Published online Jul 21, 2026. doi: 10.3748/wjg.117897
Revised: January 21, 2026
Accepted: April 8, 2026
Published online: July 21, 2026
Processing time: 207 Days and 17.6 Hours
Appendectomy reduces the occurrence and controls the severity of ulcerative colitis (UC); however, how it exerts these effects remains unclear.
To elucidate the contribution of appendix-associated immune responses in intestinal inflammation and their relevance to the effects of appendectomy in UC.
This study was conducted at Graduate School of Medicine, The University of Osaka. We included patients un
Single-cell RNA sequencing identified T, B, plasma, innate lymphoid, and mast cells, together with other myeloid cells in appendiceal tissues. A hallmark feature of the appendices in UC was an increase in immunoglobulin G (IgG)-expressing plasma cells. Immunohistochemistry revealed significantly reduced IgG levels in the large intestines of patients with UC who had undergone an appendectomy compared with levels in those who did not undergo appendectomy. Repertoire analysis revealed an increased production of IgG antibodies bearing an integrin-binding motif at antigen-recognition sites in patients with UC.
The appendix is a major site of pathogenic IgG antibody production in patients with UC, providing the immunological basis for appendectomy as a treatment for UC.
Core Tip: The appendix is a potential source of pathogenic immunoglobulin G (IgG)-producing cells in patients with ulcerative colitis (UC). Appendectomy significantly reduced IgG-positive cells in the large intestine of patients with UC. Appendectomy may alleviate UC symptoms by limiting the number of pathogenic IgG-secreting cells.
- Citation: Izutani Y, Ogino T, Sakakibara S, Kishi Y, Liu YC, Nakano Y, Fukada A, Sekido Y, Kuwahara R, Kihara T, Takeda M, Hata T, Hamabe A, Miyoshi N, Uemura M, Ikeuchi H, Hirota S, Takeda K, Mizushima T, Okuzaki D, Doki Y, Eguchi H. Contribution of the appendix to ulcerative colitis by supplying pathogenic immunoglobulin G-producing cells. World J Gastroenterol 2026; 32(27): 117897
- URL: https://www.wjgnet.com/1007-9327/full/v32/i27/117897.htm
- DOI: https://dx.doi.org/10.3748/wjg.117897
Ulcerative colitis (UC) is an inflammatory bowel disease of unknown etiology, primarily affecting the mucosa and submucosa of the large intestine, beginning in the rectum, and manifesting as diffuse non-specific inflammation. UC shows a high prevalence in Europe and North America, reaching 505 cases per 100000 people in Norway and 286 cases per 100000 people in the United States; however, these rates have stabilized in recent years. In contrast, incidence rates are increasing in Asia and other newly industrialized countries, making UC a global disease[1]. UC develops in individuals with a genetic predisposition following environmental exposures, with gut epithelial barrier defects, the microbiota, and a dysregulated immune response being strongly implicated[2].
UC cases presenting with appendiceal orifice inflammation (AOI) as a skip lesion have been reported, and the incidence of AOI varies widely among studies (ranging from 7.9% to 75%)[3]. The presence of AOI is a risk factor for worsening distal colitis and proximal extension of disease involvement[4,5]. Furthermore, in patients with severe ulcerative appendicitis, appendectomy has been shown to improve the clinical course of UC[6].
The appendix is a lymphoid organ that senses indigenous bacteria, supports gut homeostasis, and potentially contributes to disease development[7,8]. Antibody response in the appendix may contribute to the gut homeostasis by providing antibacterial immunoglobulin A (IgA). The expression of the gut-homing receptor C-C chemokine receptor 10 (CCR10) is induced by appendiceal IgA-producing plasma cells through interactions with local dendritic cells, enabling these cells to migrate to the colon and rectum[9-11].
Surgical removal of lymphoid organs is a therapeutic strategy for immune-mediated disorders, such as thymectomy for myasthenia gravis[12] and tonsillectomy for IgA nephropathy[13]. Similarly, appendectomy may reduce the incidence of and alleviate disease activity in UC. Appendectomy before UC onset reduces the risk of disease development[14,15]. Appendectomy leads to clinical remission in approximately 30% of patients with refractory UC[16]. Previously, we demonstrated that patients with UC who underwent appendectomies exhibited lower disease activity and experienced fewer relapses than those who did not undergo appendectomies[17].
