Association between Helicobacter pylori infection,mismatch repair,HER2 and tumor-infiltrating lymphocytes in gastric cancer

BACKGROUND The influence of Helicobacter-pylori(H.pylori)infection and the characteristics of gastric cancer(GC)on tumor-infiltrating lymphocyte(TIL)levels has not been extensively studied.Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information.AIM To determine the rates of deficient mismatch-repair(dMMR),HER2-status and H.pylori infection and their association with TIL levels in GC.METHODS Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral(IT),stromal(ST)and invasive-border(IB)compartments.The density of CD3,CD8 and CD163 immune cells,and dMMR and HER2-status were determined by immunohistochemistry(IHC).H.pylori infection was evaluated by routine histology and quantitative PCR(qPCR)in a subset of samples.RESULTS dMMR was found in 34.4%,HER2+in 5%and H.pylori-positive in 55.7%of samples.High IT-TIL was associated with grade-3(P=0.038),while ST-TIL with grade-1(P<0.001),intestinal-histology(P<0.001)and no-recurrence(P=0.003).dMMR was associated with high TIL levels in the ST(P=0.019)and IB(P=0.01)compartments,and STCD3(P=0.049)and ST-CD8(P=0.05)densities.HER2-was associated with high IT-CD8(P=0.009).H.pylorinegative was associated with high IT-TIL levels(P=0.009)when assessed by routine-histology,and with high TIL levels in the 3 compartments(P=0.002-0.047)and CD8 density in the IT and ST compartments(P=0.001)when assessed by qPCR.A longer overall survival was associated with low IT-CD163(P=0.003)and CD8/CD3(P=0.001 in IT and P=0.002 in ST)and high IT-CD3(P=0.021),ST-CD3(P=0.003)and CD3/CD163(P=0.002).CONCLUSION TIL levels were related to dMMR and H.pylori-negativity.Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival.

Tumor infiltrating lymphocytes in gastric cancer:Unraveling complex interactions for precision medicine

This editorial will focus on tumor immunity and the factors that alter the tumor immune micro-environment.The role of tumor infiltrating lymphocytes(TILs)will also be discussed in detail,including the types,mechanism of action,and role.Gastric cancer(GC)often presents in the advanced stage and has various factors predicting the outcomes.The interplay of these factors and their correlation with the TILs is discussed.A literature review revealed high intratumoral TILs associated with higher grade,HER2-,and Helicobacter pylori negativity.Moreover,stromal(ST)TILs correlated with lower grade and lesser recurrence risk in GC.High TILs in ST and invasive border also correlated with mismatch repair deficiency status.Further characterization of the CD3+,CD8+,and other cells is also warranted.In the future,this complex correlation of cancer cells with the immune system can be explored for therapeutic avenues.

Mesenteric adipose tissue B lymphocytes promote intestinal injury in severe acute pancreatitis by mediating enteric pyroptosis

Background:Visceral adipose tissue(VAT)has been linked to the severe acute pancreatitis(SAP)prognosis,although the underlying mechanism remains unclear.It has been reported that pyroptosis worsens SAP.The present study aimed to verify whether mesenteric adipose tissue(MAT,a component of VAT)can cause secondary intestinal injury through the pyroptotic pathway.Methods:Thirty-six male Sprague Dawley(SD)rats were divided into six different groups.Twelve rats were randomly divided into the SAP and control groups.We monitored the changes of MAT and B lymphocytes infiltration in MAT of SAP rats.Twelve SAP rats were injected with MAT B lymphocytes or phosphate buffer solution(PBS).The remaining twelve SAP rats were first injected with MAT B lymphocytes,and then with MCC950(NLRP3 inhibitor)or PBS.We collected blood and tissue samples from pancreas,gut and MAT for analysis.Results:Compared to the control rats,the SAP group showed inflammation in MAT,including higher expression of tumor necrosis factor(TNF-α)and interleukin-6(IL-6),lower expression of IL-10,and histological changes.Flow cytometry analysis revealed B lymphocytes infiltration in MAT but not T lymphocytes and macrophages.The SAP rats also exhibited intestinal injury,characterized by lower expression of zonula occludens-1(ZO-1)and occludin,higher levels of lipopolysaccharide and diamine oxidase,and pathological changes.The expression of NLRP3 and n-GSDMD,which are responsible for pyroptosis,was increased in the intestine of SAP rats.The injection of MAT B lymphocytes into SAP rats exacerbated the inflammation in MAT.The upregulation of pyroptosis reduced tight junction in the intestine,which contributed to the SAP progression,including higher inflammatory indicators and worse histological changes.The administration of MCC950 to SAP+MAT B rats downregulated pyroptosis,which subsequently improved the intestinal barrier and ameliorated inflammatory response of SAP.Conclusions:In SAP,MAT B lymphocytes aggravated local inflammation,and promoted the injury to the intestine through the enteric pyroptotic pathway.

Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis

BACKGROUND The association between tumor-infiltrating lymphocyte(TIL)levels and the res-ponse to neoadjuvant therapy(NAT)in patients with triple-negative breast cancer(TNBC)remains unclear.AIM To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients.METHODS A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31,2023.The correlation between TIL levels and the NAT pathologic com-plete response(pCR)in TNBC patients was assessed using a systematic review and meta-analysis.Subgroup analysis,sensitivity analysis,and publication bias analysis were also conducted.RESULTS A total of 32 studies were included in this meta-analysis.The overall meta-ana-lysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup(48.0%vs 27.7%)(risk ratio 2.01;95%confidence interval 1.77-2.29;P<0.001,I2=56%).Subgroup analysis revealed that the between-study hetero-geneity originated from differences in study design,TIL level cutoffs,and study populations.Publication bias could have existed in the included studies.The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols(all P≤0.01),and there was no significant between-protocol difference in the statistics among the different NAT protocols(P=0.29).Additionally,sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded.CONCLUSION TILs can serve as a predictor of the response to NAT treatment in TNBC patients.TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs,and this predictive capability is con-sistent across different NAT regimens.

Bystanders or not?Microglia and lymphocytes in aging and stroke

As the average age of the world population increases,more people will face debilitating aging-associated conditions,including dementia and stroke.Not only does the incidence of these conditions increase with age,but the recovery afterward is often worse in older patients.Researchers and health professionals must unveil and understand the factors behind age-associated diseases to develop a therapy for older patients.Aging causes profound changes in the immune system including the activation of microglia in the brain.Activated microglia promote T lymphocyte transmigration leading to an increase in neuroinflammation,white matter damage,and cognitive impairment in both older humans and rodents.The presence of T and B lymphocytes is observed in the aged brain and correlates with worse stroke outcomes.Preclinical strategies in stroke target either microglia or the lymphocytes or the communications between them to promote functional recovery in aged subjects.In this review,we examine the role of the microglia and T and B lymphocytes in aging and how they contribute to cognitive impairment.Additionally,we provide an important update on the contribution of these cells and their interactions in preclinical aged stroke.

Novel Protein C6ORF120 Promotes Apoptosis through Mitochondria-dependent Pathway in CD4+ T Lymphocytes

Generally,a healthy immune system should be in dynamic balance,which can be maintained by both promoting and resisting inflammation.Lymphocyte apoptosis is indispensable for maintaining homeostasis[1]and participates in the entire process of lymphocyte differentiation,development,maturation,and immune effects.It has been reported that a large amount of lymphocyte apoptosis occurs in lymphoid organs during severe trauma[2].Lymphocytes consist of T and B lymphocytes,among which CD4^(+)T cells were the focus of this study.CD4^(+)T lymphocytes play an important role in the innate immunity.Apoptosis of CD4^(+)T lymphocytes is an important biological process that induces CD4^(+)T cell depletion[3].Numerous studies have shown that CD4^(+)T cell apoptosis participates in many pathological processes of diseases such as HIV infection,cancer,and systemic sclerosis[4].Classical apoptosis is induced by factors that can activate several pathways,including the mitochondrial,endoplasmic reticulum,and death receptor pathways[5].The mitochondrial pathway is mainly activated by the Bcl-2 family[6].The endoplasmic reticulum(ER)pathway is affected by endoplasmic reticulum disorders.Some external factors can trigger the death receptor pathway,such as the binding of TNF-TNFR and the combination of Fas-FasL[7].Considering these pathways,it is feasible to study the specific mechanisms of lymphocyte apoptosis,primarily in CD4^(+)T cells.

