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. 2022 Apr 1;13(4):e00469.
doi: 10.14309/ctg.0000000000000469.

Identification of Immunoglobulin G Autoantibody Against Malondialdehyde-Acetaldehyde Adducts as a Novel Serological Biomarker for Ulcerative Colitis

Michael J Duryee  1   2 , Rizwan Ahmad  3 , Derrick D Eichele  4 , Carlos D Hunter  1   2 , Ananya Mitra  1 , Geoffrey A Talmon  5 , Shailender Singh  4 , Lynette M Smith  6 , Michael J Rosen  7 , Punita Dhawan  3   2 , Geoffrey M Thiele  1   2 , Amar B Singh  3   2
Affiliations

Identification of Immunoglobulin G Autoantibody Against Malondialdehyde-Acetaldehyde Adducts as a Novel Serological Biomarker for Ulcerative Colitis

Michael J Duryee et al. Clin Transl Gastroenterol. .

Abstract

Introduction: Inflammatory bowel disease (IBD) is associated with immune responses with oxidative stress wherein high levels of malondialdehyde result in the formation of a highly stable and immunogenic malondialdehyde-acetaldehyde adduct (MAA). Thus, this study evaluated the status of MAA and anti-MAA antibody isotypes in IBD and their potential as novel serological biomarkers for differentiating ulcerative colitis (UC) from Crohn's disease (CD).

Methods: Levels of MAA and anti-MAA antibodies were examined in patients with IBD (171), non-IBD gastrointestinal diseases (77), and controls (83) from 2 independent cohorts using immunohistochemistry and enzyme-linked immunosorbent assay. Receiver operating characteristic curves and Youden cutoff index from logistic regression were used to determine the sensitivity and specificity.

Results: The MAA and blood immunoglobulin G (IgG) anti-MAA antibody levels were significantly elevated in IBD compared with non-IBD patients (P = 0.0008) or controls (P = 0.02). Interestingly, patients with UC showed higher levels of IgG anti-MAA (P < 0.0001) than patients with CD including those with colonic CD (P = 0.0067). The odds ratio by logistic regression analysis predicted stronger association of IgG anti-MAA antibody with UC than CD. Subsequent analysis showed that IgG anti-MAA antibody levels could accurately identify (P = 0.0004) UC in the adult cohort with a sensitivity of 75.3% and a specificity of 71.4% and an area under the curve of 0.8072 (0.7121-0.9024). The pediatric cohort also showed an area under the curve of 0.8801 (0.7988-0.9614) and precisely distinguished (P < 0.0001) UC with sensitivity (95.8%) and specificity (72.3%).

Discussion: Circulating IgG anti-MAA antibody levels can serve as a novel, noninvasive, and highly sensitive test to identify patients with UC and possibly differentiate them from patients with CD.

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Conflict of interest statement

Guarantor of the article: Amar B. Singh, PhD.

Specific author contributions: The first 2 authors contributed equally to this work, while the last 2 authors are cocorresponding authors. M.J.D., R.A., A.M., C.D.H., and M.J.R.: conducted data acquisition. A.B.S. and G.M.T.: conceptualized the study. G.A.T.: performed pathological evaluations. L.M.S.: performed statistical analyses. A.B.S., R.A., M.J.D., and G.M.T.: wrote the manuscript. R.A., L.M.S., M.J.R., D.D.E., S.S., P.D., A.B.S., and G.M.T.: critically reviewed manuscript. All authors approved the final draft before the manuscript was submitted.

Financial support: This work was supported by grants from the Veterans Affairs (Merit Grant) BX002761B (A.B.S.) and BX002086 (P.D.); the National Institutes of Health under Award Numbers DK124095 (A.B.S.), CA216746 (P.D.), and DK117119 (M.J.R.); Department of Internal Medicine Funds (G.M.T.); and U54GM115458/NIGMS NIH HHS/United States, the Great Plains IDeA-CTR grant, and the Nebraska Research Initiative.

Potential competing interests: None to report.

Figures

Figure 1.
Figure 1.
Differential levels of anti-MAA immunoglobulin isotypes were detected in patients with IBD compared with control individuals: ELISA immunoassay was used to measure the blood level of anti-MAA immunoglobulin isotypes. Data were transformed into a natural log scale, and violin plots were used to demonstrate the differences among the groups. (a) Serum level of anti-MAA antibodies in the adult cohort and (b) plasma level of anti-MAA immunoglobulins in a pediatric cohort. ELISA, enzyme-linked immunoassay; IBD, inflammatory bowel disease; MAA, malondialdehyde-acetaldehyde adduct.
Figure 2.
Figure 2.
IgG Anti-MAA antibody precisely differentiates patients with UC from patients with CD: ELISA quantified blood IgG antibodies against MAA and data were presented as a natural log-transformed scale. (a and b) Comparative serum/plasma IgG anti-MAA antibody analysis in both adult and pediatric cohorts. (c) Blood anti-MAA IgG level significantly stratified UC from colonic CD. CD, Crohn's disease; ELISA, enzyme-linked immunoassay; IgG, immunoglobulin G; MAA, malondialdehyde-acetaldehyde adduct; UC, ulcerative colitis.
Figure 3.
Figure 3.
MAA is significantly upregulated in patients with UC: Immunofluorescence analysis of MAA was performed in the biopsy samples from patients with UC and Crohn's disease and normal colon (10 biopsies/phenotype). (a and b) Representative images and quantitative analysis of the signal intensity of MAA. Values are presented as mean + SEM. MAA, malondialdehyde-acetaldehyde adduct; UC, ulcerative colitis.
Figure 4.
Figure 4.
AUROC curves support the diagnostic performance of IgG anti-MAA antibody as a biomarker for identifying UC and differentiating from CD: ROC curve analysis by logistic regression indicates the predictive power of circulating IgG anti-MAA compared with IgA and IgM. (a and b) ROC analysis of IgG anti-MAA in association with IgA and IgM indicates the discriminating potential of IgG anti-MAA antibody in separating UC from CD in the adult cohort. (c and d) ROC curve analysis showed significant discrimination of UC from CD in the pediatric cohort. (e and f) ROC curve by logistic regression analysis significantly predicts UC on CD with colon-only involvement. AUROC, area under the receiver operating characteristic; CD, Crohn's disease; IBD, inflammatory bowel disease; IgA, immunoglobulin A; IgG, immunoglobulin G; MAA, malondialdehyde-acetaldehyde adduct; ROC, receiver operating characteristic; UC, ulcerative colitis.
Figure 5.
Figure 5.
Decision tree supports the interpretation of IgG anti-MAA biomarker in IBD: decision tree showing the accuracy of IgG anti-MAA to predict UC from CD. CD, Crohn's disease; IBD, inflammatory bowel disease; IgG, immunoglobulin G; MAA, malondialdehyde-acetaldehyde adduct; UC, ulcerative colitis.
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