Genetic susceptibility to lupus: the biological basis of genetic risk found in B cell signaling pathways

Abstract

Over 50 genetic variants have been statistically associated with the development of SLE (or lupus). Each genetic association is a key component of a pathway to lupus pathogenesis, the majority of which requires further mechanistic studies to understand the functional changes to cellular physiology. Whereas their use in clinical practice has yet to be established, these genes guide efforts to develop more specific therapeutic approaches. The BCR signaling pathways are rich in lupus susceptibility genes and may well provide novel opportunities for the understanding and clinical treatment of this complex disease.

Figure 1.. Lupus risk genes regulate B cell signaling.

Engagement of cell surface receptors, inhibitory or excitatory, induces signaling events involving numerous lupus-associated genes. LYN can bind to excitatory receptors, such the BCR, and inhibitory receptors, such as CD22 and FcγRIIb. In both cases, it acts as a kinase to initiate downstream activity, with the end result of activation or inhibition depending on the context of the receptor. BLK is also a PTK but does not interact with inhibitory receptors, resulting in the propagation of excitatory signals only. LYP is a PTP and thus, dephosphorylates second messengers in downstream activation pathways, resulting in reduced activation. BANK1 is a scaffold protein that brings PTKs into proximity with targets such as IP₃R. BANK1 can also suppress cellular activation, for example, by inhibiting CD40-dependent Akt phosphorylation. Proteins shaded in brown are coded by lupus risk-associated genetic loci. NFAT, Nuclear factor of activated T cells.

Figure 2.. Lupus risk genes regulate NF-κB activation.

Ubiquitination (Ub) is a key regulatory step for numerous cell-signaling events. A20 and TNIP1 form a complex that cleaves activating K63-linked ubiquitin chains (depicted in the figure by ovals) and add K48-linked ubiquitin chains (depicted in the figure by squares). Whereas the exact mechanism is not known, A20 and TNIP1 act in a MyD88-dependent manner to regulate inflammation, in part, by inhibiting TRAF6, which is an E3 ubiquitin ligase that is known to act downstream of CD40 and MyD88-linked extracellular (TLR1/2, TLR2/6, TLR4, and TLR5) and intracellular (TLR3, TLR7/8, and TLR9) TLRs. TRAF6 activation leads to the phosphorylation of IRF5 and IRF7, which among other functions, activate NF-κB signaling. Of note, each of these genes participates in many interactions beyond those depicted in this figure. Proteins shaded in brown are coded by lupus risk-associated genetic loci.