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. 2022 Aug;52(8):954-964.
doi: 10.1111/cea.14120. Epub 2022 Mar 14.

Anti-phospholipid antibodies are elevated and functionally active in chronic rhinosinusitis with nasal polyps

Jacob G Eide  1 , Jeffanie Wu  1 , Whitney W Stevens  1   2 , Junqin Bai  1 , Songwang Hou  3 , Julia H Huang  1 , Jacob Rosenberg  4 , Paul Utz  5 , Stephanie Shintani-Smith  1 , David B Conley  1 , Kevin C Welch  1 , Robert C Kern  1 , Kathryn E Hulse  2 , Anju T Peters  2 , Leslie C Grammer  2 , Ming Zhao  3 , Paul Lindholm  6 , Robert P Schleimer  1   2 , Bruce K Tan  1   2
Affiliations

Anti-phospholipid antibodies are elevated and functionally active in chronic rhinosinusitis with nasal polyps

Jacob G Eide et al. Clin Exp Allergy. 2022 Aug.

Abstract

Background: Polyps from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) contain increased levels of autoreactive antibodies, B cells and fibrin deposition. Anti-phospholipid antibodies (APA) are autoantibodies known to cause thrombosis but have not been implicated in chronic rhinosinusitis (CRS).

Objective: To compare APA levels (anti-cardiolipin, anti-phosphatidylethanolamine (anti-PE), and anti-β2 -glycoprotein (anti-B2GP)) in nasal polyp (NP) tissue with tissue from control and CRS without nasal polyp (CRSsNP) patients, we tested whether NP antibodies affect coagulation, and correlate APAs with anti-dsDNA IgG and markers of coagulation.

Methods: Patient specimens were assayed for APA IgG, anti-dsDNA IgG and thrombin-anti-thrombin (TaT) complex by ELISA. Antibodies from a subset of specimens were tested for modified activated partial thromboplastin time (aPTT) measured on an optical-mechanical coagulometer.

Results: Anti-cardiolipin IgG in NP was 5-fold higher than control tissue (p < .0001). NP antibodies prolonged aPTT compared to control tissue antibodies at 400 µg/mL (36.7 s vs. 33.8 s, p = .024) and 600 µg/mL (40.9 s vs. 34.7 s, p = .0037). Anti-PE IgG antibodies were increased in NP (p = .027), but anti-B2GP IgG was not significantly higher (p = .084). All APAs correlated with anti-dsDNA IgG levels, which were also elevated (R = .77, .71 and .54, respectively, for anti-cardiolipin, anti-PE, and anti-B2GP; all p < .001), but only anti-cardiolipin (R = .50, p = .0185) and anti-PE (R = 0.45, p = .037) correlated with TaT complex levels.

Conclusions: APA IgG antibodies are increased in NP and correlate with autoreactive tissue antibodies. NP antibodies have in vitro anti-coagulant activity similar to those observed in anti-phospholipid syndrome, suggesting that they may have pro-coagulant effects in polyp tissue.

Keywords: anti-phospholipid antibodies; nasal polyps; rhinosinusitis.

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Conflict of interest statement

Robert C. Kern is a consultant of Lyra Therapeutics, Sanofi Regeneron, GlaxoSmithKline, and Genentech. Anju T. Peters reports personal fees from Sanofi Regeneron, grants and personal fees from AstraZeneca and Optinose, outside the submitted work. Leslie C. Grammar III has received grants from the National Institutes of Health and Bazley Foundation to support her research. She has received grants for the institution from the National Institute of Health Food Allergy Network, AstraZeneca, and Sanofi Regeneron. She is a consultant for Astellas Pharmaceuticals. She has received royalties and payment for lectures from the American Academy of Allergy, Asthma and Immunology (AAAAI), Mount Sinai, Lippincott, UpToDate, Elsevier, Kluwers Wolter. Whitney W. Stevens has served on an advisory board for GlaxoSmithKline. Robert P. Schleimer is a consultant for Intersect ENT, GlaxoSmithKline, Merck, Sanofi, AstraZeneca/Medimmune, Genentech, Otsuka, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharm Inc, Genzyme/Sanofi Corp, and Celgene Corp. He is also a consultant with stock/stock options with Allakos, Aurasense, BioMarck, Exicure, and Aqualung Therapeutics Corp. He has a patent with Allakos related to Siglec‐8 and Siglec‐8 ligand related products that have not been developed yet. He has also received grants from the National Institutes of Health to support this and other research. Bruce K. Tan has received grants from the National Institutes of Health to support this research. He has served on advisory boards for Sanofi/Genzyme. All other authors have no conflicts of interest to report.

Figures

FIGURE 1
FIGURE 1
Autoantibody Heatmap. Significance analysis of microarrays (SAM) was used to identify significantly different IgG reactivity to autoantigens between NP tissue (n = 7) and control uncinated tissue (n = ). Significant genes were calculated with samr package with R 3.0.1 with 1000 permutations, q‐value <0.001, fold change >2. The resulting hierarchically clustered heatmap of significant antigens is presented here. Heatmap intensities represented by Log(2) fold change
FIGURE 2
FIGURE 2
Anti‐cardiolipin in NP and aPTT in vitro Testing. (A) Comparison of anti‐cardiolipin IgG levels in sinonasal tissue from CRS and control patients. Units are shown in immunoglobulin G phospholipid‐binding units (GPLU) normalized to total sample protein. There were significantly higher anti‐cardiolipin IgG in CRSwNP polyp (NP) compared to CRSsNP ethmoid (E), control ethmoid (E), and control turbinate (T) tissue (* p < .05, ** p < .01). (B) Correlation between normalized anti‐cardiolipin IgG antibodies and normalized anti‐dsDNA IgG antibodies. (C) Modified activated partial thromboplastin times (aPTT) using antibodies isolated from control human plasma (‐AB) and lupus‐positive control plasma (+AB). There was a significant increase in aPTT at both 400 µg/mL and 600 µg/mL antibodies derived from +AB samples. (D) Comparison of aPTT times between antibodies isolated from control turbinate (T) and NP tissue. There was a significant prolongation of the modified aPTT by antibodies derived from polyp tissue at both concentrations (* p < .05, ** p < .01)
FIGURE 3
FIGURE 3
Anti‐PE in NP. (A) Comparison of anti‐phosphatidylethanolamine (anti‐PE) IgG levels in control turbinate (T) and NP tissue. There was a significantly higher level of anti‐PE in NP tissue than control tissue (*** p < .001). (B) Correlation between anti‐cardiolipin and anti‐PE IgG antibodies. (C) Correlation between anti‐PE and anti‐dsDNA IgG antibodies
FIGURE 4
FIGURE 4
Anti‐B2GP in NP. (A) Comparison of anti‐β2 glycoprotein (anti‐B2GP) IgG between NP and control turbinate (T) tissue. There was no significant difference between the two groups. (B) Anti‐B2GP correlated moderately with anti‐cardiolipin IgG. (C) Anti‐B2GP correlated moderately with anti‐PE IgG. (D) Anti‐B2GP also correlated moderately with anti‐dsDNA IgG
FIGURE 5
FIGURE 5
TaT Complex in NP. (A) Comparison of Thrombin‐anti‐Thrombin (TaT) complex levels (a marker of increasing coagulation) between control turbinate (T) and NP tissue (* p < .05) (B) TaT complexes were strongly correlated with anti‐dsDNA IgG. (C) Anti‐cardiolipin IgG levels were also moderately correlated with TaT complex. (D) TaT complex levels were moderately correlated with anti‐PE IgG
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