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Biologic Effects of Bacterial Superantigens in a Xenogeneic Transplantation Model for Psoriasis

      Both clinical as well as experimental data support the concept of psoriasis being a T-cell-mediated immune disease possibly triggered by bacterial superantigens. Further analysis of its pathogenesis was facilitated by the generation of a xenogeneic transplantation model in which skin from psoriatic patients is grafted onto SCID mice lacking functional B and T cells. Applying this model it was demonstrated that psoriasis can be triggered by bacterial superantigens; this process depends on the presence of immunocytes. Mutated variants of the respective superantigens exhibiting no measurable affinity to HLA class II molecules can function as competitive inhibitors in vivo.

      Keywords

      Psoriasis as an “infectious disease”

      Although psoriasis is considered a T-cell-mediated (auto-)immune disease, increasing evidence suggests an important role for bacteria in its initiation. Exacerbation has been reported upon colonization with Staphylococcus and Streptococcus, and especially acute guttate psoriasis is frequently associated with bacterial infection. Moreover, treatment with antibiotics is known to have a beneficial effect in psoriasis. Among the potential pathogenic factors triggering the onset of psoriasis during an infection with gram-positive bacteria are superantigens. These molecules are characterized by their ability to activate T cells that share defined T cell receptor V β-segments. Superantigens are distinct with regard to the set of V β-segments they can interact with. The portion of the T cell repertoire activated by any given superantigen lies in the range of 10%. Thus, a pronounced shift in the V β-repertoire of responding T cells is expected to occur. Such a shift has indeed been reported by Leung et al in acute guttate psoriasis (
      • Leung D.Y.M.
      • Walsh P.
      • Giorno R.
      • Norris D.A.
      A potential role for superantigens in the pathogenesis of psoriasis.
      ), whereas the T cell receptor repertoire in fully established plaque-stage psoriasis is more in line with a conventional antigen present as prolonged T cell stimulus (
      • Prinz J.C.
      • Vollmer S.
      • Boehncke W-H.
      • Menssen A.
      • Laisney I.
      • Trommler P.
      Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris.
      ). To investigate the nature of the T cell stimulus in psoriasis more directly, a suitable animal model was needed.

      A scid-hu xenogeneic transplantation model for psoriasis

      Animal models are widely used in basic and applied biomedical research. Although complex by nature they often meet the criteria of controlled manipulation of the parameters of interest. In this regard the introduction of the knockout and transgenic technology allowed the generation of animal models representing powerful tools to define the biologic role of genes, gene products, and cell populations. This approach, however, has two shortcomings: (i) frequently, manipulation of a single gene results in a highly complex phenotype prompting more questions than the generation of the respective animal answered; and (ii) by definition polygeneic diseases cannot truly be modeled by the manipulation of a single gene.
      An alternative to knockout or transgenic animals is the generation of hosts suitable for accepting xenogeneic transplants, e.g., cells or organs. In 1983, Bosma et al described the autosomal recessive scid mutation resulting in the inability to genetically rearrange the receptors of the specific immune system, namely the immunoglobulins and the T cell receptors (
      • Bosma G.C.
      • Custer R.P.
      • Bosma M.J.
      A severe combined immunodeficiency mutation in mouse.
      ). These SCID-mice lacking functional B and T cells are suitable recipients for xenografts. Consequently, SCID-hu xenotransplantation systems have been used in many fields of research investigating basic principles in biology as well as complex pathomechanisms of defined diseases (
      • Boehncke W-H..
      The SCID-hu xenogeneic transplantation model: complex but telling.
      ).
      Normal human skin grafted onto SCID mice maintains its architecture for a long time and many structures remain to be of human origin (
      • Kaufmann R.
      • Mielke V.
      • Reimann J.
      • Klein C.E.
      • Sterry W.
      Cellular and molecular composition of human skin in long-term xenografts on SCID mice.
      ;
      • Yan H-C.
      • Delisser H.M.
      • Pilewski J.M.
      • Murphy G.F.
      • Herlyn M.
      • Albelda S.M.
      Human/severe combined immunodeficiency mouse chimeras: an experimental in vivo model system to study the regulation of human endothelial cell-leukocyte adhesion molecules.
      ). Application of this model in the field of psoriasis research became feasible after it was shown that lesional as well as nonlesional skin from patients could be transplanted and retained clearly distinct phenotypes (
      • Boehncke W-H.
      • Sterry W.
      • Hainzl A.
      • Scheffold W.
      • Kaufmann R.
      Psoriasiform architecture of murine epidermis overlying human psoriatic dermis transplanted onto SCID mice.
      ;
      • Nickoloff B.J.
      • Kunkel S.L.
      • Burdick M.
      • Strieter R.M.
      Severe combined immunodeficiency mouse and human psoriatic skin chimeras: validation of a new animal model.
      ).

