How the study of children with rheumatic diseases identified interferon‐α and interleukin‐1 as novel therapeutic targets

Pascual, Virginia; Allantaz, Florence; Patel, Pinakeen; Palucka, A. Karolina; Chaussabel, Damien; Banchereau, Jacques

doi:10.1111/j.1600-065x.2008.00643.x

Cited by 71 publications

(38 citation statements)

References 177 publications

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“…The extent of the increase in IFNα production has a strong correlation with the stages of the disease [12]. These findings implicate the pivotal role of IFNα in the pathogenesis of SLE, leading to the development of IFN-related antagonists as a potential therapeutic intervention in SLE [8,13].…”

Section: Introductionmentioning

confidence: 99%

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

Ouyang

Gong

Li³

et al. 2012

J Mol Med

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Increasing evidences suggest that the type I interferon α (IFN α) plays a critical role in the etiopathogenesis of systemic lupus erythematosus (SLE), which makes it a promising therapeutic target for the treatment of the disease. By screening a large size non-immune human antibody library, we have developed a human single-chain antibody (ScFv) AIFN α 1bScFv01 and corresponding whole antibody AIFN α 1bIgG01 to human interferon α 1b (IFN α 1b) with high specificity and high affinity. The IgG antibody could down-regulate the expression of ISG15 and IFIT-1 induced by either recombinant IFN α 1b or naïve IFN α from SLE patients' sera, and reduced total serum IgG and IgM antibodies level in a pristane-primed lupus-like mouse model. The crystal structure of AIFN α 1bScFv01-IFN α 1b complex solved to 2.8 Å resolution revealed that both Pro26-Gln40 region in loop AB and Glu147-Arg150 region in helix E of IFN α 1b contribute to binding with AIFN α 1bScFv01. Four residues of above two regions (Leu30, Asp32, Asp35 and Arg150) are critical for the formation of antigen-antibody complexes. AIFN α 1bScFv01 shares partial epitopes of IFN α 1b with its receptor IFNAR2 but with much higher binding affinity to IFN α 1b than IFNAR2. Thus, AIFN α 1bIgG01 exhibits its neutralizing activity through competition with IFNAR2 to bind with IFN α and prevents the activation of IFN α-mediated signaling pathway. Our results highlight the potential use of the human antibody for modulating the activity of IFN α in SLE.

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Section: Introductionmentioning

confidence: 99%

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

Ouyang

Gong

Li³

et al. 2012

J Mol Med

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“…Since it has been reported that members of IL-1 family, namely IL-1b,IL-1 receptor antagonist (IL-1Ra) and IL-18, appear to be closely associated with the development and course of SLE [7,20,21], in present study, we investigated whether abnormal serum IL-33 level was closely associated with development of SLE in Chinese population.…”

Section: Introductionmentioning

confidence: 99%

Association of increased serum IL-33 levels with clinical and laboratory characteristics of systemic lupus erythematosus in Chinese population

Yang

Liang

et al. 2010

Clin Exp Med

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormal production of autoantibodies and proinflammatory cytokines. Although interleukin-33 (IL-33), a novel number of the IL-1 family, has been reported to have proinflammatory effects, the association of IL-33 with SLE has remained unknown. The aim of this study was to examine whether the serum IL-33 level is associated with SLE. A total of 70 patients with SLE were recruited. Sera from these patients were obtained at their visit and were compared to sera from 40 healthy controls or 28 patients with rheumatoid arthritis (RA) for IL-33 level. Furthermore, blood samples from patients with SLE were determined for various SLE-related laboratory variables, including blood routine, complements, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and some autoantibodies. Serum IL-33 level was significantly increased in patients with SLE, compared with healthy controls, but was lower than that with RA. In patients with SLE, most clinical and laboratory characteristics did not correlate with serum IL-33 levels, with exceptions of thrombocytopenia, erythrocytopenia, anti-SSB antibody, ESR, CRP and IgA. By Spearman's correlation coefficient, patients with SLE showed close correlation of IL-33 with ESR, CRP and IgA, and by multivariate logistic regressions, patients with SLE showed significantly independent association of IL-33 with thrombocytopenia, erythrocytopenia and anti-SSB antibody. Our results suggest that IL-33 may play a role in acute phase of SLE, but it was not associated with course of the disease. Moreover, IL-33 may exert biologic effects on erythrocytes and platelets or their precursors in SLE.

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“…Recent studies suggested that SoJIA might be linked to abnormalities in the innate immune system [43,44]. SoJIA is typically considered a polygenic disease, and candidate-gene association studies reported many risk alleles.…”

Section: January 2015: Monogenic Form Of Systemic Juvenile Idiopathicmentioning

confidence: 99%

Update on genetics and pathogenesis of autoinflammatory diseases: the last 2 years

Aksentijevich

2015

Semin Immunopathol

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Autoinflammatory diseases are a genetically heterogeneous group of rheumatologic diseases that are driven by abnormal activation of the innate immune system. Patients present with recurrent episodes of systemic inflammation and a spectrum of organ-specific comorbidities. These diseases are mediated by the overproduction of various inflammatory cytokines, such as IL-1, IL-18, IL-6, TNFα, and type I interferon. Treatments with biologic agents that inhibit these cytokines have been very efficient in most patients. During the past 2 years, remarkable progress has been made in the identification of disease-associated genes owing mostly to new technologies. Next generation sequencing technologies (NGS) have become instrumental in finding single-gene defects in undiagnosed patients with early onset symptoms. NGS has advanced the field of autoinflammation by identifying disease-causing genes that point to pathways not known to regulate cytokine signaling or inflammation. They include a protein that has a role in differentiation of myeloid cells, a ubiquitously expressed enzyme that catalyzes the addition of the CCA terminus to the 3-prime end of tRNA precursors, and an enzyme that catalyzes the oxidation of a broad range of substrates. Lastly, newly described mutations have informed a whole new dimension on genotype-phenotype relationships. Mutations in the same gene can give rise to a range of phenotypes with a common inflammatory component. This suggests greater than anticipated contributions by modifying alleles and environmental factors to disease expressivity.

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How the study of children with rheumatic diseases identified interferon‐α and interleukin‐1 as novel therapeutic targets

Cited by 71 publications

References 177 publications

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

Structural insights into a human anti-IFN antibody exerting therapeutic potential for systemic lupus erythematosus

Association of increased serum IL-33 levels with clinical and laboratory characteristics of systemic lupus erythematosus in Chinese population

Update on genetics and pathogenesis of autoinflammatory diseases: the last 2 years

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