OBJECTIVE: To investigate the relationship between Ig class switch recombination (CSR) and mismatch repair (MMR) protein, microsatellite phenotype in extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). METHODS: Forty cases of MALT lymphoma archived in the Department of Pathology, Jiading District Central Hospital, Shanghai University of Medicine & Health Sciences were selected as the observation group, and twenty cases of benign lymphoid tissue hyperplasia were as the control group. The expressions of IgG, IgM, IgD, and IgA in both groups were detected by immunohistochemical double staining, and MMR proteins including MLH1, MSH2, MSH6, and PMS2 in both groups were detected by immunohistochemistry. Multiplex fluorescence PCR capillary electrophoresis was used to detect microsatellite phenotype in tumor and adjacent tissues of the experimental group. RESULTS: In the observation group, the proportions of single Ig heavy chain expression (modeⅠ), negative expression (modeⅡ), and multiple expression (mode Ⅲ) were 65% (26/40), 27.5% (11/40), and 7.5% (3/40), respectively, while in the control group were 0 (0/20), 5% (1/20), and 95% (19/20). The proportion of Ig heavy chain expression mode Ⅰ+Ⅱ in the observation group was 92.5%, which was significantly higher than 5% in the control group (P < 0.01). In the observation group, partial deletion of MMR protein was observed in 3 cases (7.5%), including 2 cases of MSH6 deletion and 1 case of both MSH6 and PMS2 deletion. In the control group, there was 1 case (5%) with PMS2 deletion. There was no significant difference in the deletion rate of MMR protein between the two groups ( P >0.05). A total of 5 cases of microsatellite instability (MSI) were detected in the observation group, including 1 case of low-frequency MSI (MSI-L), 4 cases of high-frequency MSI (MSI-H), and 2 cases of MSI-H with MSH6 deletion. When the loss expression of MSI-H or MMR protein was counted as a positive result, the MSI-H rate detected by PCR capillary electrophoresis was 10% (4/40), which was slightly higher than the MMR protein deletion rate detected by immunohistochemistry (7.5%, 3/40), but there was no statistically significant difference between the two groups (P >0.05). The MMR protein deletion rates among the Ig heavy chain protein expression mode Ⅰ, mode Ⅱ, and mode Ⅲ groups were 0 (0/26), 18.2% (2/11), and 33.3% (1/3), respectively. There was a statistically significant difference in the constituent ratios among the three groups (P < 0.05). The MMR protein deletion rates among the MSS, MSI-L, and MSI-H groups were 2.9% (1/35), 0 (0/1), and 50% (2/4), respectively. There was a statistically significant difference in the constituent ratios among the three groups (P < 0.05). MMR protein deficiency was positively correlated with Ig heavy chain expression pattern and MSI ( r =0.41, P < 0.05; r =0.48, P < 0.05), but Ig heavy chain expression pattern was not correlated with MSI ( r =0.02, P >0.05). CONCLUSION Ig heavy chain CSR detection is helpful for the differential diagnosis of MALT lymphoma. Low frequency MMR protein deletion and MSI-H phenotype exist in MALT lymphoma, which may be of certain value for the study of its occurrence, development and clinical treatment.
Humans ; Lymphoma, B-Cell, Marginal Zone/genetics* ; DNA Mismatch Repair ; Immunoglobulin Class Switching ; DNA-Binding Proteins/metabolism* ; MutS Homolog 2 Protein ; Microsatellite Repeats ; Phenotype ; MutL Protein Homolog 1 ; Mismatch Repair Endonuclease PMS2 ; Male

