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. 2021 May 3:12:657211.
doi: 10.3389/fimmu.2021.657211. eCollection 2021.

Lower IgA Levels in Chronic Spontaneous Urticaria Are Associated With Lower IgE Levels and Autoimmunity

Merle Sauer  1   2 , Jörg Scheffel  1 , Stefan Frischbutter  1 , Pavel Kolkhir  1   3 , Yi-Kui Xiang  1 , Frank Siebenhaar  1 , Sabine Altrichter  1 , Marcus Maurer  1 , Martin Metz  1 , Karoline Krause  1
Affiliations

Lower IgA Levels in Chronic Spontaneous Urticaria Are Associated With Lower IgE Levels and Autoimmunity

Merle Sauer et al. Front Immunol. .

Abstract

Background: The pathogenesis of chronic spontaneous urticaria (CSU) is still insufficiently understood. Recent findings suggest that immunoglobulins, in particular IgE but also IgA, play a role in the development of CSU.

Objective: Our aim was to assess differences in clinical and laboratory markers between CSU patients with and without lower levels of serum IgA and IgE.

Methods: We analyzed the data of 606 patients with CSU by dividing them into four groups based on their IgA and IgE levels. The groups were compared for their spectrum of symptoms, disease activity, concomitant autoimmunity and routine laboratory markers. Autoreactivity was assessed by basophil activation test (BAT). Moreover, IgE-anti-thyroid peroxidase (TPO) was measured.

Results: Of the patients with lower IgE levels, 66.5% also had lower IgA levels (r=0.316, p<0.001). Patients with lower IgA and lower IgE levels showed a higher prevalence of recurrent angioedema (p=0.03, p=0.04) and concomitant autoimmunity (p=0.006, p<0.001). Autoreactivity was also found more frequently in patients with lower IgA and lower IgE levels (p=0.003, p<0.001). Reduced basophil counts were linked to both, lower IgA and lower IgE levels (p<0.001), whereas low eosinophil counts were primarily present in patients with lower IgE levels (p=0.04, p<0.001). Patients with elevated IgE-anti-TPO levels had lower IgA (p=0.007) and IgE levels (p=0.001).

Conclusion: Lower IgA levels in CSU are linked to lower IgE levels and features of autoimmune urticaria. Our findings encourage to screen CSU patients for serum IgA and IgE levels and to further assess their role as disease biomarkers.

Keywords: autoimmune disease; autoreactivity; basophils; chronic spontaneous urticaria; eosinophils; immunoglobulin A; immunoglobulin E.

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Conflict of interest statement

PK received personal fees from Novartis and Roche, outside the submitted work. FS received grants and/or personal fees from Allakos, Blueprint, Hyphens, Genentech, Novartis, Pediapharm, and Uriach, outside the submitted work. SA received grants and/or personal fees from Allakos, AstraZeneca, CSL Behring, Moxie and Sanofi, outside the submitted work. MMa received grants and/or personal fees from Allakos, Amgen, Aralez, Argenx, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, and Uriach, outside the submitted work. MMe received personal fees from Amgen, Aralez, Argenx, Bayer, Moxie, Novartis, Roche, Sanofi and Uriach, outside the submitted work. KK received grants and/or personal fees from Bayer, Berlin Chemie, CSL Behring, Moxie, Novartis, Roche and Shire/Takeda, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Lower IgA levels are correlated with lower total IgE levels in the serum of CSU patients (Spearman-Rho) (A). Lower IgA levels are associated with lower total IgE levels. Boxes are displayed as median and interquartile range. The whiskers indicate the range. For statistical significance, a Mann-Whitney-U test was performed (B). IgA levels >6 g/l (A) and IgE levels >1000 kU/l (A, B) are not shown in this graphic.
Figure 2
Figure 2
Lower IgG levels are associated with lower IgA levels in the serum of CSU patients. Boxes are displayed as median and interquartile range. The whiskers indicate the range. For statistical significance, a Kruskal-Wallis test was performed (A). Correlation of IgG with IgA and IgE levels by Spearman-Rho. IgA levels >6 g/l and IgE levels >1000 kU/l are not shown in this graphic (B).
Figure 3
Figure 3
Basophil counts are lowest in CSU patients with lower IgA and IgE levels (A), whereas eosinophil counts are low in CSU patients with lower IgE levels with or without lower IgA levels (B). Boxes are displayed as median and interquartile range. The whiskers indicate the range. For statistical significance, a Kruskal-Wallis test was performed. Basophil counts >0.12/nl and eosinophil counts >0.8/nl are not shown in this graphic.
Figure 4
Figure 4
Autoimmune phenomena are more prevalent in CSU patients with lower serum IgE levels. Autoimmune phenomena were defined as the presence of clinically diagnosed autoimmune diseases and/or elevated levels of ANCA, ANA, rheumatoid factor IgM or circulating immune complexes and/of elevated levels of IgG-anti-TPO or thyroid stimulating hormone-receptor-antibodies, if they were in accordance with the clinical symptoms. For statistical significance, the z-test of two proportions with a Bonferroni correction was performed.
Figure 5
Figure 5
BAT positivity is associated with lower serum IgA and IgE levels in CSU patients. Percentage of CD63 and CD203c positive cells in the BAT after stimulation of healthy basophils with patient serum. Boxes are displayed as median and interquartile range. The whiskers indicate the range. For statistical significance, a Kruskal-Wallis test was performed (A). IgA and IgE levels correlate negatively with the percentage of activated basophils by Spearman-Rho. IgA levels >6 g/l and IgE levels >1000 kU/l are not shown in this graphic (B).
Figure 6
Figure 6
Elevated IgE-anti-TPO levels (>1.09 ng/ml, n=120) in CSU patients are associated with lower serum IgA (A) and IgE (B) levels compared to patients with normal IgE-anti-TPO levels (≤1.09 ng/ml, n=279). Boxes are displayed as median and interquartile range. The whiskers indicate the range. For statistical significance, a Mann-Whitney-U test was performed. IgA levels >6 g/l and IgE levels >1000 kU/l are not shown in this graphic.
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