Anti-integrin αvß6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis.

BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.

Anti-integrin αvß6 autoantibodies in patients with primary sclerosing cholangitis.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) possess autoantibodies against biliary epithelial cells. However, the target molecules remain unknown. METHODS: The sera of patients with PSC and controls were subjected to enzyme-linked immunosorbent assays to detect autoantibodies using recombinant integrin proteins. Integrin αvß6 expression in the bile duct tissues was examined using immunofluorescence. The blocking activity of the autoantibodies was examined using solid-phase binding assays. RESULTS: Anti-integrin αvß6 antibodies were detected in 49/55 (89.1%) patients with PSC and 5/150 (3.3%) controls (P < 0.001), with a sensitivity and specificity of 89.1% and 96.7%, respectively, for PSC diagnosis. When focusing on the presence or absence of IBD, the proportion of the positive antibodies in PSC with IBD was 97.2% (35/36) and that in PSC alone was 73.7% (14/19) (P = 0.008). Integrin αvß6 was expressed in bile duct epithelial cells. Immunoglobulin (Ig)G from 15/33 patients with PSC blocked integrin αvß6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif. CONCLUSIONS: Autoantibodies against integrin αvß6 were detected in most patients with PSC; anti-integrin αvß6 antibody may serve as a potential diagnostic biomarker for PSC.

Diagnostic criteria and endoscopic and histological findings of autoimmune gastritis in Japan.

The Japanese diagnostic criteria for autoimmune gastritis (AIG) were established by the "Study Group on the establishment of diagnostic criteria for type A gastritis," which is related to a workshop associated with the Japan Gastroenterological Endoscopy Society (JGES) and the Committee of AIG Research Group (CARP). The criteria were set as follows: the cases of confirmed diagnosis are patients in whom either the endoscopic or histological findings, or both, meet the requirements for AIG and who are confirmed to be positive for gastric autoantibodies (either anti-parietal cell or anti-intrinsic factor antibodies, or both). The presentation of endoscopic findings of early-stage AIG in the diagnostic criteria was withheld owing to the need for further accumulation and characterization of endoscopic clinical data. Therefore, diagnosis of early-stage AIG only requires histological confirmation and gastric autoantibody positivity. Suspected cases are patients in whom either the endoscopic or histological findings, or both, meet only the requirements for AIG. Histological findings only meet the requirements for early stage. AIG has been underdiagnosed in the past, but our study group's newly proposed diagnostic criteria will enable a more accurate and early diagnosis of AIG. The criteria can be used to stratify patients into various high-risk groups for gastric tumors and pernicious anemia. They would allow the establishment of an appropriate surveillance system in the coming years. Nevertheless, issues such as establishing the endoscopic findings of early-stage AIG and obtaining Japanese insurance coverage for gastric autoantibody tests require attention.

Clinical characteristics and long-term prognosis of type 1 gastric neuroendocrine tumors in a large Japanese national cohort.

OBJECTIVES: Optimal management of type 1 gastric neuroendocrine tumors (T1-GNETs) remains unknown, with few reports on their long-term prognosis. This study investigated the clinical characteristics and long-term prognosis of T1-GNETs. METHODS: We reviewed the medical records of patients diagnosed with T1-GNET during 1991-2019 at 40 institutions in Japan. RESULTS: Among 172 patients, endoscopic resection (ER), endoscopic surveillance, and surgery were performed in 84, 61, and 27, respectively, including 27, 77, and 2 patients with pT1a-M, pT1b-SM, and pT2 tumors, respectively. The median tumor diameter was 5 (range 0.8-55) mm. Four (2.9%) patients had lymph node metastasis (LNM); none had liver metastasis. LNM rates were significantly higher in tumors with lymphovascular invasion (LVI) (15.8%; 3/19) than in those without (1.1%; 1/92) (P = 0.016). For tumors <10 mm, LVI and LNM rates were 18.4% (14/76) and 2.2% (2/90), respectively, which were not significantly different from those of tumors 10-20 mm (LVI 13.3%; 2/15, P = 0.211; and LNM 0%; 0/17, P = 1.0). However, these rates were significantly lower than those of tumors >20 mm (LVI 60%; 3/5, P = 0.021; and LNM 40%; 2/5, P = 0.039). No tumor recurrence or cause-specific death occurred during the median follow-up of 10.1 (1-25) years. The 10-year overall survival rate was 97%. CONCLUSIONS: Type 1 gastric neuroendocrine tumors showed indolent nature and favorable long-term prognoses. LVI could be useful in indicating the need for additional treatments. ER for risk prediction of LNM should be considered for tumors <10 mm and may be feasible for tumors 10-20 mm. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network (UMIN) under the identifier UMIN000029927.

Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation.

