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

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.

Therapeutic Targeting of Th17/Tc17 Cells Leads to Clinical Improvement of Lichen Planus.

Lichen planus (LP) is a common, chronic relapsing inflammatory disorder of the skin and mucous membranes which often poses a major therapeutic challenge due to its refractory course. Novel pathogenesis-based therapies are urgently needed. As several studies have shown that IL-17 may contribute to LP pathogenesis, we investigated whether therapeutic targeting of IL-17+ T cells leads to clinical improvement of mucosal and cutaneous LP lesions. A total of five patients with lichen planus were treated in a compassionate use trial with either secukinumab (anti-IL-17; 3 patients with acute and chronic recalcitrant muco-cutaneous LP), ustekinumab (anti-IL-12/IL-23; 1 patient with recalcitrant oral LP) or guselkumab (anti-IL-23; 1 patient with recalcitrant oral LP). The clinical course of the patients was assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) reflecting both extent and severity of disease and functional sequelae of oral involvement for at least 12 weeks. The inflammatory infiltrate in lesional and post-lesional skin was analyzed by immunohistochemistry before and after treatment. Furthermore, the cytokine profile of peripheral blood T cells from the treated patients was assessed by flow cytometry and/or ELISpot assay. Treatment with secukinumab induced rapid and prolonged clinical amelioration of muco-cutaneous LP. Clinical improvement was accompanied by a strong reduction of the Th1 and Th17/Tc17 cellular mucosal and cutaneous infiltrate. Moreover, long-term treatment of one patient with recalcitrant oral LP with ustekinumab led to healing of the ulcerative oral lesions and a reduction of peripheral blood and lesional IL-17+ T cells. Finally, treatment with guselkumab led to a marked clinical improvement in a patient with recalcitrant erosive oral LP. These findings show for the first time that therapeutic targeting of Th17/Tc17 cells leads to a pronounced clinical amelioration of mucosal and cutaneous LP and strongly suggests that IL-17-producing T cells are central to disease pathogenesis. Thus, therapeutic targeting of Th17/Tc17 cells opens new therapeutic avenues in the treatment of recalcitrant LP.