Based on these findings, the appendix is likely to contribute to the pathogenesis of UC. However, the precise role of the appendix in the pathogenesis of UC remains to be elucidated. The appendix functions as an important immunological niche for B-cell priming and affinity maturation[18]. Accordingly, we aimed to investigate the role of appendix-associated immune responses, particularly antibody production, in intestinal inflammation and the immunological bases for appendectomy.
UC is increasingly recognized as an antibody-mediated inflammatory disease, in which immunoglobulin G (IgG)-producing plasma cells play a pathogenic role in UC[19]. Recent evidence has suggested that autoantibodies targeting integrin αvβ6 are the hallmark of UC[20,21]. Therefore, we hypothesized that the appendix may serve as a source of IgG-producing cells that contribute to colonic inflammation in UC.
In this study, using single-cell RNA sequencing (scRNA-seq), flow cytometry and immunohistochemistry, we comprehensively investigated the characteristics and potential relevance of immune cells residing in the appendix and inflamed intestinal tissues of patients with UC.
This study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committees of Osaka University School of Medicine (No. 10261) and Hyogo Medical University (No. 0407). All participants provided written informed consent prior to their inclusion in the study.
Tissue samples were obtained from patients diagnosed with UC based on clinical, endoscopic, and histopathological criteria. Eligible patients were those who underwent surgical intervention for refractory or severe UC at Osaka University Hospital or Hyogo Medical University Hospital, and from whom both appendiceal and colonic tissues were available at the time of surgery. UC tissue samples were obtained from 46 patients between 2022 and 2024. We included 15 patients with UC who had histopathological features consistent with ulcerative appendicitis. Among these, 4 were selected for scRNA-seq. In addition, we retrospectively reviewed UC histological specimens from 118 patients collected between 2016 and 2024, and patients with UC who underwent total proctocolectomy and had a prior history of appendectomy (n = 5) were included as a separate comparison group. Detailed demographic and clinical characteristics are summarized in Supplementary Table 1. Control samples were obtained from surplus surgical specimens of patients with no history of inflammatory bowel disease who underwent colectomy for colorectal cancer (CRC). Control appendiceal and colonic tissues were collected from macroscopically normal areas located at least 10 cm away from the tumor margin. We included 31 control participants between 2022 and 2024, of whom 5 were selected for scRNA-seq. None of the included patients had comorbidities or conditions known to substantially affect immunological analyses. In addition, patients with acute appendicitis (n = 10) were also included for histological examination.
Refractory and severe UC were defined as active UC. Refractory UC was defined as disease showing no clinical improvement despite treatment with corticosteroids, immunomodulators, or biological agents, whereas severe UC was defined as cases with rapid clinical deterioration during treatment that required surgical intervention. Perioperative antibiotics were routinely administered as part of standard clinical management. Patients diagnosed with inflammatory bowel diseases other than UC (such as Crohn’s disease or inflammatory bowel diseases unclassified), cases with an uncertain diagnosis, specimens with severe tissue degeneration that precluded histological evaluation, or cells that did not meet quality control criteria in single-cell analyses (including low gene-count cells, cells with high mitochondrial gene expression, and cells identified as doublets) were excluded.
Lamina propria mononuclear cells (LPMCs) were isolated according to a previously reported protocol[22].
Flow cytometry was performed using a fluorescence-activated cell sorting Aria II cytometer (BD Biosciences, Franklin Lakes, NJ, United States) with Pacific Blue-conjugated anti-EpCAM (9C4; BioLegend, San Diego, CA, United States), allophycocyanin-conjugated anti-IgA (IS11-8E10; Miltenyi Biotec, Bergisch Gladbach, Germany), fluorescein isothiocyanate-conjugated anti-IgG (M1310G05; BioLegend, San Diego, CA, United States), phycoerythrin-conjugated anti-cluster of differentiation (CD) 38 (HIT2; BioLegend, San Diego, CA, United States), Pacific Blue-conjugated anti-CD20 (2H7; BioLegend, San Diego, CA, United States), allophycocyanin-conjugated anti-CCR10 (6588-5; BioLegend, San Diego, CA, United States), 7-amino-actinomycin D Viability Staining Solution (BioLegend, San Diego, CA, United States). Data were analyzed using the FlowJo software version 10 (BD Biosciences, Franklin Lakes, NJ, United States).