Pretreatment Neutrophil/Lymphocytes Ratio in Non-Metastatic Colon Cancer as a Prognostic and Predictive Factor: A Retrospective Study

Background: In developed countries, colon cancer is the second most prevalent cancer, only exceeded by prostate cancer in men and breast cancer in women. After Hepatocellular carcinoma, breast cancer, bladder cancer, lung cancer, Non-Hodgkin Lymphoma and brain tumors, colon cancer is the 7th most common cancer in Egypt, in both sexes, representing 3.47% and 3%, in both male and female cancers, respectively. Aim of the Work: The aim of this study was to evaluate the prognostic and predictive significance of pretreatment Neutrophil/lymphocytes ratio (NLR), in terms of disease-free survival (DFS) and recurrence, in high-risk stage II and stage III Colorectal cancer patients who underwent curative resection. Patients and Methods: We retrospectively evaluated 103 patients, who were submitted to upfront surgery as first therapeutic option in curative intent, between January 2017 and December 2018. Pretreatment Neutrophil/lymphocytes ratio (NLR), as well as demographics, clinical, histopathologic, and laboratory data were analyzed. Univariate and multivariate analyses were conducted to identify prognostic factors associated with disease free survival (DFS) and recurrence. Results: The cutoff point of Neutrophils/lymphocytes ratio (NLR) was calculated with Kaplan-Meier curves and log-rank test to 3. This study revealed that neutrophils/lymphocytes ratio (NLR) was significantly associated with disease free survival (p as no difference in efficacy between both chemotherapy regimens FOLFOX and XELOX in both high-risk stage II and stage III colon cancer regarding disease free survival & the toxicity profile associated with each regimen and its grades between patients. Conclusion: Our study suggests that preoperative Neutrophils/lymphocytes ratio (NLR) more than 3 may be an independent prognostic marker for TTR (time to recurrence) in high-risk stage II and stage III colon cancer patients.

Effects of platelets on characteristics of lymphocytes cultured in vitro and optimization of adoptive immunotherapy

T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regulation and immune killing.Studies have shown that platelets play a crucial role in maintaining the stable differentiation of lymphocytes and the balance in immunomodulation.Therefore,it is necessary to study the effect of platelets on lymphocytes in vitro to better understand the role of platelets in the immune system and broaden the application of adoptive immunotherapy.Methods:Cell counting and microscopic observation were used to detect the effect of activated platelets on lymphocyte proliferation in vitro;Flow cytometry was used to detect whether changes in platelet activity affect the proportion of lymphocyte subpopulations in vitro,and to detect differences in the expression of granzyme B;lactate dehydrogenase assay(LDH)was used to determine the difference in lymphocyte killing activity caused by platelet activity in vitro.Results:This was the first to promote lymphocyte proliferation through the expression or release of certain molecules in vitro,demonstrating that platelet activation is one of the key factors.Secondly,activated platelets or inactivated platelets promoted lymphocyte subset differentiation by enhancing the proportion of CD3+CD8+T lymphocytes(CTL cells)but had a slight effect on the proportion of CD3+CD4+T(Th cells)and CD4+CD25+T lymphocytes(Treg cells).Then,it was found that either activated platelets or inactivated platelets down-regulated the proportion of natural killer(NK)T lymphocytes,while activated platelets significantly enhance the proportion of NK lymphocytes.Therefore,by further detecting the killing activity of PBMCs treated with platelets,it was found that activated platelets promoted the extensive anti-tumor activity of lymphocytes and significantly increased the expression of granzyme B.Conclusion:Our results suggest that activated platelets promote lymphocyte proliferation,optimize lymphocyte subpopulation ratio,and promote cytotoxic effect of lymphocytes in vitro,which may provide a new strategy for optimizing the adoptive immunotherapy culture system and improving its efficacy.

