118 Patient age and sex confirm known associations with antibody epitope repertoires Next, we examined the associations between antibody responses andpatient age and sex, as these factors have previously been shown to be strongly associatedwith antibody epitope repertoires .12 We compared the oldest patients (Q4, >53 years old, n = 115) to the youngest patients (Q1, <28 years old, n = 115) and identified significant associations to 199 different antibody-bound peptides (false discovery rate (FDR) < 0.05) (Table S1). Older patients with IBD showed increased antibody responses against proteins from several herpesviruses (herpes simplex virus type 1 [HSV1]/HHV-1, varicella-zoster virus [VZV]/HHV-3 and cytomegalovirus [CMV]/HHV-5), hepatitis A virus proteins and proteins from the order Bacteroidales. Younger patients with IBD showed increased antibody responses against proteins of Shiga-like toxin-producing types of Escherichia coli (e.g. serotype O157:H7), including the EspD secretor protein, translocon proteins and the translocated intimin receptor (Tir). Younger patients with IBD also more frequently demonstrated antibodies against some flagellin-coated bacteria from the Clostridiales order, rhinoviruses (particularly serotype 2) and autolysins of Staphylococcus aureus. Sex was significantly associated with two antigen peptides (FDR < 0.05) (Table S2). Female patients with IBD more frequently exhibited antibody responses against antigens from Lactobacillus acidophilus bacteria, some of which were also among the top nominally significantly associated antigen peptides (P < 0.05), an association previously reported for a population-based cohort.12 Male patients with IBD showed increased antibody responses against surface fibrils and adhesins of Haemophilus influenzae bacteria. Most of these associations between patient age and sex and antibody-bound peptides correspond very well with those reported in recent population-based cohort studies.12,22 Distinct antibody responses in patients with IBD compared to healthy individuals A comparison of the antibody epitope repertoires of patients with IBD and healthy controls,22 while controlling for the effects of age and gender, revealed 373 differentially abundant antibodybound peptides, of which 202 were overrepresented and 171 were underrepresented in IBD compared to healthy controls (FDR < 0.05) (Figure 3A, Tables S3-5). Patients with CD accounted for most differentially abundant peptides (55%) as compared to patients with UC (28%), while approximately one-fifth were shared between both IBD subtypes (17%). Results from these comparative analyses did not change substantially when an age- and sex-matched, equally sized subset of the healthy controls was selected for both patients with CD and UC (Tables S6–7). Patients with CD showed a distinct overrepresentation of antibody-bound peptides derived from bacterial flagellins (Figure 3B, Table S4, Table S8). These consisted of significantly enriched flagellin antigen peptides from bacterial taxa belonging to the order Clostridiales and family Lachnospiraceae, including Roseburia, Eubacterium, Clostridium and Agathobacter spp., as well as to taxa belonging to presumed pathogenic bacteria, including those belonging to the families Legionellaceae (e.g. Legionella pneumophila), Borreliaceae (e.g. Borrelia burgdorferi) and Burkholderiaceae (e.g. Burkholderia pseudomallei). Apart from flagellin proteins, higher frequencies of antibody-bound peptides derived from viruses were found in patients with CD, including nuclear antigens of Epstein-Barr virus (EBV) and phosphoproteins of CMV. In addition, antibodybound peptides representing other viruses (e.g. genome polyproteins of enterovirus type B and C, non-structural polyproteins of Norwalk virus), bacterial cell wall components (e.g. adhesins of Chapter 4
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