Intracellular Targets in SLE

In SLE, the magnitude or persistence of the disease is determined by the perpetuation of an exaggerated innate and adaptive immune responses towards self-antigens. Soluble mediators acting on cellular surface receptors bring signals to a variety of immune cells, and then there is a complex network of intracellular signalling that leads to a variety of transcriptional changes. These pathways can be linked to the particular cytokines or chemokines but can also be activated by receptor independent responses. The kinases that initiate these pathways are generally classified according to their structure and primary functions. While there has been much interest to develop small molecule drug targeting these intracellular targets, the attrition rate of those made to clinical development has been quite high. In SLE, a number of emerging targets has been studied and developed. Some of these are closer to the therapeutic horizon than others and will be explored specifically in this chapter. Key T cell intracellular pathways such as the calcium-calcineurin-Nuclear Factor of an Activated T cells (NFAT) pathway, and Mitogen-Activated Protein Kinases (MAPK), and B cell receptor mediated pathways such as Brunton’s tyrosine kinase (BTK), or spleen tyrosine kinase (SYK) pathway, and the Janus kinase (JAK), ubiquitin-proteasome system (UPS), and the Mechanistic Target of Rapamycin (mTOR) pathways that are present in broad ranging types of immune cells will be discussed.