Autoreactive Peripheral Blood T Helper Cell Responses in Bullous Pemphigoid and Elderly Patients With Pruritic Disorders

Abstract

Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against components of the basal membrane zone that lead to sub-epidermal loss of adhesion. Pruritus may be indicative of a pre-clinical stage of BP, since a subset of these patients shows serum IgG autoantibodies against BP230 and/or BP180 while chronic pruritus is increasingly common in the elderly population and is associated with a variety of dermatoses. Clinical and experimental evidence further suggests that pruritus of the elderly may be linked to autoimmunity with loss of self-tolerance against cutaneous autoantigens. Thus, the objective of this study was to determine autoreactive T cell responses against BP180 in elderly patients in comparison to patients with BP. A total of 22 elderly patients with pruritic disorders, 34 patients with bullous or non-bullous BP and 34 age-matched healthy controls were included in this study. The level of anti-BP180 and anti-BP230 IgG serum autoantibodies, Bullous Pemphigoid Disease Area Index (BPDAI), and pruritus severity were assessed for all patients and controls. For characterization of the autoreactive T cell response, peripheral blood mononuclear cells were stimulated ex vivo with recombinant BP180 proteins (NH2- and COOH-terminal domains) and the frequencies of BP180-specific T cells producing interferon-γ, interleukin (IL)-5 or IL-17 were subsequently determined by ELISpot assay. Patients with BP showed a mixed Th1/Th2 response against BP180 while autoreactive Th1 cells were identified in a minor subset of elderly patients with pruritic disorders. Furthermore, our T cell characterization revealed that therapeutic application of topical clobetasol propionate ointment in BP patients significantly reduced peripheral blood BP180-specific T cells, along with clinically improved symptoms, strongly suggesting a systemic immunosuppressive effect of this treatment.

Deciphering the Contribution of BP230 Autoantibodies in Bullous Pemphigoid

“…In this latter report, the authors also showed that some elderly patients with pruritus have autoreactive T-cells directed against the N- and C-domains of BP180. These autoreactive T-cells exhibited a cytokine profile similar to that typically observed in BP patients [ 82 ]. IgE antibodies against BP230, and to a lesser extent BP180, have also been found in pruritic elderly patients [ 83 ].…”

T‐cell subsets in the skin and their role in inflammatory skin disorders

“…[114][115][116] In addition, Th17 cells and autoreactive Th1/Th2 cells have been observed including a mixed spectrum of cytokines, such as IL-17, IFNγ, and IL-5. 117 Moreover, Th2 cytokines were found in blisters, which point to an additional role of Th2 cells, a fact that is further substantiated by the identification of anti-BP180/230 IgE autoantibodies. 118,119 Alopecia areata is a chronic, relapsing, skin disease leading to patchy hair loss that can reversibly affect small areas of the scalp or trunk, but can also progress to large, therapy resistant areas with complete hair loss.…”

“…Autoreactive IgG or IgE autoantibodies to the antigens BP180 or BP230 induce pruritic eczematous or urticarial lesions and subepidermal blister formation, mainly in elderly patients 114–116 . In addition, Th17 cells and autoreactive Th1/Th2 cells have been observed including a mixed spectrum of cytokines, such as IL‐17, IFN‐γ, and IL‐5 117 . Moreover, Th2 cytokines were found in blisters, which point to an additional role of Th2 cells, a fact that is further substantiated by the identification of anti‐BP180/230 IgE autoantibodies 118,119 …”

Detection of rare autoreactive T cell subsets in patients with pemphigus vulgaris

“…Analysis of T lymphocyte proliferative responses to antigenic or mitogenic stimuli is a vital parameter used in both diagnosis and monitoring of a variety of immune responses. Most commonly applied techniques are based on the incorporation of tritiated thymidine ( 3 H-TdR) or enzyme-linked immunospot (ELISPOT) analysis ( 13 , 14 ). Both rely on a rather long ex vivo expansion periods and stimulation protocols (up to 11 days).…”