      Biologic effects of bacterial superantigens in the scid-hu xenogeneic transplantation model for psoriasis

      To investigate whether bacterial superantigens are capable of triggering psoriasis we grafted nonlesional skin from psoriatic patients onto SCID mice. Subsequently, the staphylococcal superantigen exfoliative toxin was repetitively injected intradermally into the grafts to mimick chronic infection with staphylococci (Figure 1). In addition, the patients' peripheral mononuclear cells were stimulated in vitro with the respective superantigen and subsequently injected intraperitoneally into the mice. This protocol resulted in the manifestation of psoriasis in nonlesional skin from psoriatic donors, whereas no changes in the appearance of the grafts was noted in skin from healthy donors (
      • Boehncke W-H.
      • Dressel D.
      • Zollner T.M.
      • Kaufmann R.
      Pulling the trigger on psoriasis.
      ). These observations – namely the dependency of this effect from the presence of immunocytes preactivated by cytokines and staphylococcal superantigens – were confirmed by
      • Wrone-Smith T.
      • Nickoloff B.J.
      Dermal injection of immunocytes induces psoriasis.
      .
      Figure thumbnail gr1
      Figure 1Following transplantation onto SCID mice psoriasis can be triggered in human grafts from nonlesional skin by repetitive intradermal injections of bacterial superantigens along with intraperitoneal injections of activated immunocytes.
      Regarding the biologic effects of bacterial superantigens two scenarios are possible. The effects seen could either be intrinsic properties of the respective superantigens, or they could depend on the environment. The former point of view is supported by evidence for the involvement of staphylococcal superantigens in the pathogenesis of atopic dermatitis (
      • Leung D.Y.M.
      Atopic dermatitis: immunobiology and treatment with immunomodulators.
      ), whereas streptococcal superantigens are thought to be more relevant for the pathogenesis of psoriasis (
      • Leung D.Y.M.
      • Walsh P.
      • Giorno R.
      • Norris D.A.
      A potential role for superantigens in the pathogenesis of psoriasis.
      ). Whether this association is indeed so strict is still a matter of debate, because at least with reference to psoriasis reports on the presence of a T cell infiltrate primarily responsive to streptococcal superantigens (
      • Baker B.S.
      • Bokth S.
      • Powles A.
      • Garioch J.J.
      • Lewis H.
      • Valdimarsson H.
      • Fry L.
      Group A streptococcal antigen-specific T lymphocytes in guttate psoriatic lesions.
      ;
      • Leung D.Y.M.
      • Travers J.B.
      • Giorno R.
      • et al.
      Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis.
      ) stand beside findings documenting T cells reacting towards staphylococcal superantigens (
      • Bour H.
      • Demidem A.
      • Garrigue J-L.
      • Krasteva M.
      • Schmitt D.
      • Claudy A.
      • Nicolas J-F.
      In vitro T cell response to staphylococcal enterotoxin B superantigen in chronic plaque-type psoriasis.
      ;
      • Yokote R.
      • Tokura Y.
      • Furukawa F.
      • Takigawa M.
      Susceptible responsiveness to bacterial superantigens in peripheral blood mononuclear cells from patients with psoriasis.
      ). On the other hand, lack of induction of inflammatory alterations by superantigens in the SCID-hu model using grafts derived from normal human skin argues in favor of the relevance of factors intrinsic to the skin.
      We therefore analyzed the biologic effects of several superantigens representing distinct staphylococcal enterotoxin subfamilies in the SCID-hu model and were able to demonstrate differences with regard to their respective “psoriatrogenic” efficacy, although they all caused changes that resembled each other (
      • Boehncke W-H.
      • Hardt-Weinelt K.
      • Nielsson H.
      • et al.
      Antagonistic effects of the staphylococcal enterotoxin A mutant SEAK47A/0227A, on psoriasis in the SCID-hu xenogeneic transplantation model.
      ). Based on these observations we think that a predisposition intrinsic to the skin compartment is needed in order to induce psoriasis in nonlesional skin. On the other hand the “psoriatrogenic” efficacy of distinct superantigens differs markedly.

      Perspectives

      Having established the inducability of psoriasis in the SCID-hu model by superantigens we investigated the possibility of interfering with this trigger mechanism. For this purpose, a set of mutated superantigens with reduced affinity to HLA class II molecules but unaltered binding sites to T cell receptor V β-segments were synthetized. Preliminary data suggest that these molecules indeed function as competitive inhibitors to the respective wild-type superantigens in this model (Table I) (
      • Boehncke W-H.
      • Hardt-Weinelt K.
      • Nielsson H.
      • et al.
      Antagonistic effects of the staphylococcal enterotoxin A mutant SEAK47A/0227A, on psoriasis in the SCID-hu xenogeneic transplantation model.
      ). As comparable proteins are already clinically applied in the field of oncology (
      • Hansson J.
      • Ohlsson L.
      • Persson R.
      • et al.
      Genetically engineered superantigens as tolerable antitumor agents.
      ) and the SCID-hu model has also been demonstrated to be a useful tool for screening antipsoriatic drugs (
      • Boehncke W-H.
      • Kock M.
      • Hardt-Weinelt K.
      • Wolter M.
      • Kaufmann R.
      The SCID-hu xenogeneic transplantation model allows screening of anti-psoriatic drugs.
      ;
      • Dam T.N.
      • Kang S.
      • Nickoloff B.J.
      • Voorhees J.J.
      1α,25-dihydroxycholecalciferol and cyclosporine suppress induction and promote resolution of psoriasis in human skin grafts transplanted on to SCID mice.
      ), the development of this approach for treating autoimmune diseases might well be feasible.
      Table IBiologic effects of wild-type and mutated staphylococcal enterotoxin A on human nonlesional psoriatic skin grafted onto SCID mice
      Staphylococcal superantigen AAkanthosisPapillomatosisKeratinizationInfiltrate
      wild type50%-100% thickening++parakeratosisintermediate
      m23
      This mutation exhibits no measurable affinity to HLA class II molecules.
      – – orthokeratosissparse
      m23 + wild type<50% thickening– orthokeratosismoderate
      a This mutation exhibits no measurable affinity to HLA class II molecules.

      ACKNOWLEDGMENTS

      This work is supported by grant o 895/9–1 of the Deutsche Forschungs gemeinschaft.

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