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• W2068202226 abstract "The signaling of CD40 by its ligand, CD154, between T and B cells is required for humoral immune responses. Thus, blockade of this ligand-receptor interaction can prevent the development of antibody-mediated autoimmune diseases through different mechanisms. The signaling of CD40 by its ligand, CD154, between T and B cells is required for humoral immune responses. Thus, blockade of this ligand-receptor interaction can prevent the development of antibody-mediated autoimmune diseases through different mechanisms. In autoantibody-mediated diseases, autoantigen-specific responses are induced by the activation of specific T cells with self-peptides displayed on antigen-presenting cells (APCs), including B cells, macrophages, and dendritic cells. These autoreactive T cells then activate and drive autoreactive B-cell responses, leading to pathogenic antibody production and subsequent disease development. The activation of naive T cells requires at least two signals. The first signal is delivered through interaction between the TCR and autoantigen associated with major histocompatibility complex molecules on the surface of the APCs. The second signal is delivered through interaction of co-stimulatory molecules on the cell surface of T cells and APCs. Two co-stimulatory pathways, CD28–CD80/CD86 and CD40–CD154, have received the most attention in this regard. CD28 is constitutively expressed on CD4+ T cells and binds to two different ligands, B7-1 (also called CD80) and B7-2 (also called CD86), which are expressed on APCs. CD154 (also called CD40 ligand) is expressed mainly on CD4+ T cells, and CD40, the receptor for CD154, is expressed on APCs (Grewal and Flavell, 1998Grewal I.S. Flavell R.A. CD40 and CD154 in cell-mediated immunity.Annu Rev Immunol. 1998; 16: 111-135Crossref PubMed Scopus (1330) Google Scholar). If signal one is received without co-stimulation (signal two), then the T cells undergo apoptotic death, and antigen-specific anergy is created. In contrast, if both signal one and signal two are received, the T cell undergoes upregulation of soluble factors, such as IL-2, which in turn permits expansion of mature effector cells (T cells, B cells, and macrophages) to sustain immune responses. CD40 ligation induces or increases expression of accessory molecules such as CD80, CD86, and major histocompatibility complex II on the APC population. Thus, this pathway increases both signals one and two. CD40–CD154 interactions are critical for a variety of immune functions, including CD4+ and CD8+ T-cell priming, APC activation, antibody production, effector-cell maturation, and enhancement of inflammation and chemoattraction. A role for CD40–CD154 interactions in many organ-specific T cell-mediated autoimmune diseases, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, lupus nephritis, colitis, and diabetes, has been demonstrated in mouse models. Treatment of mice with anti-CD154 antibody blocks disease in these models. Blockade of CD40–CD154 interaction is also beneficial in prolonging the survival of experimentally transplanted organs, including heart, kidney, skin, and pancreatic islets (Sayegh and Turka, 1998Sayegh M.H. Turka L.A. The role of T-cell costimulatory activation pathways in transplant rejection.N Engl J Med. 1998; 338: 1813-1821Crossref PubMed Scopus (494) Google Scholar). Numerous mechanisms of the protective activity of CD40–CD154 intervention in these autoimmune diseases have been proposed, including inhibition of autoreactive T-cell priming via T cell–APC interference; inhibition of the function, expansion and migration of effector T cells; immune deviation by cytokine blockade; induction of anergy; and elicitation of regulatory cells. These regulatory cells are T lymphocytes (known as regulatory T cells) that actively suppress or downregulate immune responses to maintain immune homeostasis (von Herrath and Harrison, 2003von Herrath M.G. Harrison L.C. Antigen-induced regulatory T cells in autoimmunity.Nat Rev Immunol. 