Roles of CD4+ and CD8+ cells in UVB-induced suppression of splenic alloantigen presenting function

Abstract Whole body ultraviolet light (UV) radiation causes systemic immunosuppression. Splenic antigen-presenting cell (APC) activity is decreased by UV radiation. To determine whether splenic CD4⁺ or CD8⁺ cells are involved in the UV-induced depression of splenic alloantigen presenting function, we investigated the effect of in vivo UV radiation on the splenic stimulatory function in allogeneic mixed lymphocyte reaction in mice after the elimination of CD4⁺ or CD8⁺ cells by administering anti-CD8 or anti-CD4 Ab. Ab-treated and non-treated mice were exposed to UVB radiation (2.5 k.J/m²) twice or eight times. Two exposures to UVB radiation significantly suppressed the splenic alloantigen-presenting function of mice previously treated with anti-CD4 Ab, but hardly affected that of anti-CD8 Ab-treated or non-treated mice 2 days after the last radiation. On the other hand, eight exposures to UVB radiation suppressed this function in all mice. FACS analysis revealed that the UV induced suppression is not associated with a significant decrease in the number of IA⁺ cell, as stimulator cells. It is suggested that CD4⁺ cells are somewhat preventive of the UV-induced depression of splenic alloantigen-presenting function.     

Protracted cutaneous disorders in association with low CD4+ lymphocyte counts

Summary We report two patients with skin disorders usually associated with severe immunosuppression, who had low CD4⁺ lymphocyte counts but normal immunoglobulin levels. The patients were HIV negative, and had CD4⁺ lymphocyte counts just above 300/mm³, but they presented with cutaneous manifestations of profound immunodeficiency. Idiopathic CD4⁺ lymphocyte deficiency is a recently described syndrome which may present with dermatological disease. We discuss the symptom complex of our patients in relationship to the diagnosis of idiopathic CD4⁺ lymphocyte deficiency.     

Active psoriasis and profound CD4+ lymphocytopenia

We report the case of a patient with a long-standing history of widespread chronic plaque psoriasis, who was recently found to have a profound CD4⁺ lymphocytopenia. He is human immunodeficiency virus (HIV) negative. His psoriasis remains active and widespread, and he has had 60 cutaneous malignancies, including many squamous cell carcinomas, excised over the last 10 years. In the past he has had numerous cutaneous viral warts. Despite a low peripheral blood CD4⁺ T-cell count, similar numbers of activated T cells, identified by double labelling for CD4 and HLA-DR antigens, were found in the epidermis of our patient as other individuals with psoriasis. Thus, there appear to be sufficient activated CD4⁺ T cells in our patient's psoriatic plaques to maintain the psoriatic process.     

Selective generation of CD8+ T-cell clones from the peripheral blood of patients with cutaneous reactions to beta-lactam antibiotics

The presence, phenotype, and functional characteristics of peripheral blood penicillin-specific T lymphocytes in individuals with cutaneous allergic reactions to penicillin were investigated using in vitro long-term culture techniques. Peripheral blood mononuclear cells from two penicillin-allergic patients were stimulated in vitro with penicillin, and T-cell blasts were clonally expanded by limiting dilution. Seven T-cell clones were derived, all of which were CD3⁺ CD4^? CD8⁺ HLA-DR⁺, and produced IL-2 and IFN-γ upon stimulation. T-cell proliferation required the presence of antigen and autologous, but not allogeneic, antigen-presenting cells. In addition to the parent compound, the T-cell clones also developed a proliferative response to penicilloyl, the major metabolite of penicillin. The cloned T-cell lines were found to exhibit marked suppressor activity for Con A mitogenesis. The observed suppressor activity required cell-to-cell contact, as supernatants from these T-cell clones had no comparable inhibitory effect. These findings indicate that there is a predominance of penicillin-specific CD8⁺ T cells in the peripheral blood of individuals sensitized to beta-lactam antibiotics.     

