA DR positivity may be expressed by activated T cells. The findings here therefore suggest that many of the T lymphoid cells in two cases of large plaque (atrophic) parapsoriasis examined were activated in nature, and that HLA DR may not be a specific marker for B cells and monocytes in certain pathologic conditions. Caution should therefore presently be exercised in attempting to use this marker for the specific identification of B cells and monocytes in pathologic specimens, without simultaneous testing for T cell markers.

Peripheral blood mononuclear cells obtained from patients with various skin disorders were studied by indirect immunofluorescence using the monoclonal antibodies OKT3, OKT4, and OKT8 which react with human T cells (OKT3+ cells), helper-inducer (OKT4+) and suppressor-cytotoxic (OKT8+) T cell subsets, respectively. In parallel, the balance between peripheral blood helper and suppressor subsets was established by the determination of OKT4+/OKT8+ ratios (helper/suppressor ratios). In patients with the Sézary syndrome, but not in patients with mycosis fungoides or parapsoriasis "en plaques," highly significant increases in the helper/suppressor ratios accompanied by decreased levels of suppressor cells were found compared to controls. T cell imbalance with high helper/suppressor ratios and low percentages of circulating OKT8+ suppressor cells were also observed in patients with atopic dermatitis, lichen planus, or acute sarcoidosis (i.e. patients with erythema nodosum sarcoidosis and bilateral hilar adenopathy). In patients with cutaneous manifestations of chronic graft vs. host diseases, low helper/suppressor ratios and elevated OKT8+ cell levels were observed. T cells and T cell subset enumerations and related helper/suppressor ratios were found to be within normal range in patients with psoriasis, systemic lupus, erythematosus, discoid lupus erythematosus, bullous disorders (bullous pemphigoid, dermatitis herpetiformis, pemphigus vulgaris), and miscellaneous diseases.

Twelve patients with various types of lymphoma were treated with etretinate. The diagnosis included parapsoriasis en plaque, epidermotropic lymphoma (diffuse chronic erythroderma with atypical mononuclear cells, Sézary syndrome or MF tumours) and non-epidermotropic lymphoma. The patients received etretinate in a dose of 0.8 to 1.0 mg/kg/day for 2 to 14 months. No additional therapy was given. Patients with epidermotropic lymphomas stage I and II had a favourable clinical and histological response whereas those with deeply infiltrating tumours remained unresponsive. Patients with parapsoriasis en plaque and poikiloderma showed little response. Of the four patients who discontinued the treatment, three had recurrences after 3 to 4 months but one remained clear. The results obtained with etretinate may equal those obtained with more aggressive treatments.

Thirteen patients with stage I or II mycosis fungoides (MF) and 10 patients with large-plaque parapsoriasis en plaques (PEP) were examined for immunologic and cytogenetic disturbances. Total lymphocyte counts and immunoglobulin concentrations in the blood were normal. In vitro lymphocyte responses to polyclonal activators and various antigens in standard concentrations were normal. However, titration of phytohemagglutinin and concanavalin A (ConA) disclosed significantly lowered responses to suboptimal concentrations in the patient group, most pronounced in patients with MF II. ConA-induced leukocyte migration inhibitory factor (LIF) production, tested in an indirect leukocyte migration inhibitory assay, was low in the patient group. Furthermore spontaneous LIF production in vitro and small amounts of serum LIF were demonstrated in a few patients. The chromosomal banding pattern, sister chromatid exchange, and break frequency were within normal limits except for 3 translocations in the MF group. It is concluded that even in early-stage MF a pathologic function of blood lymphocytes can be demonstrated, when sensitive methods are applied. The findings might be important for monitoring disease activity and effect of treatment.

Skin lesions from 15 patients with mycosis fungoides (MF) and from three with parapsoriasis were studied immunohistochemically with monoclonal antibodies against T cells (Leu 1) and against T-cell subsets (Leu 2a, Leu 3a). Lymphoid cell reactivity was diverse among these sampled cases. In two cases of parapsoriasis and nine of MF, there was a predominance of helper/inducer (Leu-3a-reactive) cells over suppressor/cytotoxic (Leu-2a-reactive) cells. In one case of parapsoriasis and one (advanced tumor stage) of MF, there was suppressor/cytotoxic cell predominance. One case of MF showed strong reactivity for both T-cell subset markers. Four cases of MF (two plaque-stage and two tumor-stage) featured a predominant cell type in the dermis which was nonreactive for all three antibodies. The intraepidermal lymphoid cellularity was Leu-1-reactive in ten cases of MF and two of parapsoriasis. Among these 12 cases, the intraepidermal cellularity was Leu-2a-reactive in four and Leu-3a-reactive in three. The use of such studies of T-cell subsets on in situ cutaneous lymphoid infiltrates may demonstrate a correlation with cytomorphology, clinical stage, and disease prognosis.

