Central role of defective apoptosis in autoimmunity

Abstract

Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development likely induces cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accelerated apoptosis, are now demonstrated as central defects in diverse murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor Fas (CD95) and its ligand, FasL (CD95 L), have been identified. These errors create a lymphoid system resistant to apoptosis. In contrast, select lymphoid subpopulations of maturing autoimmune prone non-obese diabetic mice have identifiable and pathogenic T cells with both in vivo and in vitro heightened apoptosis after drug interventions. In part, these defects are due to faulty activation of transcription factors such as nuclear factor-B (NF-B) that normally protect against apoptotic death. The genetic basis of interrupted NF-B in pathogenic memory T cells in diabetes is attributable to a developmentally controlled gene defect in an essential subunit of the proteasome. No specific gene in most common forms of human autoimmune disease has yet been identified. Functional assays from diverse laboratories repeatedly demonstrate heightened apoptosis in multiple cellular signaling pathways for cell death, suggesting a common theme in disease causality.

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

“…This is in agreement with previous work suggesting that immunoproteasome impairment in mice is linked to changed cytokine patterns (17,25) and altered T cell expansion and maintenance (12,26).…”

Genomic profiling of interpopulation diversity guides prioritization of candidate-genes for autoimmunity

“…All the above genes are considered key CGs already known to be involved in some autoimmune conditions. 56,[61][62][63] Focusing on these genes as a first step in autoimmune related association studies may facilitate the discovery of true associations under less stringent study design models and more reliable data analysis schemes.…”

Conjugated linoleic acid enhances glutathione synthesis and attenuates pathological signs in MRL/MpJ-Faslpr mice

“…Apoptosis is the process that leads to the ordered destruction of cells, avoiding the release of intracellular contents into the extracellular environments, where they have a powerful inflammatory effect. Defective functioning of the cell death program has been recognized to play a critical role in the pathogenesis of autoimmune diseases (7), and a proapoptotic effect has been identified in some antineoplastic and anti-inflammatory agents used as medication (methotrexate and mycophenolate mofetil, respectively) (8,9). The MRL/ MpJ-Fas lpr (MRL/lpr) mouse is a prototypical model for human SLE in which the presence of a single gene mutation on the Fas (CD95) gene leads to reduced signaling for apoptosis (10).…”