Background/Purpose:

Increased circulating antibody secreting cells (ASC), including both CD138- plasmablasts and CD138+ plasma cells (PB/PC), correlate with SLE activity and are prominent during Lupus flares.   We tested whether this expansion is predominantly driven by typical SLE autoreactivities including anti-dsDNA, -Sm and -Ro and 9G4+ antibodies.    

Methods:

Peripheral blood lymphocytes (PBL) were collected from SLE patients (n=12; 4 mild-severe flare patients defined by SELENA-SLEDAI) with high serum levels of ≥1 autoantibody (anti-dsDNA, anti-Sm or anti-Ro).  PB/PC frequency was calculated as % of total B-cells by flow cytometry.  Anti-dsDNA, anti-Sm and anti-Ro60, 9G4+ and anti-microbial (anti-tetanus toxoid and anti-influenza) IgG ASC were detected by ELISPOT and expressed as % of total IgG ASC.   Memory cells were activated by stimulation with R848 and IL-2 for 7 days. Frequencies of antigen specific IgG memory cells were determined by ELISPOT as before. 

Results:

PB/PC frequencies were increased for up to 25-fold in SLE compared to HC and comprised up to 38 % of total B-cells.  Of total IgG ASC, frequencies of each SLE specific IgG ASC responses (anti-dsDNA, anti-Sm and anti-Ro60) never exceeded 3.4% (mean ± SD, 0.25 ± 0.65%) in patients with high serum antibody levels.   9G4+ ASC, which include several SLE-specific autoreactivities including anti-dsDNA and anti-apoptotic cells, were the most abundant autoreactivity but did not exceed 6% (mean ± SD, 2.2  ± 1.7%).  Combined, all the lupus–related autoreactivities accounted for <10% of all IgG ASC.   No correlation was found between PB/PC frequencies and SLE specific or 9G4+ IgG ASC frequencies.  Furthermore, anti-Tetanus and/or anti-influenza ASC, usually not found in healthy PBL, were found in SLE PBL in frequency similar to autoreactive responses (0.06 ± 0.09% and 0.37 ± 0.12%, respectively).   Anti-Sm, anti-Ro and 9G4 as well as anti-tetanus and anti-influenza reactive IgG memory cells were present in frequencies typically higher than that found for ASC of the same antigenic reactivity.  Notably, in 5 out of 6 patients with high anti-Ro serum titers, anti-Ro IgG memory cells represented > 2% of all IgG memory cells.  In contrast, anti-dsDNA IgG memory cell frequencies (0.01 ± 0.02%) were as low as anti-tetanus memory cell frequencies (0.12 ± 0.31%).

Conclusion:

Combined, conventional lupus autoreactivities only account for <10% of the greatly expanded numbers of circulating ASC characteristic of lupus flares.  In addition, these frequencies are lower than the frequency of memory cells for the corresponding autoantigens.  Moreover, antimicrobial responses are present in circulating ASC with frequencies similar to autoimmune responses.  While our studies did not test for other potential SLE autoreactivities, our results are consistent with a polyclonal expansion of ASC during lupus flares that is not predominantly driven by conventional autoantigens even in patients with high titers of serum antibodies.  These studies have important implications for our understanding of the mechanisms underlying lupus flares and the contribution of different cellular compartments to the generation of serum autoantibodies at different times in the course of the disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sle-flares-are-characterized-by-generalized-polyclonal-expansions-of-antibody-secreting-cells-without-preference-for-autoimmune-responses/