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Human interferon-g inducible protein-10 (IP-10), a small basic protein secreted by interferon (INF)-g stimulated keratinocytes, is chemotactic for normal CD4-positive lymphocytes and inhibits early normal and leukemic hemopoietic progenitor proliferation. Cutaneous T-cell lymphoma (CTCL) is an indolent CD4-positive lymphoma characterized by multipl...
Citations
... Chemokines are believed to have an important pathogenetic role in CTCL, as chemokines and their receptors are crucial for homing of malignant T cells and immune cells to the skin (de Masson et al., 2022, Geskin et al., 2014, Stolearenco et al., 2020, Wu et al., 2009. Pionering studies in the 1990's indicated that the Interferon-gamma (IFNγ)-inducible chemokine CXCL10 (IP10) plays a key role in homing of CD4 T cells to the epidermis (Sarris et al., 1996, Sarris et al., 1995, Tensen et al., 1998, a phenomenon named epidermotropism, which is a characteristic feature of CTCL (Edelson, 1980). Later investigations have revealed that numerous other chemokines and chemokine-receptors are also involved in the pathogenesis of CTCL (reviewed in (de Masson et al., 2022, Stolearenco et al., 2020, Wu et al., 2009. ...
... In addition, we show that S. aureus Pt culture supernatants induced selective expression of IFNγ and IFNγ-inducible CXCL10 in healthy skin. Since CXCL10 is known to play a key role in CD4 T cell epidermotropism (Sarris et al., 1996, Sarris et al., 1995, Tensen et al., 1998, we hypothesize that this could be a novel mechanism by which S. aureus modulates the TME J o u r n a l P r e -p r o o f and potentially promotes disease progresion and, consequently, another potential benefit from endolysin-mediated removal of S. aureus from lesional skin. Similar to antibiotics, resistance against bacteriophages exists. ...
Staphylococcus aureus (S. aureus) is suspected to fuel disease activity in cutaneous T cell lymphomas (CTCL). Here we investigate the effect of a recombinant, anti-bacterial protein, endolysin, XZ.700, on S. aureus skin colonization and malignant T cell activation. We show that endolysin strongly inhibits proliferation of S. aureus isolated from CTCL skin and significantly decreases S. aureus bacterial cell counts in a dose-dependent manner. Likewise, ex vivo colonization of both healthy and lesional skin by S. aureus is profoundly inhibited by endolysin. Moreover, endolysin inhibits the patient-derived S. aureus induction of Interferon-gamma (IFNγ) and IFNγ-inducible chemokine CXCL10 in healthy skin. Whereas patient-derived S. aureus stimulates activation and proliferation of malignant T cells in vitro through an indirect mechanism involving non-malignant T cells, endolysin strongly inhibits the effects of S. aureus on activation (reduced CD25 and STAT5 phosphorylation) and proliferation (reduced Ki67) of malignant T cells and cell lines in the presence of non-malignant T cells. Taken together, we provide evidence that endolysin XZ.700 inhibits skin colonization, chemokine expression, and proliferation of pathogenic S. aureus, and blocks their potential tumor-promoting effects on malignant T cells.
... 2,12 IP-10, secreted by interferon-g-stimulated keratinocytes, results in ampli®cation of T-cell expansion and epidermotropism of the resulting in®ltrate. 12 Thus, cytologic atypia of the in®ltrating T cells are the sole reliable histologic feature for distinguishing MF from psoriasis or in¯ammatory dermatoses. ...
Mycosis fungoides (MF) may evolve from pre-existing chronic atopic or psoriasiform dermatitis and the histology can be equivocal. Early patch and plaque lesions of MF may evolve into tumors, disseminate to lymph nodes, bone marrow, and internal organs, and/or undergo transformation to a large cell size.
A patient with a history of "atopic dermatitis" followed by "psoriasis" rapidly developed exfoliative erythroderma and axillary lymphadenopathy following treatment with cyclosporine. At presentation, biopsy specimens of skin lesions and lymph nodes and staging were obtained. We present the treatment and follow-up of this patient and review the medical literature for similar cases.
Multiple skin biopsy specimens from lesions revealed changes consistent with low-grade, cutaneous, T-cell lymphoma (MF) without evidence of large cell transformation and psoriasiform epidermal hyperplasia. CD30+ large cell transformation was present in the lymph node. Adenopathy and erythroderma resolved without systemic therapy following discontinuation of cyclosporine and treatment with psoralen/ultraviolet A (PUVA), isotretinoin, interferon-alpha, and antimicrobials.
This case documents a close relationship between atopy, psoriasis, and the development of cutaneous T-cell lymphoma, and illustrates that an immunosuppressive agent, cyclosporine, can dramatically alter the course of the disease.
... Of the known chemokine receptors, CXCR3 is a likely candidate to mediate chemotaxis of lymphocytes into the epidermis given that its 3 chemoattractant ligands, Mig, IP-10, and I-TAC, are known to be expressed highly in the epidermis and functionally active in a wide subset of T cells. 9,11,[19][20][21][22] Furthermore, there is evidence that the levels of IP-10 expression in the epidermis of patients with MF may be increased differentially, possibly induced by interferon-gamma and tumor necrosis factor alpha produced by lymphoma cells. 21 In this model, as the tumor undergoes transformation and loss of CXCR3 expression, cells no longer would be attracted to the epidermis via keratinocyte-produced IP-10/Mig/I-TAC. ...
Three chemokines, Mig, IP-10, and I-TAC, are expressed highly in the epidermis. We examined the expression of the receptor for these chemokines, CXCR3, in cutaneous T-cell lymphoma. We compared CXCR3 expression with that of cutaneous lymphocyte antigen (CLA) and the activation marker CD30. CXCR3 was expressed by at least a subset of tumor lymphocytes in all 25 cases of low-grade mycosis fungoides (MF), with most cells positive in 20 cases. In progressed or transformed MF, CXCR3 expression was noted in 5 of 22 cases. In 4 of 5 MF cases with sequential biopsy specimens, large cell transformation was accompanied by loss of CXCR3 expression. In contrast, CLA was expressed in 35 of 42 MF cases with no significant differences in expression level between low-grade and transformed cases. In other lymphomas, CXCR3 was expressed in 4 of 4 cases of lymphomatoid papulosis, 3 of 4 cases of CD8+ cutaneous T-cell lymphoma, and 3 of 6 cases of systemic T-cell lymphoma in skin, but not in 10 cases of cutaneous anaplastic large cell lymphoma. CXCR3 expression was associated with epidermotropic T-cell tumors but was largely absent in dermal-based tumors. This phenotypic change likely influences the loss of epidermal localization.
... We have previously reported on 2 patients in whom CTCL developed within months after cardiac bypass surgery; these patients were also negative for exposure to HTLV-1. 12 In a previous study, 13 we found no evidence of infection with HTLV-1 in 19 patients with mycosis fungoides, as indicated by the absence of the tax gene on polymerase chain reaction. Others 14 have confirmed this finding. ...
Mycosis fungoides, an uncommon form of cutaneous T-cell lymphoma, arises in the skin and frequently progresses to generalized lymphadenopathy Although the cause of cutaneous T-cell lymphoma is unknown, chronic immunosuppression may play a role. A few cases have been reported in renal transplant recipients; however, ours appears to be the 1st report of cutaneous T-cell lymphoma in a cardiac transplant recipient. In our patient, cutaneous manifestations of the disease were noted less than 1 year after transplantation. Seven years after transplantation, Sézary syndrome, a variant form of mycosis fungoides, was diagnosed by tissue biopsy and flow cytometry analysis. Photopheresis improved symptoms but was not well tolerated because of hemodynamic sequelae. Psoralen and ultraviolet A therapy also improved the patient's skin condition, but a generalized lymphadenopathy developed. The maintenance immunosuppressive regimen was changed from cyclosporine (3 mg/kg/day) and azathioprine to cyclosporine (1.5 mg/kg/day) and cyclophosphamide. Although effective in the short-term, the results of this therapeutic strategy could not be fully evaluated because the patient died of acute myocardial infarction.
... IP-10 staining was diffuse and not localized to focal keratinocytes. It was similar in intensity and pattern to IP-10 staining in the epidermis of psoriasis (24) and mycosis fungoides (17,25,26). IP-10 is hypothesized to recruit and stimulate helper T cells. ...
... Biopsies were stained using an LSAB DAKO kit, DAKO chromagen, and the appropriate primary antibody. IFNg staining was first enhanced by antigen retrieval (methods) MagnificationΩ20¿1.25. Scale bar shown in part (a) equals 100 mm. ...
AIDS is known to cause a shift of cytokines in the periphery. However, predominant cytokines in skin of patients with HIV-associated skin diseases have not been clearly defined. We hypothesized that there are distinct cytokine profiles that distinguish among the different clinical manifestations of AIDS-related skin diseases. To test this hypothesis, lesional and non-lesional skin was biopsied from 53 HIV+ patients with Kaposi's sarcoma (KS), psoriasis, and pruritus due to eosinophilic folliculitis, and from HIV negative controls with psoriasis or KS prior to therapy. Immunohistochemistry was performed with antibodies to tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, interferon (IFN)-gamma, and interferon-inducible protein (IP)-10. HIV positive individuals included 10 with psoriasis, 14 with pruritus, and 15 with Kaposi's sarcoma. HIV negative controls included 12 with psoriasis and two with KS. Semi-quantitative analysis of cytokine staining was confirmed by optical density using a digital imaging system on four representative skin sections from each disease. Optical density analyses were conducted using ANOVA and t-tests. We found that epidermis overlying HIV+ Kaposi's sarcoma was hyperproliferative and was highest in IP-10, IFN-gamma, and IL-10 (P=0.0001). HIV+ pruritus was significantly highest in TNF-alpha (P=0.0001) staining. HIV+ psoriasis represented an intermediate state for all four cytokines. Normal skin adjacent to lesions showed the same relative patterns, with lower intensities. Skin diseases seen frequently in the setting of HIV and immunodeficiency have relatively distinct levels and patterns of cytokine expression that may reflect immune dysfunction, reactivity to HIV and to opportunistic infections.
