AUTHOR=Harley Isaac T. W. , Allison Kristen , Scofield R. Hal 

TITLE=Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.953439

DOI=10.3389/fimmu.2022.953439

ISSN=1664-3224

ABSTRACT=Most B cells produced in the bone marrow have some level of autoreactivity. Despite central tolerance mechanisms that eliminate these cells, many escape to periphery. In healthy individuals, escapees are rendered functionally non-responsive to restimulation through their antigen receptor, a process termed anergy. It remains incompletely clear why this broad repertoire autoreactivity is maintained. Likewise, it is unclear why in some individuals autoreactive B cell clones become activated and drive pathophysiologic changes in autoimmune diseases. Both of these remain central questions in Immunology. 

In most individuals, autoimmune diseases arise from complex interplay of genetic risk factors and environmental influences. Advances in genome sequencing and increased statistical power from large patient cohorts has led to identification of more than 200 autoimmune disease risk loci. It has been observed that autoantibodies are detectable in the serum years to decades prior to the diagnosis of autoimmune disease. Thus, current models hold that genetic defects in the pathways that control autoreactive B cell tolerance set genetic liability thresholds across multiple autoimmune diseases. 

These seminal concepts were developed in murine models of autoimmune disease. Nonetheless, some perceive a disconnect between human risk alleles and those identified in murine models of autoimmune disease. Here, we synthesize the current state of the art in our understanding of human risk alleles in two prototypical autoimmune diseases – systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) and their spontaneous murine disease models. We compare these risk networks to those reported in murine models of these diseases, anergy and central tolerance. We highlight differences between murine and human environmental and genetic factors that may impact autoimmune disease development and expression. Finally, we show that there is substantial overlap between the molecular networks that define these disease states across species. Our synthesis and analysis of the current state of the field are consistent with the idea that the same molecular networks are perturbed in murine and human autoimmune disease. Based on these analyses, we anticipate that murine autoimmune disease models will continue to yield novel insights into how best to diagnose, prognose, prevent and treat human autoimmune diseases.