NF-kB, Autoimmunity and Mycobacteria

Many autoimmune diseases feature functional or genetic defects that can alter NF-kB function. In an animal model of type 1 diabetes and Sjogren’s syndrome, a defective proteasome prevents NK-kB-induced gene transcription by precluding cleavage of IkBa from NF-kB in the cytoplasm. Polymorphisms in such NK-kB related genes as SUMO4, NOD2, IKBL, IRF-5, TNFAIP3, TNF, TNFR1, TNFR2, IL-10 and DLG-5 have been associated with autoimmune diseases. Each of these genes has interactions with members of the NF-kB pathway and when defective can disrupt NF-kB function. Treatment of autoimmune diseases can also take advantage of the NF-kB pathway. TNF and the TNF-inducer mycobacterium bacillus calmette-guerin (BCG) selectively destroy autoreactive but not normal T lymphocytes through NF-kB dysregulation. BCG also induces proliferation of immunosuppressive T-regulatory cells by induction of transmembrane TNF, its preferential binding to TNFR2, and transcription of pro-survival genes via the normally functioning NF-kB pathway. Thus, the NF-kB pathway can play a central role in autoimmunity and its treatment. ABBREVIATIONS BCG: Bacillus Calmette-Guerin; T Cells: T-Lymphocytes; TNF: Tumor Necrosis Factor; NOD Rat: Non-Obese Diabetic Rat. INTRODUCTION This short article reviews the numerous types of genetic and functional defects altering NF-kB activity across autoimmune diseases, ranging from type 1 diabetes to lupus to multiple sclerosis. This article also reviews the benefits of the mycobacterium Bacillus Calmette-Guerin (BCG) in the treatment of autoimmune diseases through two different NF-kB-related mechanisms. In immune cells, NF-kB’s mode of activation varies according to cell type, state of activation, or developmental stage [1,2]. In T-lymphocytes (T cells), which mediate some types of autoimmunity, NF-κB normally is precluded from reaching the nucleus because its subunits are tightly bound to the inhibiting protein IκBα [3]. In response to induction by cytokines such as tumor necrosis factor (TNF) and other signals, IκBα is phosphorylated, ubiquinated, and then degraded by a proteasome. Once liberated from IκBα, NF-κB translocates to the nucleus where it binds to target DNA segments, initiating expression of various genes, including those encoding cytokines (e.g., IL-2, TNF-, and IFN-β), pro-apoptotic genes, or anti-apoptotic Central Faustman et al. (2015) Email: JSM Microbiology 3(1): 1020 (2015) 2/6 genes [4]. These life and death functions are vital for shaping the T cell repertoire and curtailing T cell proliferation after antigen exposures. More comprehensive reviews of the relationship between T cells, NFkB and autoimmunity are available [5-7].