Chemical constituents from Pithecellobium clypearia and their effects on T lymphocytes proliferation

Aim To investigate the chemical constituents from the twigs and leaves of Pithecellobium clypearia Benth and their immunomodulatory effects. Methods The constituents were separated and purified by various chromatographic methods and their structures were identified on the basis of spectral analysis. The immufiomodulatory effects of all the compounds were examined by a Con A-induced T lymphocytes proliferation assay. Results Eight compounds were isolated and identified as （-）- epigallocatechin （1）, （-）-5, 7, 3′, 4′, 5′-pentahydroxyflavan （2）, （-）-epigallocatechin-7-gallate （3）, （-）-5, 3′, 4′, 5′-tetrahydroxyfiavan- 7-gallate （4）, quercitin-3-O-α-L-rhamnpyranoside （5）, myricitin-3-O-α-L-rhamnpyranoside （6）, gallic acid （7）, and ethyl gallate （8）, respectively. Conclusion Compounds 3 and 8 were isolated from this genus for the first time, and compound 1 was isolated from this species for the first time. Compound 3 exhibited a strong inhibition on the T lymphocytes proliferation induced by Con A with an IC50 of 4.4 μmol·L^-1.

Suppressive effects of antigens on the activity of specific activated lymphocytes : A test to define the specificity of activated lymphocytes

Objective：With the regular mixed lymphocytes culture （MLC） to detect the allograft rejection, the reactivity of the activated lymphocytes （primed lymphocytes） of a recipient shows sometimes increase and sometimes decrease against the antigens from the donor, which is inconsistent with the clinical results. In order to establish a convenient method for testing the specificity of the activated lymphocytes in vitro, so as to know the rejection occurred or not by testing the existence of the specific activated lymphocytes against donor＇s HLA antigens in the recipient＇s peripheral blood. Methods： Anti-IL-2 neutralizing monoclonal antibody （anti-IL-2 N-mAb） and immunosuppressors were introduced in this test system in the presence of specific stimulators and activated lymphocytes. Results ： When the activated lymphocytes were chosen from the one-way MLC 4 d to undergo re-stimulation by specific stimulators, the activity of activated lymphocytes in the treatment group was suppressed significantly compared with that in the control group. The result of this test method is consistent with the biopsy in the clinical diagnosis of rejection. Conclusion：h suggests that the activated lymphocytes can be inactivated by specific antigens in certain conditions. This can be a useful tool to define the specificity of the activated lymphocytes.

Modulatory Effect of Pollen Extract on Apoptosis of Lymphocytes in the Elderly

Aim In this study, we investigated the changes of lymphocyte subpopulationand apoptosis process of lymphocytes in the elderly, and the modulatory effect of pollen extract(PE) on apoptosis. Methods Lymphocyte phenotypes were detected using indirect immunofluorescencetechnique. The proliferation responses were determined by MTT method. Flow cytometry and automaticimage analysis were performed to evaluate the apoptosis of lymphocytes. Results The proliferationresponses of lymphocytes in the elderly were lower than that in young adults. Decreased CD_(45) RA^+cells and increased CD_(45) RO^+ cells were found in lymphocyte population of aged people, comparedwith that of young adults. The CD_(45) RO^+ cells were prone to apoptosis. There is an inhibitoryeffect of PE on apoptosis of lymphocytes in the elderly. Conclusion It is implied that thesusceptibility of lymphocyte in the elderly to apoptosis depends on activation, so called,activation-induced cell death. Present results suggest that apoptosis of lymphocytes in aged peopleplay an important role in the pathogenesis of immunosenescence. Thus, a possibility is open fordevelopment of apoptosis-modulating drugs from pollen.

Detection of HBV DNA and its existence status in liver tissues and peripheral blood lymphocytes from chronic hepatitis B patients

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Effects of Traditional Chinese Medicine on Numbers of Lymphocytes and Goblet Cells in Villus Epithelia of Layers under Heat Stress

[Objective] This study aimed to investigate the effects of traditional Chinese medicine additives on numbers of lymphocytes and goblet cells in villus epithelia of layers under heat stress.[Method] A total of 180 88-d-old healthy Esa Brown cocks were selected.They were randomly divided into 9 experimental groups：Room temperature control,High temperature control,VC addition group,High formula I,Moderate formula I,Low formula I,High formula II,Moderate formula II and Low formula II.The formula I and formula II were to add different herbal extracts to the diet of cocks with different doses.The cocks in the VC addition group were administered orally with same-concentration VC solution.After certain time,the cocks were slaughtered.Then the numbers of epithelial lymphocytes and goblet cells in various segments of small intestine were counted by using conventional histological section and HE staining.[Result] The numbers of lymphocytes and goblet cells in villus epithelia of layers under heat stress were decreased gradually with the proceeding of experiment.The herbal extracts of formula I and formula II all could promote the generation of lymphocytes and goblet cells.But the promoting effect of formula II was best.[Conclusion] The Chinese herbal medicine additives have a good relieving effect on heat stress in layers.

