Info

Ishii et al. 1998

Pemphigus erythematosus

desmoglein 1

Gomi et al. 1999

(Senear Usher)

nuclear antigens

Ochsendorf et al. 1987

Core

Plaque

Plaque

Keratin

Core

Plaque

Plaque

Keratin

f Proteinkinase

Env = Envoplakln Per = Periplakin CM = Cell membrane

Fig. 3. Schematic representation of a desmosome with the major autoantigens of pemphigus

f Proteinkinase

Env = Envoplakln Per = Periplakin CM = Cell membrane

Fig. 3. Schematic representation of a desmosome with the major autoantigens of pemphigus

Autoreactive T Lymphocytes in Pemphigus

Current concepts strongly suggest that autoreactive T cells play a crucial role in the initiation and perpetuation of both Ab- and cell-mediated autoimmune diseases. Autoreactive T cells may provide critical help for B cells to continuously produce pathogenic auto-Ab in PV. Involvement of CD4+ T lymphocytes in the pathogenesis of PV has been further suggested by the aforementioned strong association of PV with HLA-DRpi*0402 and HLA-DRbl* 0503 (Sinha et al. 1989; Ahmed et al. 1990; Hertl and Riechers 1999). The majority of peripheral T cell lines and clones generated from several patients with PV expressed a CD4+ memory phenotype and a minority the CD8 receptor (Hertl et al. 1998). Both TH1- and TH2-like Dsg3-specific T cells were identified in PV patients (Wucherpfennig et al. 1995; Lin et al. 1997; Hertl et al. 1998). While the TH2 cytokines IL-4 and IL-13 have been shown to regulate the secretion of IgG4 and IgE by activated B cells, the TH1 cytokine IFNy induces the secretion of IgG1. Both, autoreactive TH1 and TH2 cells may be involved in the regulation of the production of pathogenic auto-Ab by B cells in PV since sera of patients with PV contain TH1-regulated IgG1 and TH2-regulated IgG4, IgA (and IgE) auto-Ab directed against Dsg3 (Bhol et al. 1995; Spaeth et al. 2001; Veldman et al, 2003) (Fig. 2). By ELISPOT assay, auto-Ab-secreting B cells were detected upon in vitro-stimulation of peripheral lymphocytes (PBMC) from PV patients with Dsg3 (Nishifuji et al. 2000). Autoreactive B cells were no more detectable upon depletion of PBMC

from CD4+ T cells. Dsg3-specific, autoreactive T cells may thus provide targets to specifically modulate the T cell-dependent production of pathogenic auto-Ab in PV and PF (Riecher et al. 1999). Noteworthy, autoreactive T cells from PV patients and healthy individuals recognize identical epitopes of Dsg3 strongly suggesting that PV is the consequence of a loss of tolerance on the B cell level (Veldman et al, 2004a). This is supported by the recent finding that Dsg3-reactive healthy individuals have higher numbers of Dsg3-secific T regulatory cells than PV patients which may be critical for the maintenance of peripheral tolerance against Dsg3 (Veldman et al, 2004b).

Autoreactive T cells were also identified in a clinical variant of PF, fogo selvagem, which is endemic in limited areas of South America (Lin et al. 2000). Peripheral CD4+ T cells from patients with endemic PF reacted to the ECD of Dsgl, the autoantigen of PF, and secreted TH2 cytokines.

Animal Models of Pemphigus Vulgaris

Passive Transfer Model of Pemphigus

Anhalt et al. (1982) demonstrated that the passive transfer of IgG from PV sera into newborn BALB/c mice induced a clinical picture resembling PV. PV-IgG caused suprabasilar acantholysis in these mice and displayed the typical intercellular staining pattern which is also seen in humans. Amagai et al. 1994) utilized this passive transfer model to demonstrate that preabsorption of PV-IgG with recombinant Dsg3 abolished the ability of the sera to induce acantholysis in mice demonstrating that anti-Dsg3 IgG are indeed critical for blister formation. Using this animal model, it has been demonstrated that anti-Dsgl auto-Ab in PF (Amagai et al. 1995) in PV sera (Amagai et al. 1994) as well as anti-Dsg3 IgG in PNP sera (Amagai et al. 1998) is critical for blister formation.