We previously demonstrated that Bordetella bronchiseptica (B. bronchiseptica) antigen (Ag) enhances the Mycoplasma hyopneumoniae Ag-specific immune response. The focus of this study was whether acellular bacterin of B. bronchiseptica could be used as an adjuvant to increase antigen-presenting capability of dendritic cells (DCs) by increasing the level of activation. The metabolic activity of DCs was increased by B. bronchiseptica, similar to lipopolysaccharide (LPS). Flow cytometry analysis revealed that B. bronchiseptica increases the expression of major histocompatibility complex class-2, cluster of differentiation (CD)40, CD54, and CD86 which are closely related to DC-mediated immune responses. B. bronchiseptica enhanced the production of cytokines related to adaptive immune responses. Furthermore, the survival rate of B. bronchiseptica-injected groups was 100% at 15 and 20 mg/kg doses, whereas that of LPS-injected groups was only 20%, 0% at 15 and 20 mg/kg doses respectively, and so B. bronchiseptica is likely to be safer than LPS. Taken together, these results indicate that B. bronchiseptica can be used as an adjuvant to enhance the antigen-presenting capability of DCs. B. bronchiseptica is a candidate for producing vaccines, especially in case of DC-mediating efficacy and safety demands. This study provides researchers and clinicians with valuable information regarding the usage of B. bronchiseptica as a safe bacteria-derived immunostimulating agent for developing efficient vaccines.
Bacterial Vaccines ; Bordetella bronchiseptica ; Bordetella ; Cytokines ; Dendritic Cells ; Flow Cytometry ; Immunization ; Major Histocompatibility Complex ; Mycoplasma hyopneumoniae ; Survival Rate ; Vaccines

Despite their being uncommon, severe cutaneous adverse drug reactions (SCARs) result in a very great burden of disease. These reactions not only carry with them a high mortality (10%–50%) and high morbidity (60%) with severe ocular complications, alopecia, oral and dental complications and development of autoimmune diseases, but also create a substantial economic burden for patients' families and society. SCARs are, therefore, an important medical problem needing a solution in many countries, especially in Asia. The clinical spectrum of SCARs comprises Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS (drug rash with eosinophilia and systemic symptoms) (also known as drug hypersensitivity syndrome or drug-induced hypersensitivity syndrome) and acute generalised exanthematous pustulosis. Recent crucial advances in determining genetic susceptibility and understanding how T cells recognise certain medications or their metabolites via the major histocompatibility complex and the effects of cofactors, have led to the implementation of cost-effective screening programs enabling prevention in a number of countries, and to further understanding of the patho-mechanisms involved in SCARs and their significance. In this review, we document comprehensively the journey of SCARs from bedside to bench and outline future perspectives in SCARs research.
Alopecia ; Asia ; Autoimmune Diseases ; Cicatrix ; Drug Hypersensitivity Syndrome ; Drug-Related Side Effects and Adverse Reactions ; Eosinophilia ; Exanthema ; Genetic Predisposition to Disease ; Humans ; Hypersensitivity ; Leukocytes ; Major Histocompatibility Complex ; Mass Screening ; Mortality ; Stevens-Johnson Syndrome ; T-Lymphocytes

Long-term maintenance of transplanted organs is one of the major factors that increases survival time of recipients. Although obtaining a major histocompatibility complex (MHC)-matched donor with the recipient is essential for successful organ transplantation, there have been limited reports on MHC matching between dogs. In this study, we analyzed the canine MHC matching rates using Maltese, one of the most popular purebred dogs, and mongrel dogs in Korea. Genomic DNA was extracted from blood leukocytes and DNA was amplified by polymerase chain reaction with primers specific to MHC microsatellite markers. The MHC matching degree was confirmed by the microsatellite markers using polyacrylamide gel electrophoresis. The MHC matching rates of each donor-recipient groups including Maltese-Maltese, mongrel-mongrel and Maltese-mongrel were 4.76%, 5.13% and 6.67%, respectively. There were no significant differences in the MHC matching degree between each group. These results demonstrate that MHC-matched donors could be selected from other breeds as much as from the same breed for transplantation. Knowledge of the MHC matching degree of purebred and mongrel dogs would offer valuable information not only for improving the success rate of organ transplantation surgery in canine patients but also for transplantation research using experimental canine models.
Animals ; DNA ; Dogs ; Electrophoresis, Polyacrylamide Gel ; Humans ; Korea ; Leukocytes ; Major Histocompatibility Complex ; Microsatellite Repeats ; Organ Transplantation ; Polymerase Chain Reaction ; Tissue Donors ; Transplants