The role of apoptosis in the development and function of T lymphocytes

Apoptosis plays an essential role in T cell biology. Thymocytes expressing nonfunctional or autoreactive TCRs are eliminated by apoptosis during development. Apoptosis also leads to the deletion of expanded effector T cells during immune responses. The dysregulation of apoptosis in the immune system results in autoimmunity, tumorogenesis and immunodeficiency. Two major pathways lead to apoptosis: the intrinsic cell death pathway controlled by Bcl-2 family members and the extrinsic cell death pathway controlled by death receptor signaling. These two pathways work to- gether to regulate T lymphocyte development and function.

Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma

Tertiary lymphoid structures(TLS)are ectopic lymphoid structures in cancers that are largely associated with favourable prognosis.However,the prognostic value of TLSs in oral squamous cell carcinoma(OSCC)is largely unknown,and the association between tumour infiltrating lymphocytes(TILs)and TLSs has been rarely explored in OSCC.In this study,associated markers of TLS,including peripheral node address(PNAd)in high endothelial venules,CD20 in B cells and CD3 in T cells,were examined in 168 OSCC patients,and survival analysis was performed between TLS-positive and TLS-negative cohorts.We detected the presence of TILs by staining CD8+cytotoxic T cells and CD57+NK cells as well.TLSs appeared as highly organized structures in 45(26.8%)cases.TLSpositive patients had a better 5-year overall survival(OS)rate(88.9%vs.56.1%,P<0.001)and relapse-free survival(RFS)rate(88.9%vs.63.4%,P=0.002).Moreover,the presence of TLS was an independent prognostic factor for both the 5-year OS rate(hazard ratio[HR]=3.784;95%confidence interval[CI],1.498–9.562)and RFS rate(HR=3.296;95%CI,1.279–8.490)in multivariate analysis.Furthermore,a higher density of CD8+T cells and CD57+NK cells was found in TLS-positive sections than in TLS-negative counterparts(P<0.001),and their combination provided a higher predictive accuracy(AUC=0.730;95%CI,0.654–0.805).In conclusion,our results suggest that TLS is an independent positive prognostic factor for OSCC patients.These findings provide a theoretical basis for the future diagnostic and therapeutic value of TLSs in OSCC treatment.

In situ detection of tumor infiltrating lymphocytes expressing perforin and fas-ligand genes in human HCC

AIM To investigate the expression of perforin and fas ligand (fas L) of tumor infiltrating lymphocytes (TILs) in human hepatocellular carcinoma (HCC). METHODS By in situ hybridization and immunohistochemistry, the perforin and fas L gene expression of TILs was studied in 20 HCC cases. RESULTS Positive expression of perforin and fas L genes was detected in 16 HCC cases. One patient had expression of perforin and fas L genes in the majority of TILs and survived 1 5 years after tumor resection without HCC relapse. This seems that the presence of a large number of activated T cells might be beneficial for the antitumor immunity. In other cases, less than 10% of TILs were able to express perforin and fas L genes. CONCLUSION Although there were a number of T cells in HCC, only few of them were immunoactive and able to kill tumor cells. It seems important to promote further proliferation of these activated T cells in vitro or in vivo .