Immunoglobulin E was determined in 13 patients with cutaneous lymphoma and in 30 patients with parapsoriasis en plaques. 11 out of the patients with cutaneous lymphomas showed mycosis fungoides. In 8 patients with parapsoriasis en plaques serum IgE was elevated. These patients revealed signs of the premalignant form of parapsoriasis en plaques. In mycosis fungoides elevated IgE is common, but normal levels are found, too.

"Parapsoriasis" is a term used to include a heterogeneous group of conditions, one variant of which, at least, eventuates in mycosis fungoides in a substantial percentage of cases. The T-cell origin of mycosis fungoides is well established. The lack of similar information on lymphoid cell types in parapsoriasis prompted an immunoperoxidase study using a specific antihuman T-cell serum in a group of seven patients with parapsoriasis. Our findings demonstrated a preponderantly T-cell infiltrate in the categories of parapsoriasis examined.

The proportions of suppressor T cells (TG) and helper T cells (TM) were determined in 5 patients with Mycosis fungoides (MF), 4 patients with parapsoriasis en plaques/poikiloderma atrophicans vasculare and 3 patients with generalized chronic dermatitis. All the MF patients showed increased proportions of suppressor T cells, whereas the others did not differ from age- and sex-matched healthy controls.

A monoclonal antibody (OKT10), which was developed recently, reacts with pro-thymocytes, T cell acute lymphoblastic leukemia (ALL) cells, cells in normal bone marrow (including plasma cells), and activated T cells. Tissues from patients with cutaneous T cell lymphoma were studied for the presence of OKT10-reactive cells with the use of an indirect immunoperoxidase technic. OKT10-reactive cells were identified in three of eight cases of mycosis fungoides, one of two cases of Sézary syndrome, with an equivocal reaction in one of ten cases of large-plaque parapsoriasis and in one of seven positive patch tests (allergic contact dermatitis). The biologic and possible clinical implications are discussed.

A review of the literature concerning the pityriasis lichenoides and the study of 34 personal cases show that three main clinical patterns are found in pityriasis lichenoides: maculo-papular, leukomelanodermal, necrotic. The course is very variable: rarely seven weeks, more often seven months and sometimes seven years. The disease is issued from an angiitis including a mostly lymphocytic infiltration. The epidermis is secondarily invaded by inflammatory cells and shows focal parakeratosis. There is no specific immunologic disorder: immunohistopathologic study is generally normal (rarely IgM or C3 deposits); no circulating immune complex is found. Some patients improved with dapsone or photochemotherapy.

The T cell nature of mycosis fungoides and Sézary syndrome was established a decade ago. The recent advent of monoclonal antibodies to T cells and other lymphoid subpopulations has resulted in an explosion of knowledge on the biology of this group of disorders. These reagents have increased our knowledge on thymic differentiation status, pathogenesis, the phenotype of premalignant vs malignant lymphocytic infiltrates, the identification of other previously unrecognized cells within lymphomas, and the phenotype of circulating vs skin lymphocytes. Therapeutic applications may result. These new developments are discussed.

A monoclonal antibody OKT 9 which detects a determinant expressed by a variety of proliferating cell types has been recently developed. This antibody was used in conjunction with the immunoperoxidase technique to study the cutaneous lymphoid infiltrates of nine patients with mycosis fungoides, one patient with lymphomatoid papulosis, two patients with Sézary syndrome, and ten patients with large plaque atrophic parapsoriasis (a condition which may terminate in overt mycosis fungoides.) OKT 9 reactive cells were identified in all cases of mycosis fungoides examined, in one case of lymphomatoid papulosis, one of two cases of Sézary syndrome, and one of ten cases of large plaque atrophic parapsoriasis. These results suggest that further studies using OKT 9 should be performed to assess whether OKT 9 reactivity may be used as a prognostic marker in cutaneous lymphomas and prelymphomas.

