ABSTRACT
Aims
Inflammatory bowel disease is characterized by various cytokine patterns. In this study, we aimed to investigate the markers that can distinguish Th1/Th2 cytokines in patients with inflammatory bowel disease.
Methods and Results
In patients with inflammatory bowel disease treated at our hospital, the Th1/Th2 ratio (interferon‐γ/interleukin‐4 ratio), serum immunoglobulin E level, leucine‐rich alpha 2 glycoprotein level, serum amyloid A level, and leukocyte fraction were measured simultaneously, and the relationship between them was examined. We enrolled 108 patients with Crohn's disease and 153 patients with ulcerative colitis. No significant difference was observed in the Th1/Th2 ratio between the ulcerative colitis and Crohn's disease groups. In the inflammatory bowel disease and Crohn's disease groups, the lymphocyte fraction was significantly correlated with the Th1/Th2 ratio (r = 0.154, p = 0.013 and r = 0.204, p = 0.0346, respectively). In ulcerative colitis, lymphocyte fraction and Th1/Th2 ratio were significantly correlated in the group without steroid treatment; however, no significant correlation was observed in the steroid‐treated group. Serum immunoglobulin E, leucine‐rich alpha 2 glycoproteins, and serum amyloid A levels did not significantly correlate with the Th1/Th2 ratio.
Conclusions
The lymphocyte fraction may serve as a marker of Th1/Th2 cytokines and could be particularly useful in non‐steroid‐treated patients.
Keywords: Crohn's disease, lymphocytes, Th1/Th2 balance, ulcerative colitis
1. Introduction
Inflammatory bowel disease (IBD) is a chronic inflammatory disease comprising Crohn's disease (CD) and ulcerative colitis (UC), and it is characterized by repeated recurrences and remissions. CD can occur in any part of the digestive tract and typically presents with fatigue, prolonged diarrhea, with or without gross bleeding, abdominal pain, weight loss, and fever. UC characteristically affects the colon and usually presents with symptoms such as rectal bleeding, frequent bowel movements, mucus discharge from the rectum, tenesmus, and lower abdominal pain. In both diseases, dysregulation of the immune response is thought to be involved in pathogenesis [1].
There are two types of immune responses: innate and adaptive immunity. CD4+ T cells (helper T cells) are thought to play a central role in adaptive immunity. T helper cells produce two distinct responses: Th1‐type cytokines (IFN‐γ and IL‐2) and Th2‐type cytokines (IL‐4 and IL‐5). CD and UC were once thought to be mediated by Th1 and Th2 cytokines, respectively [2]. However, in recent years, it is considered that besides Th1 and Th2 cells, Th17 cells, which produce cytokines such as IL‐17, and regulatory T cells are involved [3]. Therefore, it is difficult to simply distinguish between CD‐type Th1 and UC‐type Th2 cytokines, and the understanding of the immune response of IBD is complicated.
Although this complex immune response has been elucidated, Th1 and Th2 cytokines are significantly involved in the pathogenesis of IBD, and their levels can be measured using blood tests. The blood Th1/Th2 ratio in CD4‐positive cells is measured by detecting the presence of IFN‐γ and IL‐4 using flow cytometry and monoclonal antibodies. Its involvement in various diseases such as infectious diseases (leishmania and leprosy) [4], autoimmune diseases (systemic lupus erythematosus) [5], and malignant tumors (melanoma) [6] has been reported. Therefore, measuring the blood Th1/Th2 ratio may lead to a better understanding of the pathophysiology of the disease as well as its treatment. To our knowledge, no study has examined the blood Th1/Th2 ratio in patients with IBD. Therefore, in this study, we aimed to identify biomarkers that could discriminate between Th1/Th2 cytokines in patients with IBD.
2. Methods
2.1. Participants
Between November 1, 2021, and March 31, 2024, 261 patients with IBD (153 with UC and 108 with CD) were enrolled at our facility. These patients received a diagnosis of UC and CD according to the current established IBD criteria based on clinical symptoms, endoscopic findings, and histological findings [7, 8]. Patients under 16 years of age were excluded. Patients with infections, heart failure, or malignancies affecting markers were also excluded. Data on clinical background, drug use, and disease activity were extracted from the enrolled patients; however, those on steroid use and the duration of administration were not collected in this study.