In order to develop a successful vaccine against deadly diseases with a wide range of antigenic diversity, an in-depth knowledge of the molecules and signaling mechanisms between the vaccine candidates and immune cells is required. Therefore, monitoring vaccine components, such as antigen or adjuvants, and immune cell dynamics at the vaccination site or draining lymph nodes can provide important information to understand more about the vaccine response. This review briefly introduces and describes various non-invasive molecular imaging methods for visualizing immune cell dynamics after vaccination.
Antigenic Variation ; Lymph Nodes ; Molecular Imaging ; Vaccination ; Vaccines

BACKGROUND: Human leukocyte antigen class I (HLA-I) molecules play important roles in regulating immune responses. Loss or reduction of HLA-I expression has been shown to be associated with prognosis in several cancers. Regulatory T-cells (Tregs) also play critical functions in immune response regulation. Evaluation of HLA-I expression status by the EMR8-5 antibody and its clinical impact in breast cancer have not been well studied, and its relationship with Tregs remains unclear. METHODS: We evaluated HLA-I expression and Treg infiltration by immunohistochemistry in 465 surgically resected breast cancer samples. We examined the correlation between HLA-I expression and Treg infiltration and clinicopathologic characteristics and survival analyses were performed. RESULTS: Total loss of HLA-I expression was found in 84 breast cancer samples (18.1%). Univariate survival analysis revealed that loss of HLA-I expression was significantly associated with worse disease-specific survival (DSS) (p = .029). HLA-I was not an independent prognostic factor in the entire patient group, but it was an adverse independent prognostic factor for DSS in patients with advanced disease (stage II–IV) (p = .031). Treg numbers were significantly higher in the intratumoral stroma of HLA-I–positive tumors than in HLA-I–negative tumors (median 6.3 cells/high power field vs 2.1 cells/high power field, p < .001). However, Tregs were not an independent prognostic factor in our cohort. CONCLUSIONS: Our findings suggest that the loss of HLA-I expression is associated with poor prognosis in breast cancer patients, highlighting the role of HLA-I alterations in immune evasion mechanisms of breast cancer. HLA-I could be a promising marker that enables the application of more effective and precise immunotherapies for patients with advanced breast cancer.
Breast Neoplasms ; Breast ; Cohort Studies ; HLA Antigens ; Humans ; Immune Evasion ; Immunohistochemistry ; Immunotherapy ; Leukocytes ; Lymphocytes, Tumor-Infiltrating ; Major Histocompatibility Complex ; Prognosis ; T-Lymphocytes, Regulatory

