Targeting inducible costimulator expressed on CXCR5+PD-1+ TH cells suppresses the progression of pemphigus vulgaris

Kim, A. Reum; Han, Dae Yong; Choi, Ji Young; Seok, Joon; Kim, Soo Chan; Seo, Seong Hoon; Takahashi, Hayato; Amagai, Masayuki; Park, Su–Hyung; Shin, Eui Cheol; Kim, Jong Hoon

doi:10.1016/j.jaci.2020.03.036

Cited by 37 publications

(45 citation statements)

References 40 publications

(68 reference statements)

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“…In GC, Tfh cells provide promoting or inhibiting signals to B cells through the competitive mechanism according to their affinity, which is crucial to the production of high-affinity antibodies (148). Among IgG4-mediated autoimmune diseases, including IMN, some other diseases have also demonstrated abnormalities in cTfh cells (83,84,110,113,114,(149)(150)(151)(152)(153), as shown in Table 2. These diseases may share some similarities in pathophysiology.…”

Section: Th Cells Participating In the Production Of Imn Antibodiesmentioning

confidence: 99%

Helper T Cells in Idiopathic Membranous Nephropathy

et al. 2021

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Idiopathic membranous nephropathy (IMN) is an autoimmune disease in which the immune system produces an antibody response to its own antigens due to impaired immune tolerance. Although antibodies are derived from plasma cells differentiated by B cells, the T-B cells also contribute a lot to the immune system. In particular, the subsets of helper T (Th) cells, including the dominant subsets such as Th2, Th17, and follicular helper T (Tfh) cells and the inferior subsets such as regulatory T (Treg) cells, shape the immune imbalance of IMN and promote the incidence and development of autoimmune responses. After reviewing the physiological knowledge of various subpopulations of Th cells and combining the existing studies on Th cells in IMN, the role model of Th cells in IMN was explained in this review. Finally, the existing clinical treatment regimens for IMN were reviewed, and the importance of the therapy for Th cells was highlighted.

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Section: Th Cells Participating In the Production Of Imn Antibodiesmentioning

confidence: 99%

Helper T Cells in Idiopathic Membranous Nephropathy

et al. 2021

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“…In line with this, our flow cytometry analysis of peripheral T cells demonstrated a consistent increase in Treg and Tfreg cells during PDE4 inhibition, while autoantibody levels decreased ( Figure 3D). Since Tfh cells promote B cell mediated autoantibody production, a mechanism that seems to be relevant in pemphigus (17,18), increasing Treg/Tfreg numbers may exert an inhibitory effect on Tfh and B cell activity (19). On the contrary, we could not observe an effect of apremilast on the Th and Tfh inflammatory subsets, suggesting that dampening of the inflammatory process may be due to overactivation of the regulatory compartment.…”

Section: Discussionmentioning

confidence: 55%

Case Report: Apremilast for Therapy-Resistant Pemphigus Vulgaris

et al. 2020

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Background: In pemphigus, elucidating the disease-causing immune mechanism and developing new therapeutic strategies are needed. In this context, the second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) is gaining attention. cAMP is important in hematological and auto-inflammatory disorders. A class of enzymes called phosphodiesterases (PDEs) control intracellular cAMP levels. In pemphigus, cAMP levels increase following IgG binding to Dsg3. This appears to be a mechanism to preserve epithelial integrity. Objectives: To determine whether apremilast, an inhibitor of the PDE4 normally used in psoriasis, may be of benefit in the blistering skin disorder pemphigus. Methods: Here we report of a 62 years old patient with chronic debilitating and recalcitrant pemphigus not responding to several previous treatments, who received treatment with apremilast over a period of 32 weeks. Desmoglein autoantibody levels were assessed by Enzyme-linked Immunosorbent Assay (ELISA), whereas disease severity and quality of life were assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). In an attempt to explain the effects of apremilast in pemphigus, peripheral blood mononuclear cells (PBMCs) were analyzed for the duration of treatment by flow cytometry for the distribution of specialized T cell subsets. The frequencies of circulating T helper (Th) 1, Th2, Th17, Th17.1 and T follicular helper (Tfh) 1, Tfh2, Tfh17, and Tfh17.1 were analyzed by CCR6, CXCR3, and CXCR5 expression of CD4 + T cells. Further, based on the different expressions of CXCR5, CD127, and CD25, we analyzed the T regulatory (Treg) and T follicular regulatory (Tfreg) compartment. Results: In response to apremilast treatment, Dsg-specific autoantibody titers decreased, blistering ceased and lesions healed, showing a long-lasting effect. While the frequencies of most of the Th and Tfh cell subsets remained unchanged, we observed a continuous increase in Treg and Tfreg cell levels. Conclusion: Our findings are encouraging and warrant extension of the beneficial effect of PDE4 inhibition on a larger cohort of pemphigus patients.

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“…Kim et al examined costimulatory receptor expressed on T lymphocytes; called ICOS that influenced the activity of T cells in various autoimmune diseases. They showed that ICOS expressing CXCR5 + , PD‐1 + CD4 + T cells was positively correlated with the anti‐Dsg3 antibody levels in pemphigus model mouse and can predict the pemphigus disease activity 15 . Ernst et al, analyzed the expression of PD‐1 in lesional skin of pemphigus and bullous pemphigoid.…”

Section: Discussionmentioning

confidence: 99%

Serum levels of soluble PD1 in pemphigus vulgaris: A useful marker for disease severity

Zeid

Rashed

Khalifa

et al. 2020

J of Cosmetic Dermatology

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Background Pemphigus vulgaris (PV) is a life‐threatening autoimmune blistering disease targeting the skin and mucous membranes. Programmed cell death protein 1 (PD1) is an immune checkpoint which binds to two ligands, PDL1 and PDL2 resulting in negative regulation of antigen receptor signaling, thus, play a critical role in the immune regulation of autoimmune diseases. Aim In this work we aimed to assess serum levels of soluble PD1 (sPD1) in patients with active PV and in patients in remission in an attempt to evaluate its effect on disease severity. Methods In this case‐control study, 60 pemphigus vulgaris patients (30 clinically active and 30 in a clinical remission) and 30 age matched healthy control subjects were included. Severity of PV was assessed using pemphigus disease area index (PDAI) score. Serum levels of sPD1 were measured by ELISA for both patients and healthy control. Results Serum levels of sPD1 were significantly lower in PV patients than in controls (P < .001) and significantly lower in patients with active disease than in those in remission (P < .001). Serum sPD1 correlated negatively with the severity of the disease (P < .001, r = −0.4). Conclusion A defect in PD1 pathway is suggested in PV patients, and this defect plays a substantial role in determining the severity of the disease. Thus, sPD1 could be considered a useful marker for disease severity and targeting PD1 pathway could be a potential aim for future therapies of PV.

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Targeting inducible costimulator expressed on CXCR5+PD-1+ TH cells suppresses the progression of pemphigus vulgaris

Cited by 37 publications

References 40 publications

Helper T Cells in Idiopathic Membranous Nephropathy

Helper T Cells in Idiopathic Membranous Nephropathy

Case Report: Apremilast for Therapy-Resistant Pemphigus Vulgaris

Serum levels of soluble PD1 in pemphigus vulgaris: A useful marker for disease severity

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