Tissues from atrophic large plaque parapsoriasis were examined using the indirect immunoperoxidase technique with a monoclonal T cell antibody as primary antibody, and affinity isolated peroxidase conjugated goat anti-mouse IgG as second stage antibody. The "T" cell nature of the dermal infiltrate and of single exocytic epidermal lymphocytes was demonstrated. The results obtained suggest that the method utilized will be useful for the demonstration of lymphoid cell subpopulations in a variety of cutaneous disorders in which a lymphocytic infiltrate forms a significant component of the histopathology observed. This technique also has the potential of providing information on the topographic localization and differentiation of lymphocytes within the various levels of the skin. Certain technical manipulations which may result in an improvement in the quality of results obtained are also discussed.

We studied the immunohistologic findings of skin biopsy specimens from 21 patients with poikiloderma (14 with mycosis fungoides [MF] and seven with atrophic large-plaque parapsoriasis [ALPP]). Both types of poikiloderma were similar with regard to T-cell antigen expression. In each case, most T cells expressed the CD4+ (helper/inducer) phenotype and lacked Leu-8 antigen. T cells were also deficient in Leu-9 antigen in most cases (MF, 11/14 [79%]; ALPP, 4/7 [57%]). These T-cell antigen deficiencies are similar to those described previously in various types of MF and indicate that such deficiencies are common in minimally infiltrated, patch-stage MF lesions. Because combined Leu-8/Leu-9 antigen deficiencies are uncommon in inflammatory skin diseases, our findings are consistent with the view that ALPP is an early form of MF, as had been suggested previously by results of clinicopathologic studies.

Three unrelated children (one girl and two boys) have had since birth a syndrome characterized by a permanent skin rash which becomes more intense during flare-ups associated with fever, lymphadenopathy, splenomegaly, and arthritis symmetrically involving the large joints. In one boy, typical psoriasis was observed at age 3 years. In two patients, roentgenograms of the joints showed early patellar ossification and an abnormal epiphyseal appearance. The three children also had neurologic involvement, with mental retardation, enlarged head circumference, eye lesions, late closure of the anterior fontanel, and a chronic meningitis with infiltration by polymorphonuclear cells. No immunologic abnormalities were found, but polymorphonuclear cells infiltrated the skin, lymph nodes, synovial fluid, and CSF.

Patients with the skin disorder pityriasis lichenoides et varioliformis acuta (PLEVA) develop recurrent, self-healing papulonecrotic lesions that contain infiltrates of cytologically and antigenically normal T lymphocytes. DNA extracted from the lesions of 3 patients with PLEVA was analyzed for rearrangement of beta-T-cell receptor genes for the purpose of assessing the clonality of T lymphocytes within the tissues of this disease. Lesions from all 3 cases showed clonal gene rearrangements. In each of 2 cases from which two separate lesions were biopsied, identical rearrangements were found in specimens from both sites. DNA from a variety of inflammatory lesions obtained from patients with other types of skin diseases failed to show detectable rearrangements of beta-T-cell receptor genes. These results suggest that PLEVA represents a T-cell lymphoproliferative process, rather than an inflammatory disorder, as had been previously thought.

The authors present a study of behaviour of the late hypersensitivity in fourteen patients carrying parapsoriasis with age varying from 36 to 64 years being nine men and five women with time of the illness development from one to eleven years. There were thirteen white sick people and a yellow one. The parapsoriasis diagnosis was confirmed in all of them clinica and histopathologica. The patients were not getting any therapeutic with corticosteroids or immunosuppressive drugs at the time of study. They were studied immunological through methods in vivo. 1. Methods in vivo. a) Intradermoreactions with the infectious antigens: PPD, trichophytin, levedurin, E. coli. It was used as a control group of fourty normal fellows. b) Sensibility to DNCB. The results obtained allow the following thesis: 1. Low table of positivity to the intradermal reactions to the late reading only one of the antigens tested on the patients (E. coli) related to the others. According to these elements we cannot get at a conclusion for depression of the inespecific cellular immunity in our sick patients. 2. Significant statistics difference on the sensibility test to DNCB on the sick patients related to the controls, a fact which shows a certain degree of the depression of the inespecific cellular immunity. 3. The sick patients with parapsoriasis before taking some treatment should go through the study of a late hypersensitivity.