BACKGROUND & AIMS: The Notch signaling pathway is an important pathway in the adult pancreas and in pancreatic ductal adenocarcinoma (PDAC), with hairy and enhancer of split-1 (HES1) as the core molecule in this pathway. However, the roles of HES1 in the adult pancreas and PDAC formation remain controversial. METHODS: We used genetically engineered dual-recombinase mouse models for inducing Hes1 deletion under various conditions. RESULTS: The loss of Hes1 expression in the adult pancreas did not induce phenotypic alterations. However, regeneration was impaired after caerulein-induced acute pancreatitis. In a pancreatic intraepithelial neoplasia (PanIN) mouse model, PanINs rarely formed when Hes1 deletion preceded PanIN formation, whereas more PanINs were formed when Hes1 deletion succeeded PanIN formation. In a PDAC mouse model, PDAC formation was also enhanced by Hes1 deletion after PanIN/PDAC development; therefore, Hes1 promotes PanIN initiation but inhibits PanIN/PDAC progression. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction revealed that Hes1 deletion enhanced epithelial-to-mesenchymal transition via Muc5ac up-regulation in PDAC progression. The results indicated that HES1 is not required for maintaining the adult pancreas under normal conditions, but is important for regeneration during recovery from pancreatitis; moreover, Hes1 plays different roles, depending on the tumor condition. CONCLUSIONS: Our findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer.

Gastric epithelial neoplasm of fundic-gland mucosa lineage: proposal for a new classification in association with gastric adenocarcinoma of fundic-gland type.

BACKGROUND: Gastric adenocarcinoma of fundic-gland type (GA-FG) is a rare variant of gastric neoplasia. However, the etiology, classification, and clinicopathological features of gastric epithelial neoplasm of fundic-gland mucosa lineage (GEN-FGML; generic term of GA-FG related neoplasm) are not fully elucidated. We performed a large, multicenter, retrospective study to establish a new classification and clarify the clinicopathological features of GEN-FGML. METHODS: One hundred GEN-FGML lesions in 94 patients were collected from 35 institutions between 2008 and 2019. We designed a new histopathological classification of GEN-FGML using immunohistochemical analysis and analyzed via clinicopathological, immunohistochemical, and genetic evaluation. RESULTS: GEN-FGML was classified into 3 major types; oxyntic gland adenoma (OGA), GA-FG, and gastric adenocarcinoma of fundic-gland mucosa type (GA-FGM). In addition, GA-FGM was classified into 3 subtypes; Type 1 (organized with exposure type), Type 2 (disorganized with exposure type), and Type 3 (disorganized with non-exposure type). OGA and GA-FG demonstrated low-grade epithelial neoplasm, and GA-FGM should be categorized as an aggressive variant of GEN-FGML that demonstrated high-grade epithelial neoplasm (Type 2 > 1, 3). The frequent presence of GNAS mutation was a characteristic genetic feature of GEN-FGML (7/34, 20.6%; OGA 1/3, 33.3%; GA-FG 3/24, 12.5%; GA-FGM 3/7, 42.9%) in mutation analysis using next-generation sequencing. CONCLUSIONS: We have established a new histopathological classification of GEN-FGML and propose a new lineage of gastric epithelial neoplasm that harbors recurrent GNAS mutation. This classification will be useful to estimate the malignant potential of GEN-FGML and establish an appropriate standard therapeutic approach.

Essential role of Notch/Hes1 signaling in postnatal pancreatic exocrine development.

BACKGROUND: Notch/Hes1 signaling has been shown to play a role in determining the fate of pancreatic progenitor cells. However, its function in postnatal pancreatic maturation is not fully elucidated. METHODS: We generated conditional Hes1 knockout and/or Notch intracellular domain (NICD) overexpression mice in Ptf1a- or Pdx1-positive pancreatic progenitor cells and analyzed pancreatic tissues. RESULTS: Both Ptf1acre/+; Hes1f/f and Ptf1acre/+; Rosa26NICD mice showed normal pancreatic development at P0. However, exocrine tissue of the pancreatic tail in Ptf1acre/+; Hes1f/f mice atrophied and was replaced by fat tissue by 4 weeks of age, with increased apoptotic cells and fewer centroacinar cells. This impaired exocrine development was completely rescued by NICD overexpression in Ptf1acre/+; Hes1f/f; Rosa26NICD mice, suggesting compensation by a Notch signaling pathway other than Hes1. Conversely, Pdx1-Cre; Hes1f/f mice showed impaired postnatal exocrine development in both the pancreatic head and tail, revealing that the timing and distribution of embryonic Hes1 expression affects postnatal exocrine tissue development. CONCLUSIONS: Notch signaling has an essential role in pancreatic progenitor cells for the postnatal maturation of exocrine tissue, partly through the formation of centroacinar cells.

Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations.

BACKGROUND: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown. METHODS: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed. RESULTS: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression. CONCLUSIONS: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.

Identification of an Anti-Integrin αvß6 Autoantibody in Patients With Ulcerative Colitis.

BACKGROUND AND AIMS: Ulcerative colitis is the most frequent type of inflammatory bowel disease and is characterized by colonic epithelial cell damage. Although involvement of autoimmunity has been suggested in ulcerative colitis, specific autoantigens/antibodies have yet to be elucidated. METHODS: Using 23 recombinant integrin proteins, we performed enzyme-linked immunosorbent assays on sera from patients with ulcerative colitis and controls. Integrin expression and IgG binding in the colon tissues of patients with ulcerative colitis and controls were examined using immunofluorescence and coimmunoprecipitation, respectively. The blocking activity of autoantibodies was examined using solid-phase binding and cell adhesion assays. RESULTS: Screening revealed that patients with ulcerative colitis had IgG antibodies against integrin αvß6. In the training and validation groups, 103 of 112 (92.0%) patients with ulcerative colitis and only 8 of 155 (5.2%) controls had anti-integrin αvß6 antibodies (P < .001), resulting in a sensitivity of 92.0% and a specificity of 94.8% for diagnosing ulcerative colitis. Anti-integrin αvß6 antibody titers coincided with ulcerative colitis disease activity, and IgG1 was the major subclass. Patient IgG bound to the integrin αvß6 expressed on colonic epithelial cells. Moreover, IgG of patients with ulcerative colitis blocked integrin αvß6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif and inhibited cell adhesion. CONCLUSIONS: A significant majority of patients with ulcerative colitis had autoantibodies against integrin αvß6, which may serve as a potential diagnostic biomarker with high sensitivity and specificity.

Epithelial expression of Gata4 and Sox2 regulates specification of the squamous-columnar junction via MAPK/ERK signaling in mice.

The squamous-columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal-distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.

Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Although rigorous efforts identified the presence of 'cancer stem cells (CSCs)' in PDAC and molecular markers for them, stem cell dynamics in vivo have not been clearly demonstrated. Here we focused on Doublecortin-like kinase 1 (Dclk1), known as a CSC marker of PDAC. Using genetic lineage tracing with a dual-recombinase system and live imaging, we showed that Dclk1+ tumor cells continuously provided progeny cells within pancreatic intraepithelial neoplasia, primary and metastatic PDAC, and PDAC-derived spheroids in vivo and in vitro. Furthermore, genes associated with CSC and epithelial mesenchymal transition were enriched in mouse Dclk1+ and human DCLK1-high PDAC cells. Thus, we provided direct functional evidence for the stem cell activity of Dclk1+ cells in vivo, revealing the essential roles of Dclk1+ cells in expansion of pancreatic neoplasia in all progressive stages.

Phenotyping of IgG4-related diseases based on affected organ pattern: A multicenter cohort study using cluster analysis.

OBJECTIVES: Immunoglobulin G4-related disease (IgG4-RD) is a systemic, multiorgan disease of unknown etiology. We aimed to classify IgG4-RD by a combination pattern of affected organs and identify the clinical features, including the comorbidities of each subgroup. METHODS: Patients diagnosed with IgG4-RD between April 1996 and June 2018 were enrolled from three institutes. Hierarchical cluster analysis was performed using six frequently affected organs (lacrimal gland and/or orbit, salivary gland, lung, pancreas, kidney, and retroperitone and/or aorta). Clinical features, such as comorbidities and outcomes, were compared between clusters. RESULTS: In total, 108 patients enrolled in this cohort could be stratified into five distinct subgroups: group 1, lung dominant group; group 2, retroperitoneal fibrosis and/or aortitis dominant group; group 3, salivary glands limited group; group 4, Mikulicz's disease dominant group; and group 5, autoimmune pancreatitis with systemic involvement group. There were significant between-group differences in sex (male dominant in group 1, 2, and 5), history of asthma and allergies on the respiratory tract (most frequent in group 5), and malignancy (most frequent in group 5). CONCLUSION: IgG4-RD can be classified into subgroups according to the pattern of affected organs. Group 5 may have frequent complications with allergies and malignancies.

