<i>Ex vivo</i> analysis of desmoglein 1‐responsive T‐helper (Th) 1 and Th2 cells in patients with pemphigus foliaceus and healthy individuals

Gebhard, Kerstin; Veldman, Christian; Waßmuth, Ralf; Schultz, E. S.; Schuler, Gerold; Hertl, Michael

doi:10.1111/j.0906-6705.2005.00329.x

Cited by 25 publications

(25 citation statements)

References 33 publications

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“…Peripheral CD4 + T cells from patients with endemic PF developed a proliferative response to the extracellular portion of Dsg1, the autoantigen of PF, and secreted Th2 cytokines. Using MACS cytokine secretion assay, we identified Dsg1-responsive Th1 and Th2 cells at similar frequencies in patients with PF and occasionally also in healthy individuals (30). These findings are in line with the aforementioned observations in PV, indicating that the presence of autoreactive Th cells is not restricted to patients (18).…”

Section: Autoreactive T Lymphocytes In Pemphigussupporting

confidence: 88%

T cell control in autoimmune bullous skin disorders

Hertl¹

2006

Journal of Clinical Investigation

198

129

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Autoimmune bullous disorders are a group of severe skin diseases characterized clinically by blisters and erosions of skin and/or mucous membranes. A hallmark of these disorders is the presence of IgG and occasionally IgA autoantibodies that target distinct adhesion structures of the epidermis, dermoepidermal basement membrane, and anchoring fibrils of the dermis. This Review focuses on the potential role of autoreactive T cells in the pathogenesis of these disorders. Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are the best-characterized bullous disorders with regard to pathogenesis and T cell involvement. Activation of autoreactive T cells in PV and BP is restricted by distinct HLA class II alleles that are prevalent in individuals with these disorders. Autoreactive T cells are not only present in patients but can also be detected in healthy individuals. Recently, a subset of autoreactive T cells with remarkable regulatory function was identified in healthy individuals and to a much lesser extent in patients with PV, suggesting that the occurrence of autoimmune bullous disorders may be linked to a dysfunction of Tregs.Autoimmune bullous skin disorders are characterized by the presence of autoantibodies that target distinct adhesion molecules of the epidermis and dermoepidermal basement membrane zone, leading to a loss of adhesive function of the target antigen(s) and, clinically, to the appearance of blisters and erosions (1, 2) (Figures 1 and 2). Desmogleins are transmembranous components of desmosomes, adhesion units specialized in conferring epidermal keratinocyte cohesion and linked to intercellular molecules of the desmosomal plaque, which in turn interact with components of the cytoskeleton (Figure 1). In pemphigus, IgG autoantibodies against desmoglein 3 (Dsg3) and Dsg1 lead to loss of desmosomal adhesion of epidermal keratinocytes and intraepidermal blister formation (Figure 2). In the pemphigoids, IgG autoantibodies against components of the dermoepidermal basement membrane such as bullous pemphigoid (BP) antigen 180 (BP180; also referred to as BP antigen 2 and type XVII collagen), BP antigen 230 (BP230; also referred to as BP antigen 1), and laminin 5 interfere with the adhesion of basal epidermal keratinocytes to the dermoepidermal basement membrane zone (Figure 1). BP180 and BP230 are transmembranous and intracellular components, respectively, of hemidesmosomes of basal epidermal keratinocytes, while laminin 5 is a ligand of BP180 located in the lamina lucida of the basement membrane zone (Figure 1). The autoantigen of epidermolysis bullosa, type VII collagen, is the major component of anchoring fibrils that connect the dermoepidermal basement membrane with interstitial collagen bundles of the dermis (Figure 1). The autoantigen of dermatitis herpetiformis, epidermal transglutaminase, is targeted by autoantibodies of the IgA class in the papillary dermis (Figure 2).Based on the specificity of the targeted antigens, several clinically and immune serologically distinct bullous disorders have be...