2.2. Marker Measurements
Blood samples were collected at regular visits and stored at room temperature. Samples were sent to a laboratory (SRL Inc., Tokyo, Japan) for measurements. Leucine‐rich alpha 2 glycoprotein (LRG) measurements were performed with JCA‐BM8000 (JEOL Ltd., Tokyo, Japan) and NANOPIA LRG (SEKISUI MEDICAL Company Limited, Tokyo, Japan) using latex agglutination immunoassay. Immunoglobulin E (IgE) levels were measured via fluorescence enzyme immunoassay using Phadia5000 (Thermo Fisher Diagnostic Ltd., Tokyo, Japan) and ImmunoCAP (Thermo Fisher Diagnostic Ltd., Tokyo, Japan). Serum amyloid A (SAA) level was measured using the latex agglutination immunoassay method with the Latex Agglutination (LZ) test (Eiken Chemical Co. Ltd., Tokyo, Japan) and JCA‐BM8000 (JEOL Ltd., Tokyo, Japan). The Th1/Th2 ratio was measured by flow cytometry using FACS Canto II and FASTIMMUNE IFN‐γ/IL‐4/CD4 (BD Biosciences, Tokyo, Japan) after rapid sample processing. C‐reactive protein (CRP) level was routinely measured as part of general practice at our facility.
2.3. Study Design
This was a prospective single‐center study. The primary outcome measure of this study was the correlation between the Th1/Th2 ratio and laboratory values. The secondary outcome was the correlation between the Th1/Th2 ratio and laboratory values, with or without steroid use. Clinical activity in UC was assessed using the clinical activity index (CAI) according to Rachmilewitz. Clinical activity in CD was assessed using the Crohn's disease activity index (CDAI) [9, 10]. In this study, remission was defined as CAI ≤ 4 and CDAI < 150.
2.4. Statistical Analysis
IBM SPSS Statistics for Windows version 24 (IBM Corp., Armonk, N.Y., USA) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) software were used for statistical analyses [11]. The correlation was analyzed using Spearman's correlation analysis. The Mann–Whitney U test or Student's t‐test was used to evaluate differences. Statistical significance was set at p < 0.05.
2.5. Ethics Statement
This study was reviewed and approved by the Ethics Committee of our facility. This study was conducted in accordance with Good Clinical Practice principles in adherence to the Declaration of Helsinki. Written informed consent was obtained from all patients enrolled in this study.
3. Results
3.1. Patient Characteristics
In total, 108 patients with CD (median age, 40 years; 78 males and 30 females) and 153 patients with UC (median age, 46 years; 98 males and 55 females) were enrolled in this study. Table 1 summarizes the baseline characteristics of the patients with CD and UC. The median clinical activity was CDAI = 90.1 for CD and CAI = 1 for UC. The median values of the biomarkers in patients with CD were as follows: LRG, 12.6 μg/mL; CRP, 0.09 mg/dL; SAA, 4.8 mg/L; IgE, 72.9 kU/L; and Th1/Th2, 7.4. The median values in patients with UC were as follows: LRG, 12.5 μg/mL; CRP, 0.06 mg/dL; SAA, 3.5 mg/L; IgE, 95.8 kU/L; and Th1/Th2, 7.7.
TABLE 1.
Baseline patient characteristics.
