1. Interfering with baffled B cells at the lupus tollway: Promises, successes, and failed expectations 
Namrata Singh, MD, Bharat Kumar, MD, Vijay Aluri, MD, Petar Lenert, MD, PhD 
Journal of Allergy and Clinical Immunology 
Volume 137, Issue 5, Pages (May 2016)
DOI: /j.jaci
Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2. Fig 1
Interaction between low-affinity nucleoprotein-specific B cells and interferon-producing DCs in a microenvironment rich in the B-cell survival factor BAFF might result in a positive feedback amplification loop dependent on type I interferon secretion. Nucleoprotein-specific B cells that survive the negative selection process home to secondary lymphoid organs, wherein they become constantly exposed to apoptotic cell–derived nucleic acid–containing subcellular particles. An environment rich in B-cell survival factors or DC-derived type I (or type II) interferon, as well as abnormal BCR toning caused by Syk/BTK hyperphosphorylation or defective Lyn function, can result in upregulation of nucleic acid–sensing TLRs (and/or other DNA- or RNA-binding intracellular proteins). This can breach the threshold for TLR activation, resulting in a variety of B-cell effector functions, including their maturation into anti–nucleoprotein-secreting plasmablasts. Once secreted, these antibodies can combine with self-derived nucleoproteins and become internalized into plasmacytoid DCs (pDCs) through their Fc receptors. Subsequent interaction with TLR7/9 receptors triggers a robust type I interferon response, further decreasing the threshold for B-cell activation by upregulating the subset of interferon-inducible genes (interferon signature).
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci )
Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3. Fig 2
Cross-talk between BAFF, BCR, type I interferon, and TLRs in autoreactive B cells as a potential target for treating lupus. Signals through the BAFF receptor, type I interferon receptor, and BCR ease B-cell activation in part by upregulating the expression of nucleic acid–sensing TLRs. After ligand entry, TLRs bind UNC93b1 shuttle protein and translocate from the endoplasmic reticulum into an endosome-like intracellular compartment (likely autophagosome), wherein they interact with BCR-delivered self-nucleoproteins or microbe-derived nucleic acids. UNC93b1 is upregulated in B cells in patients with active SLE.74 TLRs undergo final proteolytic cleavage, generating active C-terminal TLR fragments, which dimerize and undergo conformational change on recognition of DNA- or RNA-containing ligands. This results in myeloid differentiation response gene–88 (MyD88)–dependent downstream signaling, causing robust mitogen-activated protein kinase and nuclear factor κB activation. Blocking BAFF/BAFF receptor interaction with neutralizing anti-BAFF antibodies can negatively affect the survival of low-affinity autoreactive B cells, their responsiveness to low-affinity TLR ligands, or both. Type I interferon blockade can prevent TLR upregulation in B cells and their subsequent intracellular trafficking. BTK and Syk blockade can affect not only downstream BCR signaling but also TLR-dependent mitogen-activated protein kinase and nuclear factor κB activation. INH-ODN–based TLR7 to TLR9 inhibitors can act by either competing with the BCR-mediated entry of nucleic acids into B cells or by binding to cleaved C-terminal TLR fragment, thus preventing its conformational change and downstream signal transduction. BCR signals can optimize INH-ODN entry into autophagosomes, increasing their potency for certain TLR9-mediated B-cell outcomes. However, in TLR7-engaged B cells BCR signals might negatively influence the ability of INH-ODNs to block TLR7-mediated activation.
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci )
Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions