Autoreactive Cytotoxic T Lymphocytes in Pemphigus and Pemphigoid

Abstract

In order to know whether effector cells are capable of recognizing the epidermal targets in pemphigus vulgaris (PV) and bullous pemphigoid (BP), non-adherent cells (NAC) of peripheral blood from 27 primary PV, 19 BP patients and 12 healthy volunteers were used in cytotoxic tests. Autologous, allogenic and murine epidermal keratinocytes as well as autologous and allogenic fibroblasts were employed as targets. Total esterase activity of serine proteinases was measured in supernatants of samples and the results obtained were compared with the data received in 51Cr-release assay. These two techniques yielded similar results. The effector cells of PV and BP patients were found to lyse the epidermal target cells without presensitization in vitro. Epidermal cells from involved and uninvolved skin of PV patients, as well as from perilesional skin of BP patients, were highly sensitive to cytotoxic effect on the part of effector cells. The NAC activity in BP was higher than in PV. On the one hand, the obtained data suggest that PV and BP patients develop autoreactive cytotoxic T lymphocytes, sensitized to pemphigus and pemphigoid antigens, respectively, and on the other hand that epidermocytes in pemphigus and pemphigoid patients turned to be more fragile compared to normal human epidermal keratinocytes. It was supposed that cell-mediated cytotoxic reactions are probably related to enhanced proteolytic activity in the site of bullous eruption.

Pemphigus Vulgaris Antibody Identifies Pemphaxin

“…Both humoral (38) and cellular (39) effectors of autoimmune aggression against KC are involved in the pathogenesis of this disease, and it has been demonstrated that local activation of trypsin-like serine proteases, such as plasminogen activator (40), complement (41), eicosanoids (42), and proinflammatory cytokines (29,43), all can contribute to acantholysis. The precise mechanism leading to acantholysis in PV, however, is yet to be determined.…”

Antimitochondrial Autoantibodies in Pemphigus Vulgaris

“…Using an organ culture model of PV, it has been demonstrated that PVIgG works together with FasL and tumor necrosis factor ␣ to induce apoptolysis (22). These and some other mediators of inflammation were found to be elevated in skin and/or serum of PV patients (16,19,(23)(24)(25).…”

“…Subsequent studies demonstrated that PVIgG binding to KCs causes secretion of soluble FasL, increased production and cellular amounts of FasR and FasL (soluble and membranal), co-aggregation of FasL and FasR with caspase 8 in a membranal deathinducing signaling complex, and down-regulation of the apoptosis inhibitor FLIP-l (5,10,11,14,27,28). The keratinocyte FasR can be also triggered by FasL expressed by the cytotoxic T cells (29) found in the skin of PV patients (30). Dr. Pincelli and co-workers (31) have recently reported that FasL neutralizing antibody can prevent PVIgG-induced apoptolysis both in vitro and in vivo .…”

Paraneoplastic autoimmune multiorgan syndrome: Review of the literature and support for a cytotoxic role in pathogenesis

“…These diseases include: (1) cutaneous GVHD, in which engrafted CTLs kill recipient epidermal keratinocytes [94]; (2) toxic epidermal necrolysis, in which Fas-ligand-expressing immune cells kill Faspositive keratinocytes [95]; (3) lichenoid tissue reactions, in which autologous CTLs kill keratinocytes by a soluble factor-based mechanism [96]; and (4) pemphigus vulgaris and bullous pemphigoid, in which autoreactive CTLs are present in lesional skin and the circulation of affected patients [97]. Cell-mediated cytotoxicity in pemphigus vulgaris is known to involve both autoreactive CD8þ CTLs [97] and the patient's IgGs, which recruit allogeneic peripheral blood mononuclear cells to induce antibody-dependent cellular cytotoxicity in epithelial targets [98,99]. It has been suggested that in PAMS the IgGs putatively responsible for the development of the disease may, in a similar mechanism, reflect or even induce the cell-mediated immune response that accounts for the wide range of pathologic effects seen in the disease [5].…”