Concrete is a heterogeneous material that consists of cement, aggregates, and water as basic constituents. Several cementitious materials and additives are added with different volumetric ratios to improve the strength and durability requirements of concrete. Consequently, performance of concrete when exposed to elevated temperature is greatly affected by the concrete type. Moreover, post-fire properties of concrete are influenced by the constituents of each concrete type. Heating rate, days of curing, type of curing, cooling method, and constituents of the mix are some of