| CD | UC | ||
|---|---|---|---|
| N = 108 | N = 153 | ||
| Age (year), median [IQR] | 40 [29, 48] | 46 [30, 59] | |
| Male/Female, n (%) | 78 (72.2)/30 (27.8) | 98 (64.1)/55 (35.9) | |
| Disease duration (year), median [IQR] | 9 [4, 21] | 8 [3, 14] | |
| Extent of UC, n (%) | E1/E2/E3 | 12 (7.8)/40 (26.1)/101 (66.1) | |
| Age at diagnosis of CD, n (%) | A1/A2/A3 | 8 (7.4)/90 (83.3)/10 (9.3) | |
| Location of CD, n (%) | L1/L2/L3 | 38 (35.2)/12 (11.1)/58 (53.7) | |
| Behavior of CD, n (%) | B1/B2/B3 | 46 (42.6)/38 (35.2)/24 (22.2) | |
| CAI, median [IQR] | 1 [0, 3] | ||
| CDAI, median [IQR] | 90.1 [47.5, 144.2] | ||
| Alb (g/dL), median [IQR] | 4.4 [4.2, 4.6] | 4.5 [4.2, 4.7] | |
| Hb (g/dL), median [IQR] | 14.2 [12.7, 15.1] | 14.1 [13.0, 15.6] | |
| WBC (/μL), median [IQR] | 5805 [4458, 6935] | 5680 [4640, 7000] | |
| ESR (mm/h), median [IQR] | 7 [4, 17] | 7 [3, 13] | |
| LRG (μg/mL), median [IQR] | 12.6 [10.5, 15.7] | 12.5 [10.1, 17.1] | |
| CRP (mg/dL), median [IQR] | 0.09 [0.05, 0.21] | 0.06 [0.03, 0.20] | |
| SAA (mg/l), median [IQR] | 4.8 [2.5, 8.6] | 3.5 [2.3, 6.8] | |
| IgE (kU/l), median [IQR] | 72.9 [31.0, 283.3] | 95.8 [39.0, 296.0] | |
| Th1 (%), median [IQR] | 19.5 [15.4, 28.7] | 17.7 [12.4, 25.8] | |
| Th2 (%), median [IQR] | 2.6 [2.2, 3.7] | 2.5 [1.8, 3.3] | |
| Th1/Th2, median [IQR] | 7.4 [5.1, 11.4] | 7.7 [4.8, 11.7] | |
| Neutrophil fraction (%), median [IQR] | 62.2 [53.7, 69.3] | 63.4 [58.0, 69.5] | |
| Eosinophil fraction (%), median [IQR] | 2.5 [1.3, 4.0] | 2.3 [1.2, 4.1] | |
| Basophil fraction (%), median [IQR] | 0.7 [0.5, 0.9] | 0.8 [0.5, 1.0] | |
| Lymphocyte fraction (%), median [IQR] | 27.0 [20.7, 33.3] | 26.1 [19.0, 32.1] | |
| Monocyte fraction (%), median [IQR] | 6.3 [5.3, 8.0] | 6.5 [5.2, 7.8] | |
| Medication during the study period, n (%) | Oral 5‐ASA | 80 (74.1) | 107 (69.9) |
| Systemic steroids | 2 (1.9) | 11 (7.2) | |
| Immunomodulators | 20 (18.5) | 41 (26.8) | |
| Biologics | 86 (79.6) | 72 (47.1) | |
Abbreviations: 5‐ASA, 5‐aminosalicylic acid; Alb, albumin; CAI, clinical activity index; CD, Crohn's disease; CDAI, Crohn's disease activity index; CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; Hb, hemoglobin; IgE, immunoglobulin E; IQR, interquartile range; LRG, leucine‐rich alpha 2 glycoprotein; MES, Mayo Endoscopic Subscore; SAA, serum amyloid A; SES‐CD, Simple Endoscopic Score for Crohn‐s Disease; UC, ulcerative colitis; WBC, white blood cell.
3.2. Th1/Th2 Comparison
The Th1/Th2 ratios were compared between patients with CD and those with UC (Figure 1). There was no significant difference in the Th1/Th2 ratio between the CD and UC groups (Figure 1a). There was no significant difference in the Th1/Th2 ratio between CD and UC in patients with active intestinal inflammation (CAI ≥ 5 and CDAI ≥ 150) or low activity (CAI < 5 and CDAI < 150) (Figure 1b,c). There was no significant difference in the Th1/Th2 ratio between patients with CD and UC when examined with or without concomitant oral steroid intake (Figure 1d,e).
FIGURE 1.
Comparison of Th1/Th2 ratio in Crohn's disease (CD) and ulcerative colitis (UC). Th1/Th2 ratio in all patients (a), patients in the active phase of the disease (CAI ≥ 5 and CDAI ≥ 150) (b), patients in remission (CAI ≤ 4 and CDAI< 150) (c), patients treated with steroids (d), and patients not treated with steroids (e).
