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Friday, January 8, 2016

The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects

Autoimmunity and immunodeficiency represent two sides of the same coin. Whether the human body’s defenses attack its own healthy cells or its ability to fight off disease is compromised, both result in a dysfunctional immune system. In their review article, Grimbacher et al. discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiological pathways and clinical features of monogenic defects that result in autoimmune disease (J Allergy Clin Immunol 2016; 137(1): 3-17).

Multiple single gene defects have been shown to result in rare diseases that show features of both autoimmunity and immunodeficiency. Nearly 300 monogenic traits have been associated with various forms of primary immunodeficiency diseases and auto-inflammatory syndromes. It is likely that more common autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) result from a polygenic inheritance. Genes implicated in single gene disorders have also been linked to polygenetic disorders thus confirming the intricate connections and overlays between autoimmunity and immune deficiency,

In the case of SLE, genome-wide association studies and their follow-up studies have identified more than 50 robust loci associated with susceptibility, suggesting polygenic disease development. There are also emerging monogenic SLE disease models, as factors such as early disease onset, familial SLE, and syndromal lupus likely involve monogenic defects. The authors outline nine pathophysiological pathways, which, if impaired, inevitably lead to serious disease and ultimately to autoimmunity.

Different pathways can lead to the development of a given disease.. Autoimmunity is one of these etiopathologies, and recent and continued advancement in detection methods, in particular next generation sequencing, has led to the identification of genetic defects associated with autoimmune phenotypes. The monogenic defects explored here all interrupt the equilibrium of the immune system, and they have already begun to influence and change our patients’ management. 

This review thus emphasizes of looking at immune dysfunction as a whole rather than breaking it down into silos of immunodeficiency and autoimmunity

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