PURPOSE: Vitamin D is a potent immunomodulator. However, its role in the pathogenesis of allergic rhinitis is unclear. METHODS: The aim of this study was to evaluate the antiallergic effect of intranasally applied vitamin D in an allergic rhinitis mouse model. BALB/c mice were intraperitoneally sensitized with ovalbumin (OVA) and alum before they were intranasally challenged with OVA. Then, they were intranasally administered 1, 25-dihydroxyvitamin D3 (0.02 μg) or solvent. Allergic symptom scores, eosinophil infiltration, cytokine mRNA levels (interleukin [IL]-4, IL-5, IL-10, IL-13 and interferon-γ) in the nasal tissue, and serum total immunoglobulin E (IgE) and OVA-specific IgE, IgG1, and IgG2a were analyzed and compared with negative and positive control groups. Cervical lymph nodes (LNs) were harvested for flow cytometry analysis and cell proliferation assay. RESULTS: In the treatment group, allergic symptom scores, eosinophil infiltration, and mRNA levels of IL-4 and IL-13 were significantly lower in the nasal tissue than in the positive control group. The IL-5 mRNA level, serum total IgE, and OVA-specific IgE and IgG1 levels decreased in the treatment group; however, the difference was not significant. In the cervical LNs, CD86 expression had been down-regulated in CD11c+major histocompatibility complex II-high (MHCIIhigh) in the treatment group. Additionally, IL-4 secretion in the lymphocyte culture from cervical LNs significantly decreased. CONCLUSIONS: The results confirm the antiallergic effect of intranasal 1,25-dihydroxyvitamin D3. It decreases CD 86 expression among CD11c+MHCIIhigh cells and T-helper type 2-mediated inflammation in the cervical LNs. Therefore, topically applied 1,25-dihydroxyvitamin D3 can be a future therapeutic agent for allergic rhinitis.
Administration, Intranasal ; Animals ; Anti-Allergic Agents ; Calcitriol ; Cell Proliferation ; Dendritic Cells ; Eosinophils ; Flow Cytometry ; Immunoglobulin E ; Immunoglobulin G ; Immunoglobulins ; Inflammation ; Interleukin-10 ; Interleukin-13 ; Interleukin-4 ; Interleukin-5 ; Lymph Nodes ; Lymphocytes ; Major Histocompatibility Complex ; Mice ; Models, Animal ; Ovalbumin ; Ovum ; Rhinitis, Allergic ; RNA, Messenger ; Vitamin D

PURPOSE: The use of tolerogenic dendritic cells (TolDCs) to control exacerbated immune responses may be a prophylactic and therapeutic option for application in autoimmune and allergic conditions. The objective of this work was to evaluate the effects of TolDC administration in a mouse model of allergic airway inflammation caused by mite extract. METHODS: Mouse bone marrow-derived TolDCs were induced by incubation with granulocyte-macrophage colony-stimulating factor (GM-CSF) and dexamethasone, and then characterized by flow cytometry and cytokine production by enzyme-linked immunosorbent assay (ELISA). For the in vivo model of Blomia tropicalis-induced allergy, mice transplanted with antigen-pulsed TolDCs were sensitized intraperitoneally with B. tropicalis mite extract (BtE) adsorbed to aluminium hydroxide. After challenge by nasal administration of BtE, bronchoalveolar lavage fluid (BALF), lungs, spleen and serum were collected for analysis. RESULTS: Induction of TolDCs was efficiently achieved as shown by low expression of major histocompatibility complex (MHC) II, programmed death-ligand (PD-L) 2 and pro-inflammatory cytokine production, and up-regulation of interleukin (IL)-10, upon LPS stimulation in vitro. Transplantation of 1 or 2 doses of BtE-pulsed TolDCs reduced the number of inflammatory cells in BALF and lungs as well as mucus deposition. Moreover, compared to saline-injected controls, TolDC-treated mice showed lower serum levels of anti-BtE immunoglobulin E (IgE) antibodies as well as reduced Gata3 and IL-4 gene expression in the lungs and decreased IFN-γ levels in the supernatant of splenocyte cultures Transplantation of TolDCs increased the percentage of the regulatory T cells in the spleen and the lungs. CONCLUSIONS: Preventive treatment with TolDCs protects against dust mite-induced allergy in a mouse model, reinforcing the use of tolerogenic dendritic cells for the management of allergic conditions.
Administration, Intranasal ; Animals ; Antibodies ; Antigens, Dermatophagoides ; Asthma ; Bronchoalveolar Lavage Fluid ; Dendritic Cells* ; Dexamethasone ; Dust* ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Gene Expression ; Granulocyte-Macrophage Colony-Stimulating Factor ; Hypersensitivity ; Immunoglobulin E ; Immunoglobulins ; In Vitro Techniques ; Inflammation* ; Interleukin-4 ; Interleukins ; Lung ; Major Histocompatibility Complex ; Mice ; Mites* ; Mucus ; Spleen ; T-Lymphocytes, Regulatory ; Up-Regulation