CD8+ cytolytic T lymphocytes and the skin

Abstract: T lymphocytes show a special affinity for the skin. Although the roles played by the CD4⁺ population of T lymphocytes in immunodermatology were so far actively investigated, much less is known about the roles played in the skin by CD8⁺ cytolytic T lymphocytes (CTL). The activity of CD8⁺ CTL in the immunodermatological context, however, is likely to be most important; the immuno-biology itself of CD8⁺ CTL, moreover, although far from being fully understood, shows intriguing characteristics. Immunophenotype, function and cytokine profile of CD8⁺ CTL are overviewed in the first section of this review. Phenotypically, not only CD8⁺ CTL can be subdivided into CD8⁺ CD28⁺ CD11b⁺ and CD8⁺ CD28^- CD11b⁺ subsets, but also an up-to-now undetected CD8⁺ CD28^- CD11b^- subset does exist. Functionally, not only “cytotoxic” but even “suppressor” subpopulations have been shown to exert cytolytic capabilities indeed, and “suppression” itself may be due to such a lytic capacity. According to cytokine synthesis, CD8⁺ CTL can be split into Tc1 and Tc2 subsets, each able to influence specific patterns of immune responses. The impact of CD8⁺ CTL in immunodermatology, overviewed in the second section of the current review, is crucial. The pathophysiology of inflammatory dermatoses is deeply influenced by the activity of CD8⁺ CTL: e.g., CD8⁺ CTL within psoriateic epidermis are possibly associated to the persistence of psoriatic lesions not undergoing resolution; on the other hand, in late lesions of lichen planus CD8⁺ CTL predominate, thus explaining presumably both the cytolytic attack against keratinocytes and the modulation of the inflammatory reaction up to the final resolution of the lesions; Tc1 cells are decreased in atopic dermatitis, and such a decrease can account both for IgE overproduction and for development of infections. Finally, CD8⁺ CTL can sustain against cutaneous viruses/tumors cytolytic immune responses not only of secondary but even of primary type, i.e. induced by Langerhans cells/dendritic cells either transfected or pulsed with skin virus/tumor-associated antigens, thus allowing the production of vaccines against cutaneous viral/neoplastic diseases.     

Idiopathic CD4+ lymphocytopenia associated with chronic pruritic papules

This is a case report and family study of a 65-year-old man with chronic prurigo lesions, in whom we demonstrated a selective deficiency of circulating T-helper/inducer lymphocytes (CD4⁺), in the absence of any apparent predisposing disease. He is seronegative for human immunodeficiency virus (HIV types 1 and 2) and human T-cell lymphotropic virus (HTLV-I and HTLV-II), and fulfils the criteria for the syndrome of idiopathic CD4⁺ Tlymphocytopenia. He has an atopic diathesis, has had a severe adult chickenpos infection, chronic staphylococcal infections, tinea pedis and recalcitrant warts. He has also suffered from respiratory infections, for which no specific aetiological agent has been identified. His peripheral total lymphocyte count has been persistently abnormal since it was first measured in 1969. He has a marked CD4⁺ T-cell lymphocytopenia. His son, who does not have any skin disorder, has a low CD4⁺ T-cell count.     

CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators

Summary:  CD30⁺ lymphoproliferative disorders of the skin (CD30⁺ LPD) represent a well-defined spectrum of primary cutaneous T-cell lymphomas which have been recognized as distinct entities in recent lymphoma classifications. Lymphomatoid papulosis and anaplastic large-cell lymphoma share the expression of CD30 antigen as a common phenotypic hallmark but differ in regard to their clinical and histologic features as well as their biologic behavior. This article summarizes the histologic features of CD30⁺ LPD and presents recently identified new clinicopathologic variants of CD30⁺ LPD. There is an increasing number of reactive inflammatory disorders and neoplastic diseases which are composed of or contain a significant number of CD30⁺ cells and mimic LyP or anaplastic large cell lymphoma clinically or histologically. Differential diagnostic considerations focus on other lymphoproliferative processes with CD30⁺ tumor cells as well as non-lymphoid neoplasms and inflammatory simulators. The term CD30⁺ pseudolymphoma is proposed to designate inflammatory processes with CD30⁺ T cells. The final diagnosis of CD30⁺ LPD is based on a synthesis of clinical, histologic, phenotypic, and molecular genetic findings.     