The EpCAM- and 7-amino-actinomycin D- fraction of appendix LPMCs was sorted for scRNA-seq (Supplementary Figure 1A). Single-cell library preparation was performed using the 10× Genomics Chromium platform with the Chromium Next GEM Single Cell V(D)J Reagent Kit (10× Genomics, Pleasanton, CA, United States), following the manufacturer’s instructions. For library preparation and sequencing, approximately 16000 live cells were loaded per well, generating 10000 single-cell gel bead emulsions. Sequencing was conducted on a DNBSEQ-G400 platform (MGI, Shenzhen, Guangdong Province, China) in the paired-end mode (28 bp + 100 bp or 100 bp + 100 bp). The resulting raw reads were processed using Cell Ranger version 7.1.0 (10× Genomics).
Gene expression matrices filtered by Cell Ranger were analyzed using the Scanpy package (v1.10.3)[23]. Cells with < 100 genes and genes with < 3 cells were excluded. We excluded cells with gene counts other than five median absolute deviations and those with > 10% reads from mitochondrial genes. Doublets predicted using Scrublet (v0.2.3) were removed from each sample[24]. To ensure robust analysis, specific genes, such as ribosomal genes, and T-cell receptor (TCR) alpha variable, TCR alpha joining, TCR beta joining, TCR beta variable, immunoglobulin heavy chain variable, immunoglobulin kappa light chain variable, and immunoglobulin lambda light chain variable gene segments, were excluded. Count matrices were normalized using counts per million mapped reads and log-plus one transformation. Overall, 2000 shared highly variable genes were identified using the pp.highly_variable_genes function with default flavor = “seurat”, followed by principal component analysis. Batch correction was performed using HarmonyPy (v0.0.10)[25]. A neighborhood graph was constructed based on the batch-corrected representation, followed by uniform manifold approximation and projection for dimension reduction[26].
TCR V(D)J-seq data were reannotated using the dandelion preprocess implemented in the sc-dandelion container (v0.4.0) with the --filter_to_high_confidence and chain TR option[27,28]. The processed TCR data were imported and analyzed using Scirpy[29]. For TCR analysis, cells annotated as T_CD4+ or T_CD8+ were selected, and only cells with a single pair of α and β chains were retained for the downstream analysis. The complementarity-determining region 3 amino acid sequence identity was calculated using the scirpy.pp.ir_dist function with metric = “identity”, sequence = “aa”. Clonotypes were defined based on this sequence identity using the scirpy.tl.define_clonotypes function with receptor_arms = “all” and dual_ir = “primary_only”.
B-cell receptor (BCR) V(D)J data were reannotated and preprocessed using the dandelion preprocess implemented in the sc-dandelion container (v0.4.0) with the --filter_to_high_confidence option[27,28,30,31]. The processed BCR data were imported into sc-dandelion (v0.5.0) for further analyses. For BCR analysis, cells annotated as B or plasma were selected, and only cells with a single pair of heavy (IGH) and light chains (IGL or IGK) were retained for downstream analysis. Clonotypes were determined using the dandelion.tl.define_clones function, and the threshold was calculated using the dandelion.preprocessing.calculate_threshold function.
To calculate the mutational load, the Immcantation suite’s Shazam was utilized with the sc-dandelion (v0.5.0) tool[30]. Following reannotation and preprocessing using the dandelion preprocess, the somatic hypermutation frequency was calculated using the dandelion.pp.quantify_mutations function.
To examine the presence of the arginine-glycine-aspartic acid (RGD) motif in the antigen-binding site of antibodies, we utilized InterClone, which extracts an antibody paratope to build a pseudo-sequence for clustering the BCR repertoire based on the inferred antigen specificity[32]. We assessed immunoglobulins in plasma cells containing a single pair of heavy and light chains. Preprocessed adaptive immune receptor repertoire-formatted data were processed using prepare_pseudo_seq.py to create amino acid pseudo-sequences of the complementarity-determining regions of light and heavy chains. Pseudo sequences of heavy chains were clustered using cluster_db.py, which utilizes MMseqs2[33]. We searched for the RGD motif within the amino acid sequences.
The scanpy.tl.score_genes_cell_cycle function was used to calculate scores and assign cell cycle phases. S and G2M genes identified in a published report were imported into the function[34].