Distinct cytokines such as tumor necrosis factor-a and interleukin-1 seem to be important mediators of inflammation upon binding of pemphigus auto-Ab to their desmosomal target antigens. To confirm the role of interleukin-1 and tumor necrosis factor-a in pemphigus, Feliciani et al. (2000) performed passive transfer studies using interleukin-1 deficient mice (ICE-/-, interleukin-1 beta-/-) and tumor necrosis factor-a receptor deficient mice (TNFR1R2-/-). The tumor necrosis factor-a-deficient mice showed a decreased susceptibility to the passive transfer of pemphigus auto-Ab suggesting that tumor necrosis factor-a plays a critical role in the pathogenesis of PV.

Desmoglein 3-Deficient Mouse

The most impressive evidence for the central role of Dsg3 in intraepidermal adhesion was provided by Koch et al. (1997). They genetically engineered mice with a targeted disruption of the Dsg3 gene. These mice were normal at birth but developed a runting phenotype later on. These mice presented with oral erosions/blisters leading to the observed weight loss due to the inhibited food uptake. These mice developed cutaneous blisters only when the skin was traumatized. Noteworthy, the Dsg3-/- mice developed telogen hair loss. This finding provided strong support to the idea that anti-Dsg3 auto-Ab induce mucosal but not cutaneous lesions in PV.

Relationship between Anti-Desmosomal Ab Profile and Clinical Phenotype of Pemphigus

Utilizing the Dsg3-/- mouse model, Mahoney et al. (1999) dissected the relationship between the epidermal distribution of Dsg3 and Dsgl and the pathogenic role of circulating auto-Ab targeting these structures. The role of Dsg3 in limiting blister formation in PF was demonstrated by injection of Dsgl-re-active IgG into Dsg3+/+ and Dsg3-/- mice. Upon transfer of PF IgG, the Dsg3+/+ mice developed small cutaneous blisters while the Dsg3-/- mice developed gross blisters on the skin and mucous membranes (which strongly express Dsg3 but little Dsgl (Shirakata et al. 1998). These data also explain the observation that PV patients with anti-Dsg3 auto-Ab only have exclusively oral lesions. Once anti-Dsgl Ab are present, skin lesions occur since blocking of both Dsg1 and Dsg3 is necessary to inhit desmosomal adhesion in the skin (Ding et al. 1997).

Active Animal Model of Pemphigus Vulgaris

Amagai et al. (2000a) have taken advantage of the availablity of Dsg3-/- mice to establish an active in vivo model of PV. Dsg3-/- mice were immunized with recombinant mouse Dsg3 leading to the production of anti-Dsg3 Ab. Splenocytes from the Dsg3-immunized mice were then transferred into immu-nodeficient Rag -/- mice that expressed Dsg3. The recipient mice produced anti-Dsg3 auto-Ab and developed erosions of the mucous membranes with the typical histological findings of PV. In addition, the mice showed telogen hair loss as found in the Dsg3-/- mice. This first active in vivo model of pemphigus will be very useful for the understanding of how autoimmunity develops in PV and for evaluating therapeutic strategies aimed at specifically interfering with the T cell-dependet auto-Ab production by autoreactive B cells.

Humanized PBL-SCID Mouse to Study Autoimmunity against

Desmoglein 3

Immunodeficient SCID mice reconstituted with human peripheral blood lymphocytes (PBL-SCID) have shown promise in investigating cell-mediated immune disorders including autoimmune diseases in vivo. The PBL-SCID mouse model has been successfully utilized to study T cellular immune responses to various infectious, nominal, and tumor antigens. Juhasz et al. (1993) and recently our group (Rädisch et al, in press) have made efforts to establish an in vivo model of PV by transfer of PBL from PV patients into SCID mice. In the previous study of Juhasz et al. (1993), i.p. injection of PBL from PV patients into SCID mice resulted in the detection of human pemphigus-specific Ab in the sera of 41% of the reconstituted mice; 44% of these mice had also tissue-bound intercellular IgG deposits characteristic for PV. In our study (Rädisch et al, 2002), transfer of Dsg3-responsive PBL from a DRß1*0402+ PV patient and from a Dsg3-responsive healthy DRß1*0402+ donor into SCID mice did not lead to the in vivo induction of human auto-Ab against human Dsg3. Only 1/30 mice that received PBL from the PV patient developed anti-Dsg3 reactive IgM, but no IgG auto-Ab. Reconstituting SCID mice with PBL from PV patients may thus be more difficult than anticipated and shows little promise for establishing a highly reproducible in vivo model of autoimmunity against Dsg3.

0 0

Post a comment