Abstract
We report that TLR7, IL-6, and the adaptive immune system are essential for autoimmunity and glomerulonephritis but not for liver pathology in mice expressing the ubiquitin-binding-defective ABIN1[D485N] mutant. The blood and organs of ABIN1[D485N] mice have exceptionally high numbers of patrolling monocytes (pMo), which develop independently of IL-6 and the adaptive immune system. They are detectable in the blood months before autoimmunity and organ pathology are seen and may have diagnostic potential. The splenic pMo, inflammatory monocytes (iMo), and neutrophils of ABIN1[D485N] mice expressed high levels of mRNAs encoding proteins released during NETosis, which together with the high numbers of monocyte-derived dendritic cells (MoDCs) may drive the liver pathology in ABIN1[D485N] mice, and contribute to the pathology of other organs. The splenic iMo of ABIN1[D485N] mice displayed high expression of mRNAs encoding proteins controlling cell division and were actively dividing; this may underlie the increased pMo and MoDC numbers, which are derived from iMo. An orally active IRAK4 inhibitor suppressed all facets of the disease phenotype and prevented the increase in pMo numbers.
Highlights
Systemic lupus erythematosus (SLE, lupus) is a complex disease in which the body’s immune system attacks its own organs, resulting in severe inflammation and damage of these tissues
Autoantibody production and glomerulonephritis requires IL-6 in A20-binding inhibitor of NF-κB1 (ABIN1)[D485N] mice, but liver pathology and lung inflammation do not IL-6 is known to stimulate the generation of splenic germinal centre B (GCB) cells (Kopf et al, 1998), which are required for isotype switching somatic hypermutation, leading to the production of high-affinity antibodies such as Antinuclear antibodies (ANAs) and anti-double-stranded DNA (dsDNA) autoantibodies
Neither the liver pathology (Figs 1G and S1C) nor lung inflammation (Figs 1H and S1D) were affected. These experiments suggest that the overproduction of IL-6 in ABIN1[D485N] mice contributes to germinal centre formation, antibody production, and glomerulonephritis, but is not required for the liver pathology or lung inflammation seen in this model
Summary
Systemic lupus erythematosus (SLE, lupus) is a complex disease in which the body’s immune system attacks its own organs, resulting in severe inflammation and damage of these tissues. Up to 70% of lupus patients develop nephritis, which is caused by immunoglobulins and complement components becoming deposited in the glomerulus of the kidney. For this reason, studies aimed at gaining a molecular understanding of the causes of lupus have mainly focused on the pathways leading to glomerulonephritis. The liver is an important target of SLE (Bessone et al, 2014), whereas 50% of lupus patients experience lung problems, most frequently pleuritis and pneumonitis. Antinuclear antibodies (ANAs) and double-stranded DNA (dsDNA) antibodies have been detected in the pleural fluid (Porcel et al, 2007; Toworakul et al, 2011), but whether they contribute to the lung pathology seen in lupus or are just a consequence of the disease is unclear
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