3.3. Relationship Between Th1/Th2 and Various Test Markers
The correlation between the Th1/Th2 ratio and various markers was evaluated (Table 2). In IBD, lymphocyte and neutrophil fractions were significantly positively and negatively correlated with Th1/Th2, respectively; however, SAA, LRG, and IgE levels were not correlated (r = 0.154, p = 0.013 and r = −0.134, p = 0.0298, respectively). In CD, the lymphocyte fraction significantly positively correlated with Th1/Th2 ratios, but the neutrophil fraction did not (r = 0.204, p = 0.0346 and r = −0.163, p = 0.0915, respectively). In UC, no correlation was observed between the various markers and the Th1/Th2 ratio.
TABLE 2.
Correlation coefficients between Th1/Th2 and each marker in IBD.
| IBD | CD | UC | ||||
|---|---|---|---|---|---|---|
| r | P | R | P | R | P | |
| CRP | 0.024 | 0.69 | −0.105 | 0.28 | 0.095 | 0.24 |
| ESR | 0.111 | 0.07 | 0.101 | 0.30 | 0.124 | 0.13 |
| SAA | 0.048 | 0.44 | 0.001 | 0.99 | 0.076 | 0.35 |
| LRG | 0.039 | 0.53 | −0.059 | 0.54 | 0.109 | 0.18 |
| IgE | −0.005 | 0.93 | 0.094 | 0.33 | −0.062 | 0.45 |
| Lymphocyte fraction | 0.154 | < 0.05 | 0.204 | < 0.05 | 0.122 | 0.13 |
| Neutrophil fraction | −0.134 | < 0.05 | −0.163 | 0.09 | −0.115 | 0.16 |
Abbreviations: CD, Crohn's disease; CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; IBD, inflammatory bowel disease; IgE, immunoglobulin E; LRG, leucine‐rich alpha 2 glycoprotein; SAA, serum amyloid A; UC, ulcerative colitis.
3.4. Relationship Between the Th1/Th2 Ratio and Various Laboratory Values With or Without Steroids
The Th1/Th2 ratios were compared between patients with IBD treated with and without oral steroids (Figure 2). Th1/Th2 levels were significantly higher in the oral steroid group than in the non‐steroid‐treated group (p = 0.0254). The correlation between the Th1/Th2 ratio and various laboratory parameters was evaluated in the non‐steroid‐treated group (Table 3). In IBD, lymphocyte and neutrophil fractions were significantly positively and negatively correlated with the Th1/Th2 ratio, respectively; however, SAA, LRG, and IgE levels were not significantly correlated with the Th1/Th2 ratio (r = 0.179, p = 0.0044, and r = −0.174, p = 0.0105, respectively). In CD, the lymphocyte fraction was significantly and positively correlated with the Th1/Th2 ratio, but the neutrophil fraction was not (r = 0.192, p = 0.0488). In UC, there was no significant correlation between the various markers and the Th1/Th2 ratio. The correlation between the Th1/Th2 ratio and various laboratory values was evaluated in the steroid‐treated group (Table 4). In IBD and UC, there was no significant correlation between the test values and the Th1/Th2 ratio. A small number of patients with CD were treated with steroids and could not be assessed as relevant.
FIGURE 2.
Comparison of the Th1/Th2 ratio in steroid‐treated and non‐treated patients.
TABLE 3.
Correlation coefficients between the Th1/Th2 ratio and each marker in patients with IBD treated without steroids.
| IBD | CD | UC | ||||
|---|---|---|---|---|---|---|
| r | P | r | P | r | P | |
| CRP | 0.094 | 0.69 | −0.087 | 0.28 | 0.094 | 0.24 |
| ESR | 0.112 | 0.07 | 0.096 | 0.30 | 0.112 | 0.13 |
| SAA | 0.029 | 0.44 | 0.003 | 0.99 | 0.029 | 0.35 |
| LRG | 0.105 | 0.53 | −0.063 | 0.54 | 0.105 | 0.18 |
| IgE | −0.030 | 0.93 | 0.102 | 0.33 | −0.030 | 0.45 |
| Lymphocyte fraction | 0.179 | < 0.05 | 0.192 | < 0.05 | 0.179 | 0.13 |
| Neutrophil fraction | −0.174 | < 0.05 | −0.155 | 0.09 | −0.174 | 0.16 |
Abbreviations: CD, Crohn's disease; CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; IBD, inflammatory bowel disease; IgE, immunoglobulin E; LRG, leucine‐rich alpha 2 glycoprotein; SAA, serum amyloid A; UC, ulcerative colitis.
