21 Apr 2016

Preventing the development of multi-organ autoimmunity

By Dr Jodie Abramovitch

Autoimmune disease occurs when the immune system incorrectly recognises self-tissues and organs as being potentially dangerous - like a pathogen. The immune system attacks the tissue or organ – sometimes in an organ-specific manner (eg. type I diabetes) or sometimes in a multi-organ fashion (eg. lupus) – which leads to disease symptoms. What causes the onset of autoimmune disease is not well understood and, consequently, there is no cure with treatments predominantly aimed at relieving inflammatory symptoms.

Elisha de Valle - first author of this study
In a collaborative study, Monash researchers examined the role of transcription factor NF-κB1 in a specific type of immune cell, Follicular B cells (Fo B cells), and its role in controlling multi-organ autoimmune disease. NF-κB1 is important for regulating B cell function and when Fo B cells become deregulated they can produce antibodies that target and destroy vital organs. The authors of this study used a mouse model that lacks the NF-κB1 gene and analysed the effect on Fo B cells. They found that Fo B cells lacking NF-κB1 secreted a large amount of pro-inflammatory factor IL-6 and this had an effect on surrounding immune cells. Specifically, IL-6 led to the over stimulation of B cells which resulted in the formation of  germinal centre structures (sites where antibody responses are launched) and, in turn, an increase in the presence of self-reacting antibodies against self-tissues and organs within the NF-κB1 deficient mice. Moreover, IL-6 also caused Fo B cells to proliferate at a higher rate which exacerbated the germinal centre B cell response. Without NF-κB1, the mice developed severe multi-organ autoimmune disease and had a reduced life span compared to healthy mice. This was largely attributable to the production of IL-6 by Fo B cells. Importantly, when IL-6 was blocked the development of autoimmune disease was greatly reduced.

This study revealed that NF-κB1 has an essential role in controlling the function of Fo B cells, primarily to limit the production of inflammatory factor IL-6. In the absence of NF-κB1, the production of IL-6 becomes deregulated and severe autoimmune disease can occur. These conclusions further the understanding of the mechanisms that control IL-6 production and may lead to better management of patients with autoimmune disease.

Referencede Valle EGrigoriadis GO'Reilly LAWillis SNMaxwell MJCorcoran LMTsantikos ECornish JKFairfax KAVasanthakumar AFebbraio MAHibbs MLPellegrini MBanerjee AHodgkin PDKallies AMackay FStrasser AGerondakis SGugasyan RNFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells. J Exp Med. 2016 Apr; 213:621-41. 
doi: 10.1084/jem.20151182.

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