Basophil Activation-Dependent Autoantibody and Interleukin-17 Production Exacerbate Systemic Lupus Erythematosus

This review focuses on the biology of T helper 17 (Th17) and regulatory T (Treg) cells and their role in inflammatory diseases, such as rheumatoid arthritis. Th17 cells represent a pro-inflammatory subset whereas Treg cells have an antagonist effect. Their developmental pathways are reciprocally interconnected and there is an important plasticity between Th17 and Treg cells. These features implicate that the Th17/Treg balance plays a major role in the development and the disease outcomes of animal model and human autoimmune/inflammatory diseases. During these diseases, this balance is disturbed and this promotes the maintenance of inflammation. Targeting the Th17/Treg imbalance can be performed at different levels such as inhibition of pro-inflammatory cytokines and their receptors, of pathogenic cells or their specific signaling pathways. Conversely, direct effects include administration or induction of protective cells, or stimulation of their specific pathways. Several clinical trials are underway and some positive results have been obtained. Copyright © 2014 Elsevier B.V. All rights reserved.

Following activation, CD4+ T cells differentiate into different lineages of helper T (T(H)) cells that are characterized by distinct developmental regulation and biological functions. T(H)17 cells have recently been identified as a new lineage of effector T(H) cells, and they have been shown to be important in immune responses to infectious agents, as well as in various immune diseases. Over the past two to three years, there has been a rapid progress in our understanding of the differentiation programme of T(H)17 cells. Here, I summarize our current knowledge of the unique gene expression, cytokine-mediated regulation and transcriptional programming of T(H)17 cells, and provide my personal perspectives on the future studies that are required to elucidate this lineage in more detail.

Immunoglobulin D (IgD) is an enigmatic antibody isotype that mature B cells co-express with IgM through alternative RNA splicing. We found active T cell-dependent and T cell-independent IgM-to-IgD class switching in human upper respiratory mucosa B cells. This process required activation-induced cytidine deaminase and generated local and circulating IgD-producing plasmablasts reactive to respiratory bacteria. Circulating IgD bound to basophils through a calcium-mobilizing receptor that induced antimicrobial, opsonizing, inflammatory and B cell-stimulating factors including cathelicidin, interleukin-1, interleukin-4 and B cell-activating factor BAFF upon IgD cross-linking. By showing dysregulation of IgD class-switched B cells and IgD-armed basophils in autoinflammatory syndromes with periodic fever, our data indicate that IgD orchestrates an ancestral surveillance system at the interface between immunity and inflammation.