Upstream regulator analysis was performed using Ingenuity Upstream Pathway Analysis (IPA; QIAGEN, Hilden, Germany). The activation Z-score was used to compare pathway activity between the groups, identifying the pathways or regulators with the most significant increases or decreases in the activation Z-score. The following cut-off criteria were applied for the inclusion of differentially expressed genes: (1) Cytotoxic T cells (Tc), and T follicular helper cells (Tfh): Log2 fold change ≥ 0.5 or ≤ -0.5, t-test P < 0.05; and (2) Germinal center B cells (GC B): t-test P < 0.05.
Formalin-fixed, paraffin-embedded tissue sections were used for analysis. The tissue samples were fixed in 10% formalin and dehydrated using a graded ethanol series. After embedding in paraffin, the resulting blocks were sectioned at 3 μm and mounted onto slides. For immunohistochemistry, the sections were deparaffinized, followed by antigen retrieval by boiling the specimens in 10 mmol/L citrate buffer (pH 6) for 20 minutes. Endogenous peroxidase activity was blocked by immersing the sections in methanol containing 1% hydrogen peroxide, and serum was added to block non-specific protein binding. The specimens were incubated overnight at 4 °C with the following primary antibodies: (1) Rabbit anti-IgG (1:300, ab109489; Abcam, Cambridge, United Kingdom); (2) Mouse anti-IgA (1:16000, 60099-1-IG; Proteintech, Rosemont, IL, United States); and (3) Rabbit anti-CCR10 (1:200, 22071-1-AP; Proteintech). After incubation with biotinylated secondary antibodies, avidin-horseradish peroxidase was added using the VECTASTAIN® ABC kit (Vector Laboratories, Newark, CA, United States). The chromogen used was 3,3’-diaminobenzidine (Fujifilm Wako Pure Chemical Corporation, Osaka, Japan), and hematoxylin was used for counterstaining. The stained specimens were analyzed using a BZ-X710 microscope (Keyence, Osaka, Japan). For each specimen, the areas with the highest density of positive cells were identified at low magnification, and five hotspots were selected according to predefined criteria[35]. The number of positive cells was then counted in five high-power fields (400 ×), and the average value was expressed as cells/mm².
Differences between the groups were analyzed using two-sided t-tests. Comparisons among ≥ 3 groups were performed using one-way analysis of variance, followed by Tukey-Kramer post-hoc tests. Correlations between the two groups were determined using Spearman’s rank correlation coefficient (to evaluate monotonic relationships). Statistical analyses were conducted using the JMP Pro 17.0.0 software (SAS Institute, Cary, NC, United States). Statistical significance was set at P < 0.05.
We examined proctocolectomy specimens from patients with active UC, which demonstrated continuous inflammation extending proximally from the rectum to left colon, accompanied by mucosal atrophy and a lead-pipe-like appearance of the colon. AOI was confirmed by endoscopic and macroscopic examinations (Figure 1A). Histopathological examination revealed prominent crypt loss in the rectum (Figure 1B, b1). In contrast, only minimal inflammation was observed in the ascending colon (Figure 1B, b2). However, discontinuous inflammatory changes were observed around the appendiceal orifice, with subepithelial inflammatory cell infiltration and erosion in the same region (Figure 1B, b3). Furthermore, the pathological features of AOI differ from those of typical acute appendicitis and instead resemble those of UC, consistent with ulcerative appendicitis (Supplementary Figure 1B).
Despite aggressive erosion with immune cell infiltration in the appendices of patients with UC, the lymphoid follicles remained well-structured (Figure 2A). Contrarily, ectopic lymphoid follicles were observed in the rectum of patients with UC but were rarely present in patients without UC (Supplementary Figure 1C). The number of LPMCs in the appendix was comparable between UC and control samples (Figure 2B).
We performed scRNA-seq analysis of appendiceal LPMCs from patients with UC and controls (Figure 2C). Nine donors were included in the analysis: Four patients with active UC and five controls (Supplementary Tables 2 and 3). This analysis enabled comprehensive mapping of immune cell populations in the appendix (Figure 2D).
After quality control of the single-cell transcriptome data, we obtained 59755 cells classified into T, B, plasma, natural killer, innate lymphoid, myeloid, and mast cells (Figure 2E). T cells were the largest cell compartment, accounting for 59.2% (46.3%-71.7%), followed by B cells at 22.7% (18.1%-33.8%), in UC and control samples (Figure 2F). The proportion of each immune cell type in the appendix was comparable between the groups (Figure 2F).