TABLE 4.
Correlation coefficients between the Th1/Th2 ratio and each marker in patients with IBD treated with steroids.
| IBD | UC | |||
|---|---|---|---|---|
| R | P | r | P | |
| CRP | −0.005 | 0.99 | −0.009 | 0.98 |
| ESR | −0.103 | 0.74 | −0.138 | 0.69 |
| SAA | 0.063 | 0.85 | 0.042 | 0.92 |
| LRG | 0.104 | 0.74 | 0.155 | 0.65 |
| IgE | −0.264 | 0.38 | −0.345 | 0.30 |
| Lymphocyte fraction | 0.165 | 0.59 | 0.182 | 0.60 |
| Neutrophil fraction | −0.066 | 0.84 | −0.055 | 0.88 |
Abbreviations: CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; IBD, inflammatory bowel disease; IgE, immunoglobulin E; LRG, leucine‐rich alpha 2 glycoprotein; SAA, serum amyloid A; UC, ulcerative colitis.
4. Discussion
This study examined whether SAA, LRG, IgE, and leukocyte fractions reflect Th1/Th2 ratios. To our knowledge, this is the first study to evaluate biomarkers that can be attributed to Th1/Th2 ratios in IBD. There was no significant difference in the Th1/Th2 ratio between patients with CD and UC. Previously, CD was thought to be mediated by Th1‐type cytokines and UC by Th2‐type cytokines. However, Th17 and other substances are also considered to be involved, and the immune response of IBD is becoming increasingly complex [3]. The results of this study suggest that distinguishing CD and UC based on the Th1/Th2 ratio alone is challenging. In IBD, the lymphocyte and neutrophil fractions showed a significant correlation with the Th1/Th2 ratio, whereas CD correlated only with the lymphocyte fraction. UC did not show a significant correlation with the Th1/Th2 ratio. SAA, LRG, and IgE levels were not significantly correlated with Th1/Th2 ratios.
The lymphocyte and neutrophil fractions are leukocyte fractions, and their values fluctuate in various disease states, such as inflammation. Th17 cytokines, but not Th1 and Th2, have been reported to be involved in neutrophil recruitment [12]. However, we did not find any reports on the association between Th1 and Th2 cytokines and lymphocyte or neutrophil fractions. Future studies should provide further clarity regarding this topic.
In IBD, a significant correlation was observed between both the lymphocyte and neutrophil fractions and the Th1/Th2 ratio; however, only the lymphocyte fraction correlated with the Th1/Th2 ratio in CD, and no significant correlation was observed in UC. Although the lymphocyte and neutrophil fractions show a correlation with the Th1/Th2 ratio in IBD, the influence of cytokines produced by Th17 and T‐regulatory cells is stronger in both CD and UC [3], and distinguishing CD and UC by the Th1/Th2 ratio alone is difficult. Therefore, there was no significant correlation when CD or UC alone was evaluated. Although no significant relationship was observed, the lymphocyte and neutrophil fractions tended to correlate with the Th1/Th2 ratio. Further investigations should be performed using a greater number of cases. Oral steroid administration resulted in significantly higher Th1/Th2 ratios. Th2 cytokines produced by Th2 cells have been reported to be suppressed by steroid use [13], which is consistent with an increase in the Th1/Th2 ratio following Th2 cytokine level reduction by steroid use.
In the non‐steroid‐treated group, the lymphocyte and neutrophil fractions showed a significant correlation with the Th1/Th2 ratio in IBD, and only the lymphocyte fraction correlated with the Th1/Th2 ratio in CD. However, there was no significant correlation between the Th1/Th2 ratio and lymphocyte and neutrophil fractions in the steroid‐treated group. Steroid use reportedly suppresses Th2 reactions [14]. In addition, its use causes an increase in white blood cell and neutrophil counts, thereby greatly altering the lymphocyte and neutrophil fractions. Therefore, no significant correlation was observed in the steroid‐treated group.
