Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Gomez, Alejandro M.; Vrolix, Kathleen; Martínez‐Martínez, Pilar; Molenaar, Peter; Phernambucq, Marko; Esch, Eline van der; Duimel, Hans; Verheyen, Fons; Voll, Reinhard; Manz, Rudolf A.; Baets, Marc H. De; Losen, Mario

doi:10.4049/jimmunol.1002539

Cited by 125 publications

(105 citation statements)

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“…It has been studied in animal models of autoimmunity, such as lupus and vasculitis, and has been shown to reduce autoantibody titers and improve clinical outcomes [113]. In experimental MG, bortezomib reduced antiAChR antibody titers, inhibited damage to the postsynaptic muscle membrane, and resulted in clinical improvement [114]. In cultures from thymus from patients with MG, bortezomib rapidly halted autoantibody production and depleted plasma cells [115].…”

Section: B Cells B-cell Trophic Factors and Plasma Cellsmentioning

confidence: 99%

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

2016

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Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.

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Section: B Cells B-cell Trophic Factors and Plasma Cellsmentioning

confidence: 99%

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

2016

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Section: Introductionmentioning

confidence: 99%

“…Bortezomib is a highly selective and reversible inhibitor of the 26S proteasome and has been approved for the treatment of multiple myeloma [13]. It has been shown to diminish immunoglobulin synthesis in autoimmunity [14][15][16], but also in allergic sensitization [17].In the present study, our first goal was to establish a hazelnut allergy model that displays the clinical and immunopathological characteristics of food allergy. Secondly, we sought to assess the role of IgE sensitization in our model by eliminating IgE.…”

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confidence: 99%

Bortezomib treatment diminishes hazelnut‐induced intestinal anaphylaxis in mice

et al. 2016

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Food allergy is a common health problem and can cause anaphylaxis. Avoidance of the offending food allergen is still the mainstay therapeutic approach. In this study, we investigated the role of plasma cell reduction by proteasome inhibition in a murine model of food allergy and examined the impact of this treatment on the systemic and local immune response. For this purpose, intestinal anaphylaxis was induced in BALB/c mice with the food allergen hazelnut, in conjunction with different adjuvants (alum and Staphylococcal enterotoxin B SEB) and different administration routes (oral and intraperitoneal). In both models, allergy symptoms were observed, but the clinical severity was more pronounced in the hazelnut-alum model than in the hazelnut-SEB model. Accordingly, allergen-specific immunoglobulin E (IgE) against hazelnut was detectable, and mast cell protease-1 in serum was increased after allergen provocation. Treatment with the proteasome inhibitor bortezomib reduced plasma cells and resulted in an abolishment of hazelnut allergen-specific IgE, which was associated with amelioration of clinical symptoms as well as a significant decrease in both CD19 + and follicular B lymphocytes. Our data demonstrate the importance of allergen-specific IgE in food allergy and point to B cells as potential therapeutic targets for its treatment. Keywords: Anaphylaxis B cells Food allergy Immunoglobulin E Proteasome inhibitionAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAllergic reactions to food are common, and in most cases are caused by type 1-mediated hypersensitivity reactions [1]. Severe cases of food allergy may result in anaphylaxis, which can be fatal [1,2]. Features of food allergy include sensitization paramCorrespondence: Univ. Prof. Dr. med. Margitta Worm e-mail: margitta.worm@charite.de eters, such as the presence of allergen-specific immunoglobulin E (IgE), and typical clinical symptoms. These frequently consist of skin symptoms, such as urticaria and/or angioedema, but also include variable systemic responses, such as respiratory and cardiovascular symptoms [1][2][3]. Until now, the primary therapeutic approach for patients with food allergy has been strict avoidance of the offending food allergen [1]. Hazelnut (Corylus avellana) is a common cause of food allergy in Europe [4][5][6][7], and affects 0.1-0.5% of the population [8]. Hazelnut-allergic Eur. J. Immunol. 2016. 46: 1727-1736 a risk of severe or even fatal reactions [4][5][6]. Although sublingual immunotherapy and/or oral tolerance-induction has recently been shown to be effective for the treatment of peanut-allergic patients [9,10], their use in clinical practice is limited and currently restricted to specialized centers because of the risk of severe side effects. Another therapeutic approach to treat food allergy is the depletion of IgE. Indeed, the efficacy of an anti-IgE treatment has been demonstrated in patients suffering from food allergy [11]. Likewise, the anti-Ig...

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“…Bortezomib has been studied in animal models of autoimmune diseases including experimental MG, where it caused reduction of AChR antibody titers, inhibited damage to the postsynaptic endplate region and resulted in clinical improvement [Verbrugge et al 2015;Gomez et al 2011]. The drug has been approved for multiple myeloma and mantle cell lymphoma and, although it is an excellent candidate agent in MG, enthusiasm is diminished because it causes peripheral neuropathy, a considerable concern in MG patients.…”

Section: B Cells B-cell Trophic Factors and Autoantibodies (#2 Inmentioning

confidence: 99%

Future perspectives in target-specific immunotherapies of myasthenia gravis

Dalakas

2015

Ther Adv Neurol Disord

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Myasthenia gravis (MG) is an autoimmune disease caused by complement-fixing antibodies against acetylcholine receptors (AChR); antigen-specific CD4+ T cells, regulatory T cells (Tregs) and T helper (Th) 17+ cells are essential in antibody production. Targetspecific therapeutic interventions should therefore be directed against antibodies, B cells, complement and molecules associated with T cell signaling. Even though the progress in the immunopathogenesis of the disease probably exceeds any other autoimmune disorder, MG is still treated with traditional drugs or procedures that exert a non-antigen specific immunosuppression or immunomodulation. Novel biological agents currently on the market, directed against the following molecular pathways, are relevant and specific therapeutic targets that can be tested in MG: (a) T cell intracellular signaling molecules, such as anti-CD52, anti-interleukin (IL) 2 receptors, anti-costimulatory molecules, and anti-Janus tyrosine kinases (JAK1, JAK3) that block the intracellular cascade associated with T-cell activation; (b) B cells and their trophic factors, directed against key B-cell molecules; (c) complement C3 or C5, intercepting the destructive effect of complement-fixing antibodies; (d) cytokines and cytokine receptors, such as those targeting IL-6 which promotes antibody production and IL-17, or the p40 subunit of IL-12/1L-23 that affect regulatory T cells; and (e) T and B cell transmigration molecules associated with lymphocyte egress from the lymphoid organs. All drugs against these molecular pathways require testing in controlled trials, although some have already been tried in small case series. Construction of recombinant AChR antibodies that block binding of the pathogenic antibodies, thereby eliminating complement and antibody-depended-cell-mediated cytotoxicity, are additional novel molecular tools that require exploration in experimental MG.

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Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Cited by 125 publications

References 47 publications

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

Bortezomib treatment diminishes hazelnut‐induced intestinal anaphylaxis in mice

Future perspectives in target-specific immunotherapies of myasthenia gravis

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