Signaling Mutations and Autoimmunity

Abstract

Mutations in a number of signaling components in mice can lead to strong autoimmune phenotypes. In some cases, these mutations likely compromise important feedback inhibitory pathways that downregulate antigen receptor signaling. For example, a deficiency of Lyn leads to a severe lupus-like autoimmunity. This autoimmunity may result from loss of a feedback inhibitory pathway in which Lyn phosphorylates CD22, triggering recruitment of the tyrosine phosphatase SHP-1 to the plasma membrane, which then dampens BCR signaling. Loss of Lyn also compromises an inhibitory pathway involving Fc gamma RIIb and SHIP, an inositol phosphatase. Mutation of Fyn exacerbates the autoimmunity caused by loss of Lyn. This may be due in part to a nonimmunological compromise in the integrity of the podocytes in the kidney, which may make the kidneys more susceptible to immune complex-induced damage. Fyn-deficient mice exhibit a number of immunological abnormalities and also exhibit some autoimmunity, although this is less severe than what is seen in Lyn-deficient mice. Recently a gain of function mutation in CD45 that may enhance activity of Src family tyrosine kinases has also been found to cause autoimmune disease, suggesting that the level of Src family tyrosine kinase activity is an important determinant of immune tolerance. Finally, several studies suggest that there is a significant interaction between Src family tyrosine kinases and the Fas pathway that is important for self-tolerance. Although these studies are still at an early stage, it seems clear that alterations in regulators of antigen receptor signaling can contribute to autoimmunity.

Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2

“…The activation of JAKs triggers the phosphorylation of IL-6R and gp130, followed by the activation of various secondary messengers and transcription factors including STAT3, MAPKs, and Akt providing growth and proliferation signals (15). Genetic ablation or polymorphisms in key suppressors of JAK/STAT signaling (e.g., SOCS-1, SHP-1) have been implicated in increased serum IL-6 levels and risk of developing SLE in humans (16,17).…”

B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

“…Studies over the past few years have provided a wealth of new information regarding the selection processes that, ultimately, result in biologic effects. Notably, transgenic expression or inactivation of genes encoding certain signaling molecules was found to lead to autoimmune phenomena and to disease, suggesting that a tight balance in BCR signaling pathways is required to prevent pathogenic autoimmune reactions (3)(4)(5)(6).…”

Altering immune tolerance therapeutically: the power of negative thinking

“…Moreover, mutations of other molecules involved in B cell inhibitory pathways culminate in autoimmunity (reviewed in ref. [41]; Table 2). Thus, Lyndeficient mice manifest SLE-like disease, and their B cells are hyper-responsive to BCR cross-linking.…”