2003; 3: 223-232Crossref PubMed Scopus (279) Google Scholar). Regulatory T cells can be induced by immunization with a self-antigen (for example, oral tolerance) and by treatment with antibodies specific for various T-cell molecules, including CD3, CD45RB, and CD154 (Waldmann, 2002Waldmann H. Reprogramming the immune system.Immunol Rev. 2002; 185: 227-235Crossref PubMed Scopus (28) Google Scholar). Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease. Clinically, PV targets the skin and mucosal epithelia. Histologically, PV is characterized by detachment of suprabasal keratinocytes (suprabasal acantholysis), leaving a row of basal keratinocytes attached to the dermis, which produces a “tombstone-like” appearance. PV patients have circulating autoantibodies that recognize desmoglein-3 (Dsg3). Dsg3 is a 130-kilodalton desmosomal glycoprotein that belongs to the desmoglein subfamily of the cadherin superfamily (Stanley et al., 1982Stanley J.R. Yaar M. Hawley-Nelson P. Katz S.I. Pemphigus antibodies identify a cell surface glycoprotein synthesized by human and mouse keratinocytes.J Clin Invest. 1982; 70: 281-288Crossref PubMed Scopus (170) Google Scholar), a class of molecules that play an important role in mediating cell–cell adhesion. Anti-Dsg3 autoantibodies are pathogenic, as determined by passive transfer studies in which IgG isolated from sera of pemphigus patients, when injected into neonatal mice, induced acantholysis with the classic immunohistological features seen in human patients (Anhalt et al., 1982Anhalt G.J. Labib R.S. Voorhees J.J. Beals T.F. Diaz L.A. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease.N Engl J Med. 1982; 306: 1189-1196Crossref PubMed Scopus (584) Google Scholar). The pathogenic relevance of Dsg3 is further demonstrated by an active-disease model of PV. In this PV mouse model, Dsg3 knockout (Dsg3−/−) mice are immunized with mouse Dsg3, and splenocytes from the immunized Dsg3−/− mice are adoptively transferred to Rag2−/− mice. The recipient mice produce high levels of anti-Dsg3 autoantibodies in circulation and a PV disease phenotype, including patchy hair loss and suprabasilar acantholysis in oral mucosa and esophagus (Amagai et al., 2000Amagai M. Tsunoda K. Suzuki H. Nishifuji K. Koyasu S. Nishikawa T. Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus.J Clin Invest. 2000; 105: 626-631Crossref Scopus (225) Google Scholar). Rag2−/− mice receiving naive Dsg3−/− splenocytes also develop PV. PV is associated with specific HLA class II alleles, including DRB1*0402, DRB1*1401, DQB1*0302, and DQB1*0503. Dsg3-reactive Th2 cells are present at elevated frequency in the peripheral circulation of PV patients compared with healthy control subjects (Hertl and Veldman, 2003Hertl M. Veldman C. T-cellular autoimmunity against desmogleins in pemphigus, an autoantibody-mediated bullous disorder of the skin.Autoimmun Rev. 2003; 2: 278-283Crossref PubMed Scopus (36) Google Scholar). Depletion of CD4+ T cells from the peripheral lymphocytes of PV patients blocks the production of anti-Dsg3 antibodies by autoreactive B cells after in vitro stimulation with Dsg3. These findings suggest that autoreactive T cells are crucial for induction and regulation of autoreactive B cells and production of anti-Dsg3 autoantibodies. Very recently, Veldman et al. identified Dsg3-reactive regulatory T cells in healthy carriers of DRB1*0402 and DQB1*0503 alleles. These regulatory T cells secrete IL-10 and suppress the immune response of Dsg3-reactive T helper cells in an antigen-specific manner that is dependent on the cytokines IL-10 and transforming growth factor-β; this suggests that Dsg3-specific regulatory T cells may be crucial in the maintenance of tolerance against Dsg3 autoantigen (Veldman et al., 2004Veldman C. Hohne A. Dieckmann D. Schuler G. Hertl M. Type I regulatory T cells specific for desmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris.J Immunol. 2004; 172: 6468-6475Crossref PubMed Scopus (136) Google Scholar). In this issue, Aoki-Ota et al. report using a PV mouse model to investigate the role of CD40–CD154 interaction in the generation of pathogenic antibodies and to understand the mechanism of CD40–CD154 blockade in protection against PV development (Aoki-Ota et al., 2006Aoki-Ota M. Kinoshita M. Ota T. Tsunoda K. Iwasaki T. Tanaka S. et al.Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model.J Invest Dermatol. 