SAA, a class of conservative acute‐phase proteins comprising 104 amino acids, is essential in immune‐mediated inflammatory processes such as IBD [15]. It is involved in immunomodulation, especially T cell immunity. No significant correlation between SAA levels and the Th1/Th2 ratio was found in this study. This may be because SAA is more closely related to Th17 cells than to Th1 and Th2 cells [16]. LRG is a useful biomarker for assessing disease activity in patients with IBD [17]. Unlike CRP, LRG expression is thought to be induced not only by IL‐6 but also by other inflammatory cytokines [18]. Therefore, LRG is thought to be involved with Th1 and Th2 cytokines, and its correlation with the Th1/Th2 ratio was examined in this study. However, no significant correlation was observed, suggesting that its association with Th1 and Th2 cytokines was weak. Th2 cells constitute the major source of IL‐4, which plays an important role in the induction of IgE synthesis. Th1 cells also produce IFN‐γ, which inhibits IL‐4‐induced IgE synthesis [19]. Therefore, the correlation between IgE levels and the Th1/Th2 ratio was examined; however, no significant correlation was observed. This is presumably because cytokines other than those produced by Th1 and Th2 cells affect the induction of IgE synthesis. Thus, it is difficult to distinguish CD and UC based on the Th1/Th2 ratio alone, and it is important to consider the involvement of other inflammatory cytokines such as Th17 during treatment. Nonetheless, Th1 and Th2 cytokines are involved in the pathogenesis of IBD, and speculation regarding the Th1/Th2 ratio may lead to future treatments for IBD. This study suggests that the lymphocyte fraction may be useful as a marker for Th1/Th2 cytokines.
This study had some limitations. First, it was a single‐center study, and many patients had mild diseases. This also raises questions about whether the differences in the number of patients with UC and CD should be evaluated as well. Second, this study focused on the serum Th1/Th2 ratio and did not examine the Th1/Th2 ratio in the intestinal tract. Additionally, the association between serum Th1/Th2 levels and histological inflammation was not evaluated. Although the correlation between the Th1/Th2 ratios in the gut and blood remains unclear, the Th1/Th2 ratio in the blood, which is more easily collected, was selected for this study. Third, we did not examine the Th1/Th2 ratio in healthy individuals or patients with IBD with heterochrony. Fourth, the number of cases in the steroid‐treated group was low.
5. Conclusion
In IBD, the lymphocyte fraction has been suggested as a marker of Th1/Th2 cytokines. The accumulation of more such cases is expected to improve our understanding of the disease in the future.
Ethics Statement
This study was reviewed and approved by the Ethics Committee of our facility. This study was conducted in accordance with Good Clinical Practice principles in adherence to the Declaration of Helsinki.
Consent
Written informed consent was obtained from all patients enrolled in this study.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
We would like to express our appreciation to the staff of the gastroenterology department, ward, outpatient clinic, laboratory medicine department, and endoscopic and photodynamic medicine department at Hamamatsu University School of Medicine.
Asai Y., Ishida N., Takebe T., et al., “Lymphocyte Fractions as Indicators of T‐Helper 1/T‐Helper 2 Cytokine Profiles in Inflammatory Bowel Disease,” JGH Open 9, no. 8 (2025): e70243, 10.1002/jgh3.70243.
Data Availability Statement
All data required to evaluate the conclusions of this study are presented herein. Additional data related to this study can be requested from the corresponding author.