In the scRNA-seq dataset, we identified 7224 plasma cells comprising 11 distinct sub-clusters after re-clustering, largely defined by the expressed Ig class in the dataset (Figure 3A and B). The IgA-positive plasma cells in clusters C1, C2, and C6 exhibited distinct light chain expression patterns and maturation stages (Figure 3B and C). IgG-producing cells (C3, C4, and C8) showed higher expression of plasma cell maturation genes (XBP1, CD38, and CXCR4) and enhanced N-glycosylation (ST6GAL1, Figure 3B and D). Cells in C9 were predominantly IgM-producing and exhibited a lower expression of MZB1, CD38, and CXCR4 (Figure 3B). Cells in C5 exhibited higher expression of human leukocyte antigen-DR alpha and pan B-cell markers CD19 and MS4A1 (Figure 3B). Combined with the elevated scores in the S phase of the cell cycle, these features suggested that the cells were plasmablasts (Figure 3E). In the remaining clusters, C11 were dying cells, as evidenced by higher expression levels of MALAT1 and NEAT1 (Figure 3B). C7 cells expressed antibodies of different Ig classes without distinct characteristics. C10 cells showed CD3D expression, suggesting that they might be doublets.
Comparable analyses highlighted different antibody responses in the appendices of patients with UC and controls. The proportions of C3 and C5 were significantly higher; those of C1 were lower in patients with UC than in controls. C1 accounted for > 50% of the plasma cells in controls, suggesting that the appendix contributes to gut IgA production under steady-state conditions; however, this proportion decreased by 20% in UC. Conversely, C3, a cluster of IgG-producing cells, was barely identified in controls but increased to 20% in UC. C4 and C8 were also IgG-expressing plasma cell populations, showing an insignificant increased proportion in UC compared with that in controls. Another cluster with an elevated proportion in UC was C5, a cluster of immature plasma cells or plasmablasts (Figure 3F).
There was a significant difference in the Ig isotypes generated by plasma cells and plasmablasts in the appendix between the UC and control group. IgG-expressing plasma cells were more abundant in the appendices of patients with UC than in controls (P = 0.024; Figure 3G). Conversely, IgA-expressing plasma cells were significantly reduced in patients with UC (P = 0.039; Figure 3G). In the IgG subclass analysis, IgG1 was predominant in patients with UC (P = 0.030; Supplementary Figure 2A). C5 also exhibited a higher IgG prevalence in UC. The proportion of IgG-expressing cells in C5 was significantly higher in patients with UC than in controls (P = 0.034; Supplementary Figure 2B and C).
The scRNA-seq data included 12783 B cells: (1) Naïve B; (2) Memory B; and (3) GC B cells (Figure 4A and B). Paired BCR V(D)J heavy and light chain sequences were detected in 36.0% of the B cells (data not shown). The overall B-cell characteristics, including subset composition, Ig isotype, and somatic mutation frequency, were comparable between patients with UC and controls (Figure 4C-E).
The GC B cells proportion, the main source of gut-associated IgA in the appendix, varied across individual samples with no significant difference observed between the groups. Averagely, 12.0% of the B-cell population were GC B cells in controls, whereas this subset accounted for 4.8% of patients with UC (Figure 4C).
Pathway analysis revealed that interferon-α/β signaling, antigen presentation and HSP90-related pathways were enhanced in GC B cells from UC samples compared with those from controls (Figure 4F). IPA indicated that GC B cells could be activated not only by Toll-like receptor ligands, such as poly rI:rC-RNA and Escherichia coli lipopolysaccharide, but also by inflammatory cytokines, including interleukin-6. They also exhibited activation of nuclear factor-kappa B and class II major histocompatibility complex transactivator, which enhances major histocompatibility class II expression (Figure 4G).
The scRNA-seq dataset included 34895 T cells, categorized into 11 subsets after re-clustering (Supplementary Figure 3A and B). The major subsets were T helper (Th) activated, CD4 T naive/central memory (Tn/cm), and CD8 T cytotoxic (Tc) subsets, each accounting for approximately 20% of the total T cells in the UC and control groups, and the subset composition of T cells was comparable between the UC and control groups (Supplementary Figure 3C). Paired TCR V(D)J α and β sequences were detected in 67% of T cells, with clonal expansion observed in Tc, Th1/17, and cycling T (Supple
Gene ontology analysis revealed that Tc cells from patients with UC exhibited upregulated pathways related to T-cell priming and activation (e.g., “Costimulation by CD28 family” and “TCR signaling”) and cell-cell interactions (e.g., “immunoregulatory interactions between a lymphoid and a non-lymphoid cell” and “cell surface interactions at the vascular wall”) (Supplementary Figure 3F). Pathways related to cellular stress and mitosis were downregulated in patients with UC (Supplementary Figure 3F). Tfh cells in patients with UC exhibited increased cellular stress (cellular response to heat stress) and reduced respiratory activity (respiratory electron transport) compared with those in controls (Supplementary Figure 3G).
