IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration

Kulkarni, Upasana; Karsten, Christian M.; Kohler, Thomas P.; Hammerschmidt, Sven; Bommert, Kurt; Tiburzy, Benjamin; Meng, Lingzhang; Thieme, Lara; Recke, Andreas; Ludwig, Ralf J.; Pollok, Karolin; Kalies, Kathrin; Bogen, Bjarne; Böttcher, Martin; Kamradt, Thomas; Hauser, Anja E.; Langer, Christian; Huber‐Lang, Markus; Finkelman, Fred D.; Köhl, Jörg; Wong, D.; Manz, Rudolf A.

doi:10.1016/j.jaci.2015.10.018

Cited by 63 publications

(62 citation statements)

References 67 publications

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“…In the present study, reduced neutrophil frequencies were observed in blood and inflamed skin of IL-2/JES6-1-treated mice. Lymphocyte-derived IL-10 can block neutrophil migration and distribution within tissues (40). Given that increased IL-10 + CD4 T populations were detected following IL-2/JES6-1 treatment, it is possible that IL-10 could play a role in blocking neutrophil influx into skin tissue after this treatment.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

Beidaq

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Hofmann

et al. 2016

The Journal of Immunology

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Contact hypersensitivity (CHS) of murine skin serves as a model of allergic contact dermatitis. Hapten-specific CD8 T cells and neutrophils represent the major effector cells driving this inflammatory reaction whereas Foxp3+ regulatory T cells (Tregs) control the severity of inflammation. However, whether in vivo expansion of endogenous Tregs can downregulate CHS-mediated inflammation remains to be elucidated. In this study, we addressed this issue by using injection of an IL-2/anti–IL-2 mAb JES6-1 complex (IL-2/JES6-1) as a means of Treg induction in 2,4,6-trinitrochlorobenzene–induced CHS. IL-2/JES6-1 injection before or after hapten sensitization led to a considerable reduction of skin inflammation, even when rechallenged up to 3 wk after the last treatment. Conversely, Treg depletion re-established the CHS response in IL-2/JES6-1–treated mice. IL-2/JES6-1 injection resulted in increased frequencies of natural and peripheral Tregs in spleen and draining lymph nodes (LNs), elevated IL-10 and TGF-β production by CD4 T cells, reduced CD86 expression by dendritic cells, and led to lower numbers of hapten-specific IFN-γ–producing CD8 T effector cells in LNs. Neutrophil and CD8 T cell infiltration was reduced in inflamed ear tissue, whereas CTLA-4+Foxp3+ Treg frequencies were augmented. Adoptive transfer of LN cells of sensitized mice into recipients treated with IL-2/JES6-1 showed impaired CHS. Our results show that in vivo Treg expansion results in a prolonged CHS suppression, a sustained reduction of hapten-specific CD8 T cells, and a decrease in effector cell influx in inflamed tissue.

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Section: Discussionmentioning

confidence: 99%

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

Beidaq

Link

Hofmann

et al. 2016

The Journal of Immunology

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“…Nevertheless, these observations suggest that similar to what is long known for antibody class switch (50), antibody sialylation is also modulated by the interaction of activated B cells with T follicular helper cells (49). Interestingly, both T cell differentiation into follicular helper T cells and cytokine profiles are modulated by activated B cells and plasma cells themselves, via presentation of antigen, co-stimulatory molecules, and B cell-derived cytokines (51–56). Following TLR stimulation, B cells produce different cytokines than dendritic cells (57).…”

Section: Generation and Maintenance Of Autoantibodiesmentioning

confidence: 99%

“…This indicates that skin-resident cells or keratinocytes may be a source of these cytokines known to modulate blistering and inflammation in EBA. In addition, excess production of IL-10, i.e., induced by polyclonal B cell activation, has been shown do directly dampen C5a-driven inflammatory responses in EBA (56). …”

Section: Autoantibody-induced Inflammationmentioning

confidence: 99%

Mechanisms of Autoantibody-Induced Pathology

et al. 2017

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Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.

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“…The former is illustrated by a hazard ratio of 2.2 for developing infections even in patients with the MM precursor disease monoclonal gammopathy of unknown significance (MGUS) [8], the latter by an excess risk for malignancies such as non-melanoma skin cancer or acute myeloid leukemia/myelodysplastic syndrome in MM patients [9]. Malfunction of components of the innate and adoptive immune system in MM patients has also been described [10–12]. In addition, MM cells can specifically shield themselves from T cell responses by overexpressing protective molecules such as PD-L1, especially in the context of inflammatory cytokines [13].…”

Section: Immunotherapy Of MM – a Long Journey To Successmentioning

confidence: 99%

Immunologic approaches for the treatment of multiple myeloma

Rasche

Weinhold

Morgan

et al. 2017

Cancer Treatment Reviews

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The FDA approval of two monoclonal antibodies in 2015 has heralded a new era of targeted immunotherapies for multiple myeloma (MM). In this review we discuss the recent approaches using different immunological components to treat MM. In particular, we review current monoclonal antibody based therapies, engineered T- and NK cell products, ‘off-target’ immunomodulation, and strategies utilizing allogeneic cell transplantation in MM. We discuss how an immunologic approach offers promise for the treatment of this genetically heterogeneous disease, and how patients with acquired drug resistance may particularly benefit from these therapies. We also describe some of the limitations of the current strategies and speculate on the future of personalized immunotherapies for MM.

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IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration

Abstract: We provide evidence that plasmacytosis-associated overexpression of IL-10 inhibits neutrophil migration and neutrophil-mediated inflammation but also promotes immunodeficiency.

Cited by 63 publications

References 67 publications

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

Mechanisms of Autoantibody-Induced Pathology

Immunologic approaches for the treatment of multiple myeloma

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