References
- 1. Wallace K. L., Zheng L. B., Kanazawa Y., and Shih D. Q., “Immunopathology of Inflammatory Bowel Disease,” World Journal of Gastroenterology 20 (2014): 6–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Cherwinski H. M., Schumacher J. H., Brown K. D., and Mosmann T. R., “Two Types of Mouse Helper T Cell Clone. III. Further Differences in Lymphokine Synthesis Between Th1 and Th2 Clones Revealed by RNA Hybridization, Functionally Monospecific Bioassays, and Monoclonal Antibodies,” Journal of Experimental Medicine 166 (1987): 1229–1244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Iacomino G., Aufiero R. V., Iannaccone N., et al., “IBD: Role of Intestinal Compartments in the Mucosal Immune Response,” Immunobiology 225 (2020): 151849. [DOI] [PubMed] [Google Scholar]
- 4. Infante‐Duarte C. and Kamradt T., “Th1/Th2 Balance in Infection,” Springer Seminars in Immunopathology 21 (1999): 317–338. [DOI] [PubMed] [Google Scholar]
- 5. Muhammad Yusoff F., Wong K. K., and Mohd Redzwan N., “Th1, Th2, and Th17 Cytokines in Systemic Lupus Erythematosus,” Autoimmunity 53 (2020): 8–20. [DOI] [PubMed] [Google Scholar]
- 6. Lauerova L., Dusek L., Simickova M., et al., “Malignant Melanoma Associates With Th1/Th2 Imbalance That Coincides With Disease Progression and Immunotherapy Response,” Neoplasma 49 (2002): 159–166. [PubMed] [Google Scholar]
- 7. Magro F., Gionchetti P., Eliakim R., et al., “Third European Evidence‐Based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra‐Intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo‐Anal Pouch Disorders,” Journal of Crohn's and Colitis 11 (2017): 649–670. [DOI] [PubMed] [Google Scholar]
- 8. Gomollón F., Dignass A., Annese V., et al., “3rd European Evidence‐Based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 1: Diagnosis and Medical Management,” Journal of Crohn's and Colitis 11 (2017): 3–25. [DOI] [PubMed] [Google Scholar]
- 9. Rachmilewitz D., “Coated Mesalazine (5‐Aminosalicylic Acid) Versus Sulphasalazine in the Treatment of Active Ulcerative Colitis: A Randomised Trial,” British Medical Journal 298 (1989): 82–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Summers R. W., Switz D. M., J. T. Sessions, Jr. , et al., “National Cooperative Crohn's Disease Study: Results of Drug Treatment,” Gastroenterology 77 (1979): 847–869. [PubMed] [Google Scholar]
- 11. Kanda Y., “Investigation of the Freely Available Easy‐To‐Use Software “EZR” for Medical Statistics,” Bone Marrow Transplantation 48 (2013): 452–458. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Kawaguchi M., Adachi M., Oda N., Kokubu F., and Huang S. K., “IL‐17 Cytokine Family,” Journal of Allergy and Clinical Immunology 114 (2004): 1265–1273. [DOI] [PubMed] [Google Scholar]
- 13. Saeki M., Kaminuma O., Nishimura T., Kitamura N., Mori A., and Hiroi T., “Th9 Cells Induce Steroid‐Resistant Bronchial Hyperresponsiveness in Mice,” Allergology International 66S (2017): S35–S40. [DOI] [PubMed] [Google Scholar]
- 14. Schmidt J., Fleissner S., Heimann‐Weitschat I., Lindstaedt R., and Szelenyi I., “The Effect of Different Corticosteroids and Cyclosporin A on Interleukin‐4 and Interleukin‐5 Release From Murine TH2‐Type T Cells,” European Journal of Pharmacology 260 (1994): 247–250. [DOI] [PubMed] [Google Scholar]
- 15. Chen R., Chen Q., Zheng J., et al., “Serum Amyloid Protein A in Inflammatory Bowel Disease: From Bench to Bedside,” Cell Death Discovery 9 (2023): 154. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Lee J.‐Y., Hall J. A., Kroehling L., et al., “Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease,” Cell 180 (2020): 79–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Shimoyama T., Yamamoto T., Yoshiyama S., Nishikawa R., and Umegae S., “Leucine‐Rich Alpha‐2 Glycoprotein Is a Reliable Serum Biomarker for Evaluating Clinical and Endoscopic Disease Activity in Inflammatory Bowel Disease,” Inflammatory Bowel Diseases 29 (2023): 1399–1408. [DOI] [PubMed] [Google Scholar]
- 18. Naka T. and Fujimoto M., “LRG Is a Novel Inflammatory Marker Clinically Useful for the Evaluation of Disease Activity in Rheumatoid Arthritis and Inflammatory Bowel Disease,” Immunological Medicine 41 (2018): 62–67. [DOI] [PubMed] [Google Scholar]
- 19. Haas H. and Schlaak M., “The Th1/Th2 Concept—Its Importance for Regulation of IgE,” Immunität und Infektion 22 (1994): 88–93. [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data required to evaluate the conclusions of this study are presented herein. Additional data related to this study can be requested from the corresponding author.