Autoreactive IgE is prevalent in systemic lupus erythematosus and is associated with increased disease activity and nephritis

Abstract

The presence of autoantibodies in systemic lupus erythematosus, particularly those of the IgG subclass, have long been associated with disease onset and activity. Here we explored the prevalence of autoreactive IgE in SLE and its relevance to disease in French (n = 79) and United States (US) (n = 117) cohorts with a mean age of 41.5 ± 12.7 and 43.6 ± 15.3 years and disease duration of 13.5 ± 8.5 and 16.6 ± 11.9 years, respectively. Our findings show that approximately 65% of all SLE subjects studied produced IgE antibodies to the seven autoantigens tested. This positivity was increased to almost 83% when only those subjects with active disease were considered. SLE subjects who were positive for anti-dsDNA, -Sm, and -SSB/La -specific IgE showed a highly significant association in the levels of these antibodies with disease activity similar to that of the corresponding IgG's. A strong association of IgE autoantibodies with active nephritis was also found in the combined cohort analysis. A test of the predictive value of autoreactive IgE's and IgGs for disease activity (SLE Disease Activity Index (SLEDAI) ≥ 4) revealed that the best predictors were dsDNA-specific IgE and IgG, and that the age of an SLE subject influenced this predictive model. The finding argue that the overall levels of IgE autoantibodies, independently or in combination with IgG autoantibodies, may serve as indicators of active disease.

Figure 1. Elevated levels of dsDNA-, Sm-, SSA/Ro- and SSB/La-specific IgE antibodies in SLE subjects versus healthy controls.

A. Relative levels from a combined analysis of the US and French SLE cohorts for IgE antibody levels to the four aforementioned antigens. Mann Whitney test was used to compare the different groups. Mean ± SEM is shown. AU, Arbitrary Units. **p<0.01; ****p<0.0001. B. Prevalence of IgE autoantibodies to the aforementioned four common SLE autoantigens. Percentage of patients positive for IgE autoantibodies (2SD over the mean of healthy controls) to at least one of the four autoantigens tested. dsDNA-specific IgE (as the most prevalent autoreactive IgE) was used as the reference. The percent of anti-Sm IgE positive individuals are those without dsDNA-IgE, percent of anti-SSA/Ro positive individuals are without dsDNA- and Sm-IgE’s, and anti-SSB/La positive individuals are those without dsDNA, Sm and SSA/Ro reactivties. Therefore, patients in the group of those positive for anti-dsDNA IgE were also positive for the rest of IgE autoantibodies tested, but none of the subjects in the anti-SSB/La IgE positive group had detectable IgE autoantibodies for dsDNA, Sm, or SSA/Ro.

Figure 2. Comparison of the levels of dsDNA-, Sm-, SSA/Ro- and SSB/La-specific IgEs with disease activity.

A. Combined analysis of the levels of autoreactive IgE’s in the US and French SLE cohorts with disease activity as defined by SLEDAI score. Inactive, SLEDAI  = 0; Mild, SLEDAI >0 to <4; Active, SLEDAI ≥4. B. Combined US and French SLE cohort analysis of IgE autoantibodies with complement levels in serum. Low levels of complement were considered as C3<80 mg/dl or C4<15 mg/dl. Kruskal-Wallis with Dunn’s multiple comparisons test was used to compare the different groups. Mean ± SEM is shown. AU, Arbitrary Units. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.

Figure 3. Association of autoreactive IgE’s with lupus nephritis.

Relative levels of dsDNA-, Sm-, SSA/Ro- and SSB/La-specific IgE autoantibodies in the combined US and French SLE cohort with no nephritis, inactive or active nephritis. Kruskal-Wallis with Dunn’s multiple comparisons test was used to compare the different groups. Mean ± SEM is shown. AU, Arbitrary Units. *p<0.05.

Figure 4. Identification of novel IgE autoantigens in SLE, overall prevalence, and association of all tested autoreactive IgE’s with SLE disease activity.

A. Relative levels of APEX, MPG and CLIP4 specific IgEs and IgGs in US and French SLE cohorts. B. Overall prevalence of IgE autoantibodies in SLE for seven tested autoantigens tested (dsDNA, Sm, SSA/Ro and SSB/La, APEX, MPG and CLIP4). C. Comparison of the levels of all tested autoreactive IgE antibodies (as in B) in US and French cohorts with disease activity as measured by SLEDAI score. Inactive, SLEDAI  = 0; Mild, SLEDAI >0 to <4; Active, SLEDAI ≥4. D. Prevalence of all tested autoreactive IgE’s in US and French SLE subjects with active disease. Mann Whitney test or Kruskal-Wallis with Dunn’s multiple comparisons test (more than two groups) was used to compare the different groups. Mean ± SEM is shown. **p<0.01; ***p<0.001, ****p<0.0001.