Lupus researchers identify why the body attacks its own defenses
Scientists have discovered that lupus patients produce antibodies that attack protective molecules meant to clear cellular debris and prevent inflammation. The finding could reshape how doctors monitor and treat this unpredictable disease, which costs the U.S. healthcare system billions annually and primarily affects young women.
Originaltitel: Autoreactivity to protective molecules in systemic lupus erythematosus
<p>Systemic lupus erythematosus (SLE) is a chronic autoimmune disease primarily affecting women of young age. It is a multi-organ disease with a diversity of clinical manifestations affecting the heart, skin, joint, lung, and kidneys, and disease flares and times of remission are typically seen in an oscillating pattern in patients with SLE. SLE is characterized by extensive autoantibody production, dysregulation of the immune system, and formation of immune complexes which are not properly cleared. The pathophysiology of the disease is complex and monitoring SLE can be difficult. The aim of this thesis was to investigate the significance of protective molecules and autoantibodies targeting them in a group of well-characterized patients with SLE.</p><p>The pentraxin family is a group of highly conserved pattern recognition molecules with immunomodulatory functions involved in recognition and clearance of pathogens as well as cellular debris and apoptotic cells. The short pentraxin C-reactive protein (CRP) and the long pentraxin pentraxin-3 (PTX3) are members of the family with overlapping functions. CRP is natively pentameric (pCRP) and can undergo irreversible dissociation to its monomeric subunits (mCRP) in certain conditions. These two isoforms of CRP are known to exert contrasting immunologic effects, where mCRP is seen as the more pro-inflammatory isoform. In Paper I of this thesis, we measured these two CRP isoforms in the serum of patients with SLE and found that their ratio in paired samples could differentiate between patients in active disease versus remission. In Paper II we investigated pCRP and mCRP on the surface of extracellular vesicles (EVs) in SLE and discovered an abundance of mCRP-bound EVs in active SLE and in anti-CRP autoantibody positive patients, as well as a higher ratio of mCRP/pCRP-bound EVs in active disease. These findings suggest the mCRP/pCRP ratio as a potential biomarker for monitoring disease activity, and a possible role of mCRP-bound EVs in SLE pathophysiology.</p><p>Autoantibodies targeting CRP as well as PTX3 have been found in SLE. Anti-CRP antibodies are seen to reflect disease activity while anti-PTX3 antibodies are suggested to have a protective role in SLE. Herein, anti-CRP and anti-PTX3 antibodies were measured and the linear binding epitopes of CRP and PTX3 were investigated in Paper III and Paper IV. We found a variety of epitopes scattered across the full sequence of both proteins, and some of them associated with disease activity and clinical variables of importance in SLE. The levels of anti-PTX3 were seen in lower levels among patients with active SLE compared to those with quiescent disease.</p><p>In conclusion, combined assessment of pCRP and mCRP might be useful in monitoring disease activity, and mCRP-bound EVs associated with active disease and anti-CRP antibody positivity. In addition, anti-CRP and anti-PTX3 antibodies target various epitopes with different potential implications in SLE. Further studies are needed to investigate the potential pathophysiological implications of these studies.</p>