2006; 126: 107-115Google Scholar). To address the first question, the authors administered anti-CD154 mAb into Rag2−/− recipient mice before adoptive transfer of splenocytes from Dsg3-immunized Dsg3−/− mice. Anti-CD154 antibody treatment abolished PV blister formation; this was associated with a reduction in the levels of B cells producing anti-Dsg3 IgG and the levels of anti-Dsg3 antibodies. More significantly, the anti-CD154 mAb-induced tolerance to Dsg3 (as evidenced by the lack of pathogenic antibody production) was not transient and long lasting without continuous treatment. It is worth noting that the authors should test whether anti-CD154 mAb pretreatment blocks PV in Rag2−/− mice adoptively transferred with naive Dsg3−/− splenocytes, as the immunized Dsg3−/− splenocytes used are already challenged with antigen; therefore, naive Dsg3−/− splenocytes may respond to the anti-CD154 mAb differently from immunized Dsg3−/− splenocytes. To elucidate the mechanism of protection, the authors tested whether regulatory cells might be involved. They first showed that once the immunized Dsg3−/− splenocytes transferred into Rag2−/− mice became resistant to PV by anti-CD154 mAb pretreatment, the protection could not be reversed by a second transfer of immunized Dsg3−/− splenocytes. Then, they demonstrated that PV resistance could be transferred from protected donors to non-tolerized recipients: Rag2−/− mice receiving naive Dsg3−/− splenocytes developed PV, whereas Rag2−/− mice receiving the same number of naive Dsg3−/− splenocytes plus tolerized splenocytes from the anti-CD154 mAb-pretreated and immunized Dsg3−/− splenocyte-transferred mice did not develop PV. These data strongly suggest that the CD40–CD154 blockade induces tolerance to Dsg3 by induction of regulatory cells capable of downregulation of immune responses to Dsg3. This key conclusion is further sustained by the authors' demonstration that protected mice were still unresponsive to Dsg3 after being rechallenged by active Dsg3 immunization. Another interesting finding of this study is that blockade of CD40–CD154 interaction has only marginal therapeutic effects in the treatment of established PV. Similar observations have also been made in other models of autoimmune diseases. These findings indicate that fully activated antigen-specific B cells maintain their functions (for example, production of pathogenic autoantibodies) in a T cell-independent and co-stimulatory signal-independent fashion. Therefore, efficacy of this therapeutic paradigm would depend on the disease stages of patients. Therapies based on induction of protective regulatory T cells would be more effective in preclinical disease. A critical question is whether anti-CD154 mAb will induce immune regulatory cells in PV mice that are in remission and prevent them from future disease relapse. The role of the CD40–CD154 pathway and the effects of CD40–CD154 intervention have been extensively studied in animal models of different autoimmune diseases. Aoki-Ota et al. now provide evidence that the CD40–CD154 interaction is essential for activation and expansion of Dsg3-specific B cells in the splenocyte transfer model of PV. Blockade of CD40–CD154 signaling leads to induction or an increased level of immune regulatory T cells, which are able to suppress Dsg3-specific B-cell functions and subsequent disease development. Further investigation is necessary to isolate and characterize the nature and functions of such anti-CD154 mAb-induced regulatory cells. This should allow confirmation of the tolerance-inducing potential of anti-CD154 mAb and induced regulatory cells and lead to a better understanding of the mechanisms involved, and it may be an important step toward an antigen-specific therapy for PV. The author states no conflict of interest. This work was supported in part by US Public Health Service NIH grants AI40768 and AI61430 (Z.L.), AR052109 (N.L.), and AR32599, AR32081, and AR07369 (L.A.D.)." @default.
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• W2068202226 title "Inhibition of Pemphigus Vulgaris by Targeting of the CD40–CD154 Co-Stimulatory Pathway: A Step Toward Antigen-Specific Therapy?" @default.
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