Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris

Lee, Jinmin; Lundgren, Daniel K.; Mao, Xuming; Vieira, Sílvio M.; Nuñez-Cruz, Selene; Williams, Erik F.; Assenmacher, Charles-Antoine; Radælli, Enrico; Oh, Sangwook; Wang, Baomei; Ellebrecht, Christoph T.; Fraietta, Joseph A.; Milone, Michael C.; Payne, Aimee

doi:10.1172/jci138416

Cited by 88 publications

(54 citation statements)

References 29 publications

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“…More recently, this same group completed a preclinical study of Dsg3-CAART for the treatment of mucosal PV in humans. Their study found Dsg3-CAAR T cells specifically killed human anti-Dsg3 B cells from PV patients ex vivo and showed activity consistent with a threshold dose in vivo [ 34 ]. Results from this study has supported an investigational new drug application for a Phase I clinical trial.…”

Section: Methods To Target Antigen-specific B Cells: the “How?”mentioning

confidence: 99%

Therapeutic Targeting of Autoreactive B Cells: Why, How, and When?

Stensland

Cambier

2021

Biomedicines

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B lymphocytes play critical roles in the development of autoimmunity, acting as autoantibody manufacturers, antigen-presenting cells, and producers of cytokines. Pan-B cell depletion has demonstrated efficacy in treatment of many autoimmune disorders, but carries with it an unfavorable safety profile due to global immune suppression. Hence, attention has turned to the potential of autoantigen-specific B cell targeted therapies, which would deplete or silence pathogenic self-antigen-reactive cells while sparing B cells needed for immune defense. Here, we discuss the antigen-specific B cell-targeted approaches that are under development or are under consideration, that could be employed to allow for more precise therapy in the treatment of autoimmunity. Lastly, we discuss some of the challenges associated with antigen-specific B cell targeting that may impact their clinical applicability.

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Section: Methods To Target Antigen-specific B Cells: the “How?”mentioning

confidence: 99%

Therapeutic Targeting of Autoreactive B Cells: Why, How, and When?

Stensland

Cambier

2021

Biomedicines

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“…A specific mention should be given to PV, which was the first autoimmune disease described as predominantly IgG4 autoantibody-mediated and has been extensively studied. High quality data from a prospective, multicenter, open-label, randomized trial of continued rituximab administration in PV demonstrated complete and sustained remission at the end of the second year of follow-up in 89% of 46 patients who received rituximab; rapid normalization of antidesmoglein-3 (DSG-3) antibody titers post B cell depletion was also shown, thereby underscoring the short-lived nature of ASCs producing anti-DSG-3 autoantibodies (314,315). In TTP, rituximab induction therapy of 40 patients resulted in a rapid and sustained recovery of platelet counts and, in parallel, a rapid and sustained decrease of pathogenic, predominantly IgG4 anti-A disintegrin and metalloproteinase with thromboSpondin-1 motifs; 13th member of the family (ADAMTS13) autoantibody titers (310).…”

Section: Non-neurological Autoimmune Disorders Associated With Igg4 Autoantibodiesmentioning

confidence: 98%

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders

2021

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As B cells differentiate into antibody-secreting cells (ASCs), short-lived plasmablasts (SLPBs) are produced by a primary extrafollicular response, followed by the generation of memory B cells and long-lived plasma cells (LLPCs) in germinal centers (GCs). Generation of IgG4 antibodies is T helper type 2 (Th2) and IL-4, -13, and -10-driven and can occur parallel to IgE, in response to chronic stimulation by allergens and helminths. Although IgG4 antibodies are non-crosslinking and have limited ability to mobilize complement and cellular cytotoxicity, when self-tolerance is lost, they can disrupt ligand-receptor binding and cause a wide range of autoimmune disorders including neurological autoimmunity. In myasthenia gravis with predominantly IgG4 autoantibodies against muscle-specific kinase (MuSK), it has been observed that one-time CD20+ B cell depletion with rituximab commonly leads to long-term remission and a marked reduction in autoantibody titer, pointing to a short-lived nature of autoantibody-secreting cells. This is also observed in other predominantly IgG4 autoantibody-mediated neurological disorders, such as chronic inflammatory demyelinating polyneuropathy and autoimmune encephalitis with autoantibodies against the Ranvier paranode and juxtaparanode, respectively, and extends beyond neurological autoimmunity as well. Although IgG1 autoantibody-mediated neurological disorders can also respond well to rituximab induction therapy in combination with an autoantibody titer drop, remission tends to be less long-lasting and cases where titers are refractory tend to occur more often than in IgG4 autoimmunity. Moreover, presence of GC-like structures in the thymus of myasthenic patients with predominantly IgG1 autoantibodies against the acetylcholine receptor and in ovarian teratomas of autoimmune encephalitis patients with predominantly IgG1 autoantibodies against the N‐methyl‐d‐aspartate receptor (NMDAR) confers increased the ability to generate LLPCs. Here, we review available information on the short-and long-lived nature of ASCs in IgG1 and IgG4 autoantibody-mediated neurological disorders and highlight common mechanisms as well as differences, all of which can inform therapeutic strategies and personalized medical approaches.

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“…Here, the causative antigen desmoglein 3 (DSG3) is identical in most patients and it is thus possible to design targeted therapies for the whole patient group. In fact, modified CAR T cell approaches neutralizing exclusively Dsg3-specific cells resulted in impressive and sustainable clinical improvements (28,29).…”

Section: Discussionmentioning

confidence: 99%

Low numbers of cytokine transcripts drive inflammatory skin diseases by initiating amplification cascades in localized epidermal clusters

Schaebitz

Hillig

Farnoud

et al. 2021

Preprint

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Abundant polyclonal T cells infiltrate chronic inflammatory diseases and characterization of these cells is needed to distinguish disease-driving from bystander immune cells. Here, we investigated 52,000 human cutaneous transcriptomes of non-communicable inflammatory skin diseases (ncISD) using spatial transcriptomics. Despite the expected T cell infiltration, we observed only 1-10 pathogenic T cell cytokine per skin section. Cytokine expression was limited to lesional skin and presented in a disease-specific pattern. In fact, we identified responder signatures in direct proximity of cytokines, and showed that single cytokine transcripts initiate amplification cascades of thousands of specific responder transcripts forming localized epidermal clusters. Thus, within the abundant and polyclonal T cell infiltrates of ncISD, only a few T cells drive disease by initiating an inflammatory amplification cascade in their local microenvironment.

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Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris

Cited by 88 publications

References 29 publications

Therapeutic Targeting of Autoreactive B Cells: Why, How, and When?

Therapeutic Targeting of Autoreactive B Cells: Why, How, and When?

Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders

Low numbers of cytokine transcripts drive inflammatory skin diseases by initiating amplification cascades in localized epidermal clusters

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