γδ T cells are abundant in the gut mucosa and play an important role in adaptive immunity as well as innate immunity. Although γδ T cells are supposed to be associated with the enhancement of Ab production, the status of γδ T cells, particularly in the synthesis of IgA isotype, remains unclear. We compared Ig expression in T cell receptor delta chain deficient (TCRδ⁻/⁻) mice with wild-type mice. The amount of IgA in fecal pellets was substantially elevated in TCRδ⁻/⁻ mice. This was paralleled by an increase in surface IgA expression and total IgA production by Peyer's patches (PPs) and mesenteric lymph node (MLN) cells. Likewise, the TCRδ⁻/⁻ mice produced much higher levels of serum IgA isotype. Here, surface IgA expression and number of IgA secreting cells were also elevated in the culture of spleen and bone marrow (BM) B cells. Germ-line α transcript, an indicator of IgA class switch recombination, higher in PP and MLN B cells from TCRδ⁻/⁻ mice, while it was not seen in inactivated B cells. Nevertheless, the frequency of IgA+ B cells was much higher in the spleen from TCRδ⁻/⁻ mice. These results suggest that γδ T cells control the early phase of B cells, in order to prevent unnecessary IgA isotype switching. Furthermore, this regulatory role of γδ T cells had lasting effects on the long-lived IgA-producing plasma cells in the BM.
Adaptive Immunity ; Animals ; B-Lymphocytes* ; Bone Marrow ; Immunity, Innate ; Immunoglobulin A* ; Immunoglobulin Class Switching* ; Lymph Nodes ; Mice ; Mucous Membrane ; Peyer's Patches ; Plasma Cells ; Receptors, Antigen, T-Cell, gamma-delta ; Recombination, Genetic ; Spleen ; T-Lymphocytes*

BACKGROUND: Evidence of antibody-mediated injury in the absence of donor-specific HLA antibodies (HLA-DSA) has recently emerged, suggesting a role of antibodies in targeting non-HLA antigens expressed on renal allograft tissue. However, the clinical significance of pre-transplant non-HLA antibodies remains unclear. We compared the histological and clinical impact of pre-transplant HLA-DSA and non-HLA antibodies, especially angiotensin II type I receptor (anti-AT1R) and MHC class I-related chain A (anti-MICA), in kidney transplant patients. METHODS: Pre-transplant HLA-DSA, anti-AT1R, and anti-MICA were retrospectively examined in 359 kidney transplant patients to determine the effect of each antibody on allograft survival and clinical characteristics. RESULTS: Pre-transplant HLA-DSA, anti-AT1R, and anti-MICA were detected in 37 (10.3%), 174 (48.5%), and 50 patients (13.9%), respectively. Post-transplant antibody-mediated rejection was associated with a pre-transplant HLA-DSA (+) status only. The development of microvascular inflammation (MVI) was associated with pre-transplant HLA-DSA (P=0.001) and anti-AT1R (P=0.036). Anti-AT1R (+) patients had significantly lower allograft survival compared with anti-AT1R (−) patients (P=0.042). Only pre-transplant anti-AT1R positivity was an independent risk factor for allograft failure (hazard ratio 4.824, confidence interval 1.017–24.888; P=0.038). MVI was the most common histological feature of allograft failure in patients with pre-transplant anti-AT1R. CONCLUSIONS: Pre-transplant anti-AT1R is an important risk factor for allograft failure, which may be mediated by MVI induction in the allograft tissue.
Allografts ; Angiotensin II* ; Angiotensins* ; Antibodies* ; Humans ; Inflammation ; Kidney Transplantation ; Kidney* ; Major Histocompatibility Complex* ; Receptor, Angiotensin, Type 1 ; Retrospective Studies ; Risk Factors