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Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses.

ABSTRACT: IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.

SUBMITTER: Spencer S

PROVIDER: S-EPMC6719421 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses.

Spencer Sarah S Köstel Bal Sevgi S Egner William W Lango Allen Hana H Raza Syed I SI Ma Chi A CA Gürel Meltem M Zhang Yuan Y Sun Guangping G Sabroe Ruth A RA Greene Daniel D Rae William W Shahin Tala T Kania Katarzyna K Ardy Rico Chandra RC Thian Marini M Staples Emily E Pecchia-Bekkum Annika A Worrall William P M WPM Stephens Jonathan J Brown Matthew M Tuna Salih S York Melanie M Shackley Fiona F Kerrin Diarmuid D Sargur Ravishankar R Condliffe Alison A Tipu Hamid Nawaz HN Kuehn Hye Sun HS Rosenzweig Sergio D SD Turro Ernest E Tavaré Simon S Thrasher Adrian J AJ Jodrell Duncan Ian DI Smith Kenneth G C KGC Boztug Kaan K Milner Joshua D JD Thaventhiran James E D JED

The Journal of experimental medicine 20190624 9

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by <i>IL6R</i> We describe two patients with homozygous mutations in <i>IL6R</i> who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations ...[more]

PMID: 31235509

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Project description:UnlabelledBackgroundInterleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R) are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer.MethodsWe examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb)-induced colitis in immune-sufficient Mdr1a-/- mice and in T- and B-cell-deficient Rag2-/- mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression.ResultsTreatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a-/- mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a-/- mice treated with an anti-IL-7R antibody. In Rag2-/- mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity.ConclusionsResults from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development in Hb-infected mice by controlling the expansion of multiple leukocyte populations, as well as the activity of these immune cells. Our findings demonstrate an important function of IL-7R-driven immunity in experimental colitis and indicate that the therapeutic efficacy of IL-7R blockade involves affecting both adaptive and innate immunity.

Dataset Information

Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses.

Publications

Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses.

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