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Section: Autoreactive T Lymphocytes In Pemphigussupporting

confidence: 88%

T cell control in autoimmune bullous skin disorders

Hertl¹

2006

Journal of Clinical Investigation

198

129

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“…The occurrence of autoreactive T cells in healthy individuals is in line with previous investigations on potent autoAgs3 36 39 – 41 and further supports the idea that also peripheral tolerance mechanisms are disturbed in SLE 42. In contrast to other reports,29 43 44 no phenotypic differences were seen between TCCs derived from patients with SLE and HCs including expression of cell surface markers and cytokine profile.…”

Section: Discussionsupporting

confidence: 89%

Characterisation of cellular and humoral autoimmune responses to histone H1 and core histones in human systemic lupus erythaematosus

et al. 2008

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“…In PV, Dsg3-specific autoaggressive T cells were predominantly of the Th2 type, whereas Dsg-reactive T cells in the healthy individuals were mainly Th1 cells (7)(8)(9). A similar dichotomy of autoreactive T cells in patients and healthy donors was also found in the pathogenetically related but distinct autoimmune bullous skin disorders, pemphigus foliaceus and bullous pemphigoid, which are also mediated by pathogenic IgG autoantibodies (31,32).…”

Section: Discussionmentioning

confidence: 65%

Pathogenic IgG Antibodies against Desmoglein 3 in Pemphigus Vulgaris Are Regulated by HLA-DRB1*04:02–Restricted T Cells

Eming

Hennerici

Bäcklund

et al. 2014

The Journal of Immunology

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Pemphigus vulgaris (PV) is considered as a model for an autoantibody-mediated organ-specific autoimmune disorder. IgG autoantibodies directed against the desmosomal cadherin desmoglein 3 (Dsg3), the major autoantigen in PV, cause loss of epidermal keratinocyte adhesion, resulting in blisters and erosions of the skin and mucous membranes. The association of human autoimmune diseases with distinct HLA alleles is a well-known phenomenon, such as the association with HLA-DRB1*04:02 in PV. However, direct evidence that HLA-DRB1*04:02–restricted autoreactive CD4+ T cells recognizing immunodominant epitopes of Dsg3 initiate the production of Dsg3-reactive IgG autoantibodies is still missing. In this study, we show in a humanized HLA-DRB1*04:02–transgenic mouse model that HLA-DRB1*04:02–restricted T cell recognition of human Dsg3 epitopes leads to the induction of pathogenic IgG Abs that induce loss of epidermal adhesion, a hallmark in the immune pathogenesis of PV. Activation of Dsg3-reactive CD4+ T cells by distinct human Dsg3 peptides that bind to HLA-DRβ1*04:02 is tightly regulated by the HLA-DRB1*04:02 allele and leads, via CD40-CD40L–dependent T cell–B cell interaction, to the production of IgG Abs that recognize both N- and COOH-terminal epitopes of the human Dsg3 ectodomain. These findings demonstrate key cellular and humoral immune events in the autoimmune cascade of PV in a humanized HLA-transgenic mouse model. We show that CD4+ T cells recognizing immunodominant Dsg3 epitopes in the context of the PV-associated HLA-DRB1*04:02 induce the secretion of Dsg3-specific IgG in vivo. Finally, these results identify Dsg3-reactive CD4+ T cells as potential therapeutic targets in the future.

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Ex vivo analysis of desmoglein 1‐responsive T‐helper (Th) 1 and Th2 cells in patients with pemphigus foliaceus and healthy individuals

Cited by 25 publications

References 33 publications

T cell control in autoimmune bullous skin disorders

T cell control in autoimmune bullous skin disorders

Characterisation of cellular and humoral autoimmune responses to histone H1 and core histones in human systemic lupus erythaematosus

Pathogenic IgG Antibodies against Desmoglein 3 in Pemphigus Vulgaris Are Regulated by HLA-DRB1*04:02–Restricted T Cells

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