Liver tumor infiltrating lymphocytes: Comparison of hepatocellular and cholangiolar carcinoma

AIM: To investigate the role of tumor inf iltrating lym-phocytes (TIL) in primary hepatocellular and cholangio-lar carcinomas of the liver.METHODS: Immunohistochemical analysis was per-formed including antibodies to CD3, CD4, CD8, CD20, CD56 and TIA-1 in formalin-f ixed and paraff in-embed-ded tissue of 35 liver resection specimens of hepatocel-lular or cholangiocellular carcinomas. Semiquantitative evaluation was performed with emphasis on the area of the tumor itself and of the tumor/liver interface.RESULTS: All hepatocellular carcinomas showed in-filtration of lymphocytes predominantly around the tumor in the tumor/liver interface consisting mainly of CD3+ CD4+ T lymphocytes [164.3/10 high power f ields (HPF)] and in the tumor itself of CD8+ cells (54.9/10 HPF). Cholangiocarcinomas contained a heterogeneous amount of TIL, composed mainly of CD3+ T cells with a predominance of CD8+ cells in the tumor tissue (52.6/10 HPF) and of CD4+ cells in the interface region (223.1/10 HPF). CD56+ cells of the innate immune system were scarce. There was no significant difference between hepatocellular or cholangiolar carcinoma. No correlation with the clinicopathological data was seen. CONCLUSION: Liver TIL consists of intratumoral CD8+ T cells and peritumoral CD4+ T cells indepen-dent of histogenetic origin. Different functions of lym-phocytes in these regions seem possible.

Effects of Sterigmatocystin, Deoxynivalenol and Aflatoxin G_1 on Apoptosis of Human Peripheral Blood Lymphocytes in vitro

Objective To explore the effects of Sterigmatocystin (ST), Deoxynivalenol (DON) and Aflatoxin G1 (AFG1) on apoptosis of human peripheral blood lymphocytes (HPBLs) in vitro and thus to further elucidate the putative roles of these three mycotoxins on human immunosystem. Methods The effects of ST, DON and AFG1 on apoptosis of HPBLs were studied with cell culture, flow cytometric (FCM) DNA analysis and DNA agarose gel electrophoresis. Results DNA agarose gel electrophoresis results showed the characteristic 'ladder' pattern of apoptosis in HPBLs treated with ST, DON and AFG1. Flow cytometric DNA analysis revealed that typical subdiploid peaks of apoptosis in DNA histogram could be seen in all groups treated with the three mycotoxins. Significant time-effect and dose-effect relationships were found between the apoptosis rates and treatment time as well as concentrations of the three mycotoxins. Conclusion ST, DON and AFG1 can induce apoptosis of HPBLs in vitro and may have some negative effects on human immunosystem.

Effect of Chinese Herbal Medicinal Ingredients on IL-2 mRNA Levels of T Lymphocytes in Mice Measured Using Semiquantification RT-PCR

In this study, the IL-2 mRNA levels of T lymphocytes in normal mice stimulated by nine Chinese herbal medicinal ingredients （CHMIs） were measured using semiquantification reverse transcription polymerase chain reaction. The results showed that astragalus polysaccharide （APS）, epimedium polysaccharide （EPS）, Chinese angelica polysaccharide （CAPS）, propolis flavone （PF）, and astrogalosides （AS） promoted IL-2 mRNA levels in T lymphocytes in vitro and in vivo to differing degrees, and the level of IL-2 mRNA induced by propolis polysaccharide （PPS） in vitro was higher than that induced by the control, which differed from that of PPS in vivo.

Intestinal epithelium, intraepithelial lymphocytes and the gut microbiota-Key players in the pathogenesis of celiac disease

Celiac disease(CD) is a chronic immune-mediated disorder triggered by the ingestion of gluten in genetically predisposed individuals. Before activating the immune system, gluten peptides are transferred by the epithelial barrier to the mucosal lamina propria, where they are deamidated by intestinal tissue transglutaminase 2. As a result, they strongly bind to human leucocyte antigens(HLAs), especially HLA-DQ2 and HLA-DQ8, expressed on antigen-presenting cells. This induces an inflammatory response, which results in small bowel enteropathy. Although gluten is the main external trigger activating both innate and adaptive(specific) immunity, its presence in the intestinal lumen does not fully explain CD pathogenesis. It has been hypothesized that an early disruption of the gut barrier in genetically susceptible individuals, which would result in an increased intestinal permeability, could precede the onset of gluten-induced immune events. The intestinal barrier is a complex functional structure, whose functioning is dependent on intestinal microbiotahomeostasis, epithelial layer integrity, and the gutassociated lymphoid tissue with its intraepithelial lymphocytes(IELs). The aim of this paper was to review the current literature and summarize the role of the gut microbiota, epithelial cells and their intercellular junctions, and IELs in CD development.