Oral submucosal dendrocytes: factor XIIIa+ and CD34+ dendritic cell populations in normal tissue and fibrovascular lesions

Factor XIIIa+ and CD34+ dendritic cells, believed to be subsets of monocyte/macrophages, have been identified in dermis and in dermal tumors. The purpose of this study was to determine the presence and distribution of analogous cell types in oral submucosa and oral fibro-vascular lesions. Antibodies to XIIIa, CD34, S-100 protein, and macrophage antigen (MAC 387) were tested on formalin-fixed, paraffin-embedded tissue sections from normal mucosa, peripheral fibroma (PF), peripheral ossifying fibroma (POF), peripheral giant cell granuloma (PGCG), pyogenic granuloma (PG), lymphangioma (La), benign fibrous histiocytoma (BFH), idiopathic histiocytosis (IH), angiofibroma (Af) using an ABC immunoperoxidase technique. Numbers of positively stained cells were compared to unstained cells in the tumors. XIIIa positive submucosal dendrocytes (CD34-, S-100-, MAC 387-) were found in abundance in normal tissue in characteristic distributions: collagen-associated, vessel-associated, and lymphoid-associated. The percentage of XIIIa+ cells in the oral tumors was as follows: PF: 10-30%, POF: 5-10%, PGCG: 0-5%, PG: 5-20%, La: 0%, BFH: 5-25%, IH: 0%, and Af: 10-20%. CD34+ dendrocytes (XIIIa-, S-100-, MAC 387-) were few in number and were found in deeper submucosa, especially around skeletal muscle. Other than blood vascular endothelium, CD34+ cells were not generally seen in the oral tumors studied. It is concluded that two previously unrecognized dendrocyte populations reside in normal submucosa. XIIIa+ cells participate in the formation of some oral reactive and neoplastic lesions.     

T6+ and HLA-DR+ cell numbers in epidermis of immunosuppressed renal transplant recipients

The increased susceptibility of the skin of chronically immunosuppressed individuals to viral infections and sunlight-induced malignancies suggests specific drug-induced, dysfunction of local immune mechanisms within the sun-exposed skin of these individuals. To help understand the effect of immunosuppressive therapy alone in the absence of ultraviolet light on the immune system of skin, biopsies were collected from non-sun-exposed buttock skin of control, healthy volunteers and kidney transplant recipients immunosuppressed with either azathioprine/prednisone or cyclosporin A/prednisone and examined for incidences of T6+, and HLA-DR+ cells. No significant differences in the incidences of these 2 cell types were found (a) between control individuals and transplants recipients, (b) between transplant recipients receiving either of the immunosuppressive drug regimes, or (c) between transplant recipients who either had or had not developed skin cancer.     

Phenotypic analysis of CD23+ peripheral blood mononuclear cells in atopic dermatitis

There is an increase in the number of CD23+ cells in peripheral blood mononuclear cells (PBMC) in atopic dermatitis (AD). We analysed the subpopulation of CD23+ PBMC in 11 patients with AD and in 10 healthy controls and found that B cells (CD20+) and non-T, non-B cells (CD3- CD20-) (mainly monocytes) were responsible for the elevation of CD23+ cells. CD23+ T cells (CD3+) comprised only 4.6% of total CD23+ cells in AD. The percentage of CD23+ cells did not correlate with the serum log IgE level nor with clinical severity of AD. Interleukin 4 (IL-4) induced the expression of CD23 antigen in PBMC both in AD and in healthy controls in a dose-dependent manner in vitro. This enhancing effect of IL-4 was completely abrogated by the addition of anti-IL-4 monoclonal antibody. Other cytokines such as IL-1, IL-2, IL-3, IFN-alpha, IFN-gamma and TNF-alpha had no significant effects on CD23 expression.     

Selective activation of circulating CD4+ lymphocytes in severe adult atopic dermatitis

An analysis of peripheral blood lymphocyte subsets and their expression of activation markers was performed using flow cytometry in 12 adult patients with severe atopic dermatitis, and compared with 14 normal individuals. Repeated measurements were made over an 8-week period during which disease activity was also assessed. Increased percentages of activated and unactivated CD4+ lymphocytes, and decreased percentages of CD8+ cells were observed in atopic dermatitis. Increasing disease activity was associated with an increase in the proportion of activated and unactivated CD4+ lymphocytes and a fall in the proportion of CD8+ cells. This study demonstrates that in adults with severe atopic dermatitis, increasing disease activity is associated with selective activation of CD4+ lymphocytes and a relative expansion of the CD4+ cell subset.     