Section staining revealed abundant IgG-positive cells surrounding the lymphoid follicles and within the lamina propria of the appendices in UC, whereas such cells were scarce in the controls (Figure 5A). Flow cytometry confirmed that IgG-expressing cells were significantly more abundant in appendiceal LPMCs in UC than in controls (P = 0.032). Conversely, IgA-expressing cells were significantly more abundant in controls (P = 0.030; Figure 5B).
Immunostaining of intestinal tissues demonstrated that the frequency of IgG-positive cells was significantly higher in the appendix than in the left and right colons of patients with UC (P = 0.044 and P < 0.001, respectively; Figure 5C and D). These findings, including continuous lesions extending from the rectum and skip regions, correlate with the characteristic pathological features of UC. The IgA-positive cells were uniformly distributed throughout the large intestine (Supplementary Figure 4A).
The elevated frequency of IgG-expressing cells in the appendix was characteristic of ulcerative appendicitis but was not found in those without UC or with acute appendicitis (P < 0.0001). IgA-positive cell frequencies did not differ significantly between the ulcerative and acute appendicitis groups (Figure 5E).
Histopathological analysis was conducted on proctocolectomy specimens obtained from patients with UC with a history of appendectomy. In patients with UC who had undergone appendectomy, IgG-positive cells, but not IgA-positive cells, were significantly reduced in the rectum and left and right colons (P < 0.001, P = 0.004, and P = 0.036, respectively; Figure 5F and Supplementary Figure 4B).
The scRNA-seq analysis revealed that CCR10, a critical gut-homing receptor of intestinal immune cells, was exclusively expressed in plasma cells within the appendix (Figure 6A). Flow cytometry identified cells co-expressing IgG and CCR10 in appendiceal LPMCs from patients with UC (Figure 6B). Serial section analysis demonstrated that the inflamed appendix and rectum of patients with UC harbored CCR10-positive cells that co-localized strongly with IgG, but not IgA (Figure 6C and D, appendix and rectum). In the appendix, a positive correlation was observed between IgG-positive and CCR10-positive cells (ρ = 0.700, P < 0.001), as determined by Spearman’s rank correlation (Figure 6E).
Next, we analyzed the BCR repertoire of appendiceal plasma cells to gain further insights into the appendiceal antibody response. Paired BCR V(D)J heavy and light chain sequences were detected in 76.4% of plasma cells (data not shown). Repertoire analysis revealed comparable mutation frequencies in Ig genes of IgA, IgG, and other isotypes between the groups (Figure 7A-C). The proportion of IgG with the RGD motif, a potential binding site of integrins, was proportionally increased in the appendix of patients with UC than in that of controls (P = 0.035, two-sided t-test; Figure 7D).
In this study, we investigated the immunopathological role of the appendix in UC using a comprehensive approach to analyze appendiceal immune cells. Our analysis revealed that the appendix serves as a potential source of pathogenic IgG-producing cells in patients with UC, in contrast to their rare presence in controls. We further demonstrated that appendectomy significantly reduced IgG-positive cells, but not IgA-positive cells, in the large intestine of patients with UC. Basal plasmacytosis is a hallmark of UC and is strongly associated with disease relapse[36,37]. Taken together, our findings suggest that appendectomy may alleviate UC symptoms by limiting the number of pathogenic IgG-secreting cells.
In our analysis, UC samples showed an increase in IgG-positive plasma cells compared with those in controls, highlighting the pathogenic conversion in the appendiceal antibody response in UC. A previous study demonstrated that autoantibodies targeting integrin αvβ6 are a key immunological feature of UC[20]. To assess integrin-binding capacity, we analyzed paratope sequences of appendix-derived antibodies, as the presence of surface RGD motifs predicts a binding potential to integrins, including αvβ6[38,39]. Using this approach, we identified a significantly higher frequency of RGD-containing IgG in the appendices of patients with UC, suggesting an increased potential for integrin αvβ6 binding. Although RGD-containing IgA sequences have also been detected in the appendix under steady-state conditions, these antibodies are likely nonpathogenic, as they are transcytosed into the gut lumen[40,41].
