Basophils and Autoreactive IgE in the Pathogenesis of Systemic Lupus Erythematosus

Charles, Nicolas; Rivera, Juan

doi:10.1007/s11882-011-0216-5

Cited by 40 publications

(30 citation statements)

References 55 publications

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“…For instance, IFN‐γ primes human pre‐pure basophils for enhanced histamine release upon FcεRI cross‐linking which is consistent with in vitro and in vivo studies demonstrating an increased IgE‐dependent releasability of human basophils during respiratory virus infection . Besides, our data may also be relevant for the recently suggested role of basophils in the pathogenesis of systemic autoimmune disease in which T H 1 cytokines are involved .…”

Section: Discussionsupporting

confidence: 89%

Balance between IL‐3 and type Iinterferons and their interrelationship with FasL dictates lifespan and effector functions of human basophils

Hagmann

Odermatt

Kaufmann

et al. 2016

Clin Experimental Allergy

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SummaryBackground In contrast to eosinophils and neutrophils, the regulation of the lifespan of human basophils is poorly defined, with the exception of the potent anti-apoptotic effect of IL-3 that also promotes pro-inflammatory effector functions and phenotypic changes. Type I IFNs (IFN-a, IFN-b), which are well known for their anti-viral activities, have the capacity to inhibit allergic inflammation. Objective To elucidate whether type I IFNs have the potential to abrogate the lifespan and/or effector functions of human basophils. Methods We cultured human basophils, and for comparison, eosinophils and neutrophils, with IL-3, interferons, FasL and TRAIL, alone or in combination, and studied cell survival, effector functions and signalling pathways involved. Results Despite an identical pattern of early signalling in basophils, eosinophils and neutrophils in response to different types of interferons, only basophils displayed enhanced apoptosis after type I IFN treatment. IFN-c prolonged survival of eosinophils but did not affect the lifespan of basophils. IFN-a-mediated apoptosis required STAT1-STAT2 heterodimers and the contribution of constitutive p38 MAPK activity. Whereas the death ligands FasL and TRAIL-induced apoptosis in basophils per se, IFN-a-mediated apoptosis did neither involve autocrine TRAIL signalling nor did it sensitize basophils to FasL-induced apoptosis. However, IFN-a and FasL displayed an additive effect in killing basophils. Interestingly, IL-3, which protected basophils from IFN-a-, TRAIL-or FasL-mediated apoptosis, did not completely block the additive effect of combined IFN-a and FasL treatment. Moreover, we demonstrate that IFN-a suppressed IL-3-induced release of IL-8 and IL-13. In contrast to IFN-a-mediated apoptosis, these inhibitory effects of IFN-a were not dependent on p38 MAPK signalling. Conclusions and Clinical Relevance Our study defines the unique and granulocyte-typespecific inhibitory and pro-apoptotic function of type I IFNs and their cooperation with death ligands in human blood basophils, which may be relevant for the anti-allergic properties of type I IFNs.

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Section: Discussionsupporting

confidence: 89%

Balance between IL‐3 and type Iinterferons and their interrelationship with FasL dictates lifespan and effector functions of human basophils

Hagmann

Odermatt

Kaufmann

et al. 2016

Clin Experimental Allergy

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“…As indicated above, murine and human data led us to propose the following working hypothesis: basophils, due to their permanent, systemic and low intensity stimulation, amplify autoantibody production and CIC formation by supporting both autoreactive T and B cells in SLO [46]. This hypothesis supports the notion that basophils have a deleterious role in lupus pathogenesis.…”

Section: Basophil Activation Pathways In Slementioning

confidence: 61%

The deleterious role of basophils in systemic lupus erythematosus

Pellefigues

Charles

2013

Current Opinion in Immunology

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Systemic lupus erythematosus is a complex autoimmune disease of multifactorial origins. All compartments of the immune system appear to be affected, at least in some way, and to contribute to disease pathogenesis. Due to an escape from negative selection autoreactive T and B cells accumulate in SLE patients leading to the production of autoantibodies mainly raised against nuclear components and their subsequent deposition into target organs. We recently showed that basophils, in an IgE and IL-4 dependent manner, contribute to SLE pathogenesis by amplifying autoantibody production. Here, we summarize what we have learned about the deleterious role of basophils in lupus both in a mouse model and in SLE patients. We discuss which possible pathways could be involved in basophil activation and recruitment to secondary lymphoid organs during SLE, and how basophils may amplify autoantibody production.

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“…Based on the strength of our observations in vitro, we suggest that excessive type 1 IFN production may be the driving factor of the spontaneous inflammatory disorder exhibited by Rabex-5-deficient mice. Indeed, increased histamine and IgE serum levels, reported in Rabex-5-deficient mice, are also characteristics of type 1 IFNmediated disorders such as systemic lupus erythematous (4,27). This conclusion is further supported by the numerous studies that have linked STAT1, which we have observed to be overactive in Rabex-5-deficient cells, to this disorder (28).…”

Section: Discussionmentioning

confidence: 99%

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

Millrine

Tei

Gemechu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Immunomodulatory drugs (IMiDs) are a family of compounds derived from thalidomide. Binding of the IMiD molecule to the Lon protease Cereblon initiates the degradation of substrates via the ubiquitin proteasome pathway. Here, we show that Cereblon forms a complex with Rabex-5, a regulator of immune homeostasis. Treatment with lenalidomide prevented the association of Cereblon with Rabex-5. Conversely, mutation of the IMiD binding site increased Cereblon–Rabex-5 coimmunoprecipitation. The thalidomide binding region of Cereblon therefore regulates the formation of this complex. Knockdown of Rabex-5 in the THP-1 macrophage cell line up-regulated Toll-like receptor (TLR)-induced cytokine and type 1 IFN production via a STAT1/IRF activating pathway. Thus, we identify Rabex-5 as a IMiD target molecule that functions to restrain TLR activated auto-immune promoting pathways. We propose that release of Rabex-5 from complex with Cereblon enables the suppression of immune responses, contributing to the antiinflammatory properties of IMiDs.

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Basophils and Autoreactive IgE in the Pathogenesis of Systemic Lupus Erythematosus

Cited by 40 publications

References 55 publications

Balance between IL‐3 and type Iinterferons and their interrelationship with FasL dictates lifespan and effector functions of human basophils

Balance between IL‐3 and type Iinterferons and their interrelationship with FasL dictates lifespan and effector functions of human basophils

The deleterious role of basophils in systemic lupus erythematosus

Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production

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