Flow cytometric analysis and sorting of HLA-DR+CD1+ Langerhans cells

There is a considerable need for reliable methods for enumeration and enrichment of Langerhans cells (LCs), since they continue to be the subject of intensive investigation in normal and diseased skin. It has been claimed that standard labelling with either anti-HLA-DR or OKT6 antibodies alone may fail to identify potentially important subsets of LCs with the phenotypes HLA-DR+CD1- and HLA-DR-CD1+. We report here on flow cytometric analysis of suction blister-derived normal epidermal cell (EC) suspensions, double stained with phycoerythrin-conjugated anti-HLA-DR and fluoresceinated OKT6. In seven separate experiments, no evidence for the existence of either HLA-DR+CDI- or HLA-DR-CDI+ ECs was obtained. We found that HLA-DR+CDI+LCs, which constituted a mean of 2.5% (+/- 0.3 SEM) of all ECs, could be readily identified on the basis of fluorescence, and that their light scatter characteristics were those of moderately sized cells of low granularity. We further describe our method for flow cytometric enrichment of such HLA-DR+CDi+ LCs for functional studies, based on selection on both fluorescence and light scatter criteria. Enrichment is to greater than 90% purity, and the method is applicable to the small number of ECs (approximately 1 x 10(6] obtained from a suction blister.     

Primary cutaneous CD30+ anaplastic large-cell lymphomas mimicking keratoacanthomas

Primary cutaneous anaplastic large cell lymphoma (ALCL) may be associated with keratoacanthoma (KA)-like epithelial hyperplasia and dense eosinophilic and neutrophilic infiltrates. Diagnosis in such cases is challenging both clinically and histologically, because the large atypical lymphoid cells may be obscured by the massive infiltrate of eosinophils and neutrophils, or confused with invasive squamous cell carcinoma or KA. We recently encountered two cases of CD30+ ALCL presenting with a KA-like tumour on the eyelid and nose, respectively. One showed features of KA histologically, with marked tissue eosinophilia and neutrophilia.     

Lymphoma- and leukemia-associated cutaneous atypical CD30+ T-cell reactions

Cutaneous CD30+ lymphoid infiltrates appear cytologically atypical and occasionally may be misinterpreted as recurrent disease when they occur in patients treated for other primary hematologic malignancies. We recently encountered two such cases and present our findings. One patient with B-cell lymphoma and another with myeloid leukemia developed cutaneous eruptions after chemotherapy displaying highly atypical perivascular lymphoid cells on histology that mimicked recurrent disease. In both cases, the lymphocytes were CD30+ T cells by immunohistochemistry. The skin lesions spontaneously resolved and have not recurred. Because one case was initially misinterpreted as recurrent leukemia, we conclude that close clinical correlation and immunophenotypic confirmation should be done for atypical cutaneous lymphoid infiltrates in patients with primary hematologic malignancies. We discuss the differential diagnosis of atypical CD30+ infiltrates in this setting, which include recurrent lymphoma or myeloid leukemia, primary cutaneous anaplastic large cell lymphoma (ALCL), lymphomatoid papulosis (LyP), carbamazepine-induced CD30+ pseudolymphoma, viral infection and an atypical eruption of lymphocyte recovery.     

Detection of Epstein-Barr virus in cutaneous and lymph nodal anaplastic large cell lymphomas (Ki-l+)

Summary Epstein-Barr virus (EBV) is a gamma DNA herpes virus which is thought to play a part in the pathogenesis of some non-Hodgkin's lymphomas in individuals with or without immunodeficiency. We investigated 16 lymph nodal and 12 cutaneous anaplastic large cell lymphomas (ALCLs) (Ki-1 ⁺), all of which were in patients without immunodeficiency, for the presence of EBV genomes. The highly sensitive polymerase chain reaction (PCR) technique was employed for detection of viral DNA in extracts from formalin-fixed, paraffin-embedded tissue sections. In addition, we performed radioactive and non-radioactive in situ hybridization (ISH) for localization of EBV at the single cell level. EBV-DNA was demonstrated by PCR in five cases of nodal ALCLs (31 %). All cutaneous ALCLs were negative. EBV-encoded small nuclear RNAs (EBERs) could be identified by ISH in the tumour cells of one of the five EBV-DNA-positive patients. Our results further support the concept that EBV may be involved in the development of a proportion of nodal ALCLs, hut not in cutaneous ALCLs.     

CD8+ cutaneous anaplastic large-cell lymphoma: report of two cases with immunophenotyping, T-cell-receptor gene rearrangement and electron microscopic studies

Two cases are reported of cutaneous anaplastic large-cell lymphoma with the suppressor/cytotoxic (CD8) phenotype. In both cases there was a solitary skin tumour in which there was a dense infiltrate with large irregularly shaped cells which on immunophenotyping expressed CD8. DNA hybridization analysis showed rearrangements of the T-cell-receptor gene in both cases.