The current study suggests that IgG-secreting plasma cells generated in the appendix migrate to the colon and rectum in patients with UC. These cells express the gut-homing receptor CCR10, similar to IgA-producing plasma cells, and appendectomy reduces their numbers in inflamed colorectal tissues. Our single-cell analysis further indicates that local inflammatory stimuli may induce IgG production. Because CCR10 is normally expressed on IgA-producing plasma cells[9-11], its expression on IgG+ plasma cells may result from class-switch recombination, during which CCR10 is retained. Ulcerative inflammation itself may also enhance both IgG production and CCR10 expression. Consequently, IgG+/CCR10+ plasma cells originating from the appendix may home throughout the colon and contribute to the widespread inflammation observed in UC.
Despite an increased proportion of IgG-positive plasma cells in the appendices of patients with UC, the origin of B-cell responses driving their production remains unclear. The scRNA-seq analysis identified GC B cells in the appendix whose BCRs had a substantial degree of somatic mutations in both patients with UC and control donors. This suggests that affinity maturation occurs in the appendix under steady-state and UC conditions. Although the overall magnitude of the GC reaction was comparable between groups, GC B cells derived from patients with UC exhibited enhanced innate immune responses and inflammation. Therefore, appendiceal IgG production in UC may be driven by local inflammation. Alternatively, the antibody response outside the GC may be attributed to the emergence of appendiceal IgG-secreting cells in patients with UC.
Single-cell transcriptome analysis, combined with TCR V(D)J analysis, identified clonal expansion of Tc and cycling cells within the CD8 T population, as well as Th1/17 cells among CD4 T cells in the appendix of both patients with UC and control donors. Previous studies have shown accumulation of these subsets in the colorectal mucosa of patients with UC[42,43]. As the appendix functions as a priming site for various T-cell subsets that subsequently migrate to the intestine via circulation[8], it is plausible that appendiceal T cells, including Tc cells, contribute to UC immunopathophysiology. Furthermore, Tfh cell dysfunction in UC may result from feedback mechanisms and cytokine imbalances that accompany excessive immune responses in the B-cell system[44,45].
As a limitation, our study had a relatively small sample size, largely because of the scarcity of suitable donors. Consistent with the notion that appendectomy may reduce disease activity in UC, cases requiring subsequent surgical intervention for refractory or severe disease after appendectomy were exceedingly rare. Additionally, this study was conducted exclusively among donors of Japanese descent, which may limit the generalizability of the findings. The lack of a control group comprising patients with UC in post-treatment remission may limit the robustness of the study design and complicate the interpretation of the findings. Although the control group included appendiceal samples from patients with CRC, CRC-associated microenvironmental or immunological alterations may have influenced the results. We cannot rule out the possibility that CRC-specific microenvironmental alterations or immunological backgrounds may act as confounding factors. Although perioperative antibiotics were administered in all surgical cases, the possibility that antibiotic exposure itself may have influenced local immune responses cannot be completely excluded. Future cross-sectional studies of the appendix in UC and other diseases may provide a clearer understanding of its role in UC pathogenesis.
This study identifies appendiceal IgG-secreting plasma cells as a pathological hallmark of UC and demonstrates that appendectomy in UC patients reduces IgG-producing cells in the colorectal lesions. Importantly, this study does not suggest appendectomy as a universal standard treatment for UC. Rather, it provides a mechanistic rationale supporting appendectomy as a potential therapeutic option in patients with ulcerative appendicitis or AOI. In this context, appendectomy could potentially prevent disease exacerbation in patients with UC exhibiting a marked increase in IgG-producing plasma cells in the appendix, particularly those bearing RGD motifs. Further analysis is needed to identify the immune cells driving the pathogenic conversion of the appendiceal antibody response in UC and clarify their roles in both steady-state and disease conditions.
We thank all the patients and medical staff at Osaka University Hospital and Hyogo Medical University Hospital who contributed to this study. We acknowledge the NGS Core Facility at the Research Institute for Microbial Diseases of the University of Osaka for sequencing and data analysis.
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