Hes1 Is Essential in Proliferating Ductal Cell-Mediated Development of Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is frequently driven by aberrant KRAS activation and develops in the liver with chronic inflammation. Although the Notch signaling pathway is critically involved in ICC development, detailed mechanisms of Notch-driven ICC development are still unknown. Here, we use mice whose Notch signaling is genetically engineered to show that the Notch signaling pathway, specifically the Notch/Hes1 axis, plays an essential role in expanding ductular cells in the liver with chronic inflammation or oncogenic Kras activation. Activation of Notch1 enhanced the development of proliferating ductal cells (PDC) in injured livers, while depletion of Hes1 led to suppression. In correlation with PDC expansion, ICC development was also regulated by the Notch/Hes1 axis and suppressed by Hes1 depletion. Lineage-tracing experiments using EpcamcreERT2 mice further confirmed that Hes1 plays a critical role in the induction of PDC and that ICC could originate from PDC. Analysis of human ICC specimens showed PDC in nonneoplastic background tissues, confirming HES1 expression in both PDC and ICC tumor cells. Our findings provide novel direct experimental evidence that Hes1 plays an essential role in the development of ICC via PDC. SIGNIFICANCE: This study contributes to the identification of the cells of origin that initiate ICC and suggests that HES1 may represent a therapeutic target in ICC.

CXCR4 in Tumor Epithelial Cells Mediates Desmoplastic Reaction in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) features abundant stromal cells with an excessive extracellular matrix (ECM), termed the desmoplastic reaction. CXCR4 is a cytokine receptor for stromal cell-derived factor-1 (CXCL12) expressed in PDAC, but its roles in PDAC and the characteristic desmoplastic reaction remain unclear. Here, we generated a mouse model of PDAC with conditional knockout of Cxcr4 (KPC-Cxcr4-KO) by crossing Cxcr4 flox mice with Pdx1-Cre;KrasLSL-G12D/+;Trp53LSL-R172H/+ (KPC-Cxcr4-WT) mice to assess the development of pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancers. Tumor cell characteristics of those two types were analyzed in vitro. In addition, CXCR4 expression in human pancreatic cancer specimens was evaluated by IHC staining. In KPC-Cxcr4-KO mice, the number and pathologic grade of PanIN lesions were reduced, but the frequency of pancreatic cancers did not differ from that in KPC-Cxcr4-WT mice. The pancreatic tumor phenotype in KPC-Cxcr4-KO mice was significantly larger and undifferentiated, characterized by abundant vimentin-expressing cancer cells, significantly fewer fibroblasts, and markedly less deposition of ECM. In vitro, KPC-Cxcr4-KO tumor cells exhibited higher proliferative and migratory activity than KPC-Cxcr4-WT tumor cells. Myofibroblasts induced invasion activity in KPC-Cxcr4-WT tumor cells, showing an epithelial-mesenchymal interaction, whereas KPC-Cxcr4-KO tumor cells were unaffected by myofibroblasts, suggesting their unique nature. In human pancreatic cancer, undifferentiated carcinoma did not express CXCR4 and exhibited histologic and IHC features similar to those in KPC-Cxcr4-KO mice. In summary, the CXCL12/CXCR4 axis may play an important role in the desmoplastic reaction in PDAC, and loss of CXCR4 induces phenotype changes in undifferentiated carcinoma without a desmoplastic reaction. SIGNIFICANCE: The current study uncovers CXCR4 as a key regulator of desmoplastic reaction in PDAC and opens the way for new therapeutic approaches to overcome the chemoresistance in patients with PDAC.

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1 to 3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rbf/f ) in mice did not affect pancreatic exocrine cells, the α-cell/ß-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated PanNET with a Ki67-labeling index of 2.7%. In contrast, pancreas-specific induction of a p53 mutation (Pdx1-Cre;Trp53R172H ) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre;Trp53R172H;Rb f/f ) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53R172H;Rbf/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET. SIGNIFICANCE: Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2-3).

Impaired expression of innate immunity-related genes in IgG4-related disease: A possible mechanism in the pathogenesis of IgG4-RD.

Background: IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. The pathogenesis of this disease is not clear. Transcriptome analysis was performed to identify genes over- and under-expressed in patients with IgG4-RD.Method: DNA microarray analysis was performed using RNA from peripheral blood mononuclear cells of two patients with IgG4-RD and four healthy individuals. Genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy were identified. Four genes related to innate immunity such as transcobalamin I (TCN1), secretory leukocyte peptidase inhibitor (SLPI), bactericidal/permeability-increasing protein (BPI) and lactotransferrin (LTF) were assessed by real-time PCR in 15 IgG4-RD patients and 13 healthy individuals.Result: DNA microarray analysis identified 30 genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy. Real-time RT-PCR showed that the levels of mRNAs encoding TCNI and SLPI, except for BPI and LTF, were significantly lower in patients with IgG4-RD than in healthy people. The levels of all four mRNAs in patients with IgG4-RD were significantly increased after steroid treatment.Conclusion: These results indicate that reduction in expression of innate immunity-related genes may participate in the pathogenesis of IgG4-RD that steroid treatment may rectify impaired innate immunity as well as acquired immunity.