Blood, Vol. 90 No. 1 (July 1), 1997:
pp. 472b-473
CORRESPONDENCE
Cutaneous T-Cell Lymphomas and Bacterial Superantigens
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LETTER |
To the Editor:
Epidermotropic cutaneous T-cell lymphomas (CTCL), ie, mycosis fungoides (MF ) and Sezary syndrome (SS), result from the malignant, clonal lymphoproliferation of cells exhibiting at their surface the CD3+CD4+ phenotype of mature helper/inducer T cells.1 The expression by most Sezary cells of the T-cell receptor (TCR) 
heterodimer and the presence at their surface of the CD45RO marker of memory T cells raised the hypothesis that an antigen-specific stimulation of Sezary cells could be involved in the pathogenesis of CTCL.2 In this field, Jackow et al3 recently reported the results from a study addressing the immunopathogenic role of staphylococal superantigens in CTCL. As it is widely known by clinicians that infection of the skin may exacerbate exfoliation and erythema in patients with MF/SS, the purpose of this study is of interest. However, the methodology used in this work and some of the authors' conclusions appeal specific comments and criticisms. First, the investigators claimed that they showed evidence for an oligoclonal expansion of V2+ T cells in the skin samples from MF/SS patients showing a cutaneous infection with Staphylococcus aureus strains producing toxic shock syndrome toxin-1 (TSST-1), a toxin with superantigenic properties which selectively stimulate TCRV2-bearing CD4 lymphocytes. Considering that the V family-specific reverse transcriptase-polymerase chain reaction (RT-PCR) is only a semi-quantitative method, it appears that the relative expression of V2 in the skin from infected patients does not differ significantly from the one observed in the noninfected subgroup, or neither with the levels evidenced in the normal skin from controls. Indeed, it would have been warranted to correlate the results from the RT-PCR analysis with those obtained by using immunostaining techniques with anti-V2 monoclonal antibodies, which would allow a more quantitative evaluation together with a statistical analysis of the V2 representation in both the skin and the blood compartments.4
Furthermore, we5 and other investigators4 have shown that differently from a classical antigen-specific immune response, superantigen dependent T-cell expansions exhibit a high diversity of the TCR V-D-J junctional segments in terms of amino acid length and protein sequence. Because the RT-PCR amplification of the V-C junctional segments does not allow to assess the diversity of this hypervariable, so-called complementary determining region 3 (CDR3), but only indicate the repertoire of V segments used by the T-cell infiltrate, we believe that the data from Jackow et al failed to show that the representation of the V2 subset was driven by a superantigenic stimulation.
Another important question is whether a superantigen is able to induce the activation of malignant cells in patients with CTCL. Functional in vitro studies have been hampered by the difficulty to expand Sezary cells by using classical mitogenic stimulations, contrasting with the proliferation of V2-expressing T cells from patients with SS induced by TSST-1.6 However, because there was no determination of the V segment used by the malignant clone in Jakow's study, the V2 subset might include both normal and tumoral cells. Indeed, the use of clonotypic tools such as CDR3 length analysis and CDR3 sequencing is warranted to evaluate the contribution of tumoral cells to the proliferative response toward a bacterial superantigen.5
Finally, the lack of a biased usage of V segments by Sezary cells emphasizes that a common superantigenic, chronic stimulation is not involved in the initiation of MF/SS.7 Even though these data do not rule out the possibility that bacterial superantigens might be involved in the exacerbation of the Sezary cell expansion and/or the cutaneous inflammation observed in patients with CTCL, further investigations are warranted to address these hypotheses.
Philippe Musette
Unité de Biologie Moléculaire du Gène INSERM U277
Hervé Bachelez
Institut de Recherche sur la Peau Hopital Saint-Louis Département d'Immunologie Institut Pasteur Paris, France
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REFERENCES |
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Response
The comments made by Musette and Bachelez regarding CTCL and Staphylococcus infections (Jackow et al, Blood 89:32, 1997) are excellent and very appropriate. Their recommendations for further research into this area are certainly planned and the work done was a prospective and preliminary pilot survey to determine the prevalence of Staphylococcus strains found in CTCL patients. We disagree that clinicians are widely aware of the role played by Staphylococcus infections worsening the disease. We documented for the first time that certain TSST-1 strains may be important.
As these authors are aware, there are many ways to study the T-cell repertoire in CTCL lesions. As this was our first venture into defining T-cell clones, we chose the technique that is one generally accepted in the literature for most T-cell-mediated, autoimmune disease surveys of the T-cell repertoire. We agree that further studies using antibodies, sequencing, and distinguishing the "malignant" from "benign" clones would be desirable. However, have these commenting authors been able to define when a clonal T-cell expansion becomes a malignant clonal T-cell expansion? Techniques that are too specific may overemphasize or over-represent certains clones which are then assumed to be "malignant." The cumulative genetic mutations which take a clone of T cells to "malignancy" in CTCL have yet to be determined. Our technique looked at the proportional representation of all the clones and found oligoclonal expansion in most patients. We believe that this is a new finding which others have seen, but not reported, because of their faith in the presence of "the malignant clone." We did not state that V2 was the malignant clone but that it was overexpanded only in Sezary patients who had associated TSST-1 Staph.
We disagree that the lack of biased usage of V segments implies lack of a common superantigen stimulation. We showed that many different Staph superantigens are found in CTCL patients and, furthermore, that V2 over-expansion was limited to CTCL patients with TSST-1+ organisms and was not seen in patients with other toxins. Only one control showed increased V2 TCR in skin and two in blood. From a survey of the literature on reported TCR V usage in CTCL, it would appear that the majority of variable gene segments able to respond to superantigens (ie, V 2,5.1,6,8,) are overrepresented in these studies (see references for Table 4). If CTCL is a disease of antigen persistence, as suggested by Tan, then skin flora (also present in normals) may be one antigen capable of persistent stimulation.
Clotilde M. Jackow
Madeleine Duvic
Department of Dermatology University of Texas Medical School Section of Dermatology Department of Medical Specialties MD Anderson Cancer Center Houston, TX