Background:
Substantial clinicohistologic overlap exists between lupus erythematosus profundus (LEP) and lymphomas involving the subcutis, including subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and primary cutaneous gamma/delta T-cell lymphoma (GDTCL). Unequivocal markers separating the entities are not established.
Objectives:
To explore the usefulness of interferon alpha (INF-α)-induced protein, myxovirus resistance protein 1 (MxA), in the differential diagnosis of these entities, as studies show that the expression pattern of MxA follows the distribution of the inflammatory infiltrate in cutaneous lupus, while INF- α is not known to operate in lymphoma.
Materials and methods:
MxA immunohistochemistry was performed on skin biopsies from 5 patients with a clinical and histological diagnosis of SPTCL, 9 patients with GDTCL and 9 patients with LEP.
Results:
In SPTCL and GDTCL, MxA was primarily seen in macrophages and generally did not exceed 20% of the infiltrate. In contrast, a significant portion of the subcutaneous infiltrate was positive for MxA in LEP, with 50% of the infiltrate staining on average. A greater number of macrophages and lymphocytes stained with a greater intensity as well (P<0.001). Moreover, endothelial cell staining was uniquely identified in LEP but not in lymphoma.
Conclusion:
Although specificity is not 100%, minimal staining of MxA is a predictor for SPTCL or GDTCL. Conversely, extensive staining for MxA both qualitatively and quantitatively is a feature of LEP. Endothelial staining also appears to be specific for LEP.
Kutane T-Zell-Lymphome sind lymphoproliferative klonale Hauterkrankungen, deren Pathogenese noch weitgehend unbekannt ist.
In den letzten Jahren haben wir neue Erkenntnisse gewonnen, die auf die Bedeutung von Zytokinen und Chemokinen im spezifischen
Hautmilieu hinweisen. Bei diesen Erkrankungen, die von T-Helfer-2-Zellen ausgehen, wäre Interferon-γ zur Eindämmung der Lymphoproliferation
sehr wirksam, wenn die klonalen T-Lymphozyten nicht gegen Interferon resistent wären. Diese Interferonresistenz kann möglicherweise
zur Behandlung der Erkrankungen eingesetzt werden.
Cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative skin disorders whose pathogenesis is poorly understood.
Cytokines and chemokines are important factors which can modify the cutaneous microenvironment allowing the accumulation of
lymphocytes. Most of these neoplasms seem to be T helper-2 cells. While interferon gamma is the natural inhibitor of clonal
T-cell proliferations, interferon resistance has been recently found in these cells. This interferon resistance may be an
Achilles heel that can be targeted by molecular therapeutic interventions.
We have previously shown that Interferon-Inducible Protein-10 (IP-10), a cytokine chemotactic for CD4-positive lymphocytes, is overexpressed by lesional epidermal keratinocytes and probably accounts for the epidermotropism of cutaneous T-cell lymphoma (CTCL). The tax gene of human T-lymphotropic virus-I (HTLV-I) immortalizes CD4-positive lymphocytes, induces IFN-gamma, and has been detected in patients with classical CTCL who are seronegative for HTLV-I. TNF-alpha is synergistic with IFN-gamma for the induction of IP-10. We therefore decided to define the presence of tax, IFN-gamma, TNF-alpha, and IP-10 in lesions of 19 adults with classical CTCL who were seronegative for HTLV-I. Lesional mRNAs for actin, TNF-alpha, IFN-gamma, and tax were detected by reverse-transcriptase polymerase chain reaction (RT-PCR) amplification. In addition IP-10, TNF-alpha, and IFN-gamma were detected and localized with immunocytochemistry of frozen sections. In agreement with previous observations IP-10 was overexpressed in lesional keratinocytes of all 19 patients. By RT-PCR, mRNA for IFN-gamma was detected in lesions of 8, and for TNF-alpha in lesions of 13 patients. By immunocytochemistry, TNF-alpha was expressed by lesional keratinocytes in 10 of 13 tested patients, whereas IFN-gamma was focally expressed by lesional lymphocytes and faintly by lesional keratinocytes in 9 of 13 tested patients. tax mRNA was not detected in lesions of any patient, but was easily detectable in cutaneous lesions or peripheral blood of control patients who were seropositive for HTLV-I. We conclude that TNF-alpha and IFN-gamma may cause epidermotropism by inducing IP-10. However, the tax gene of HTLV-I does not appear to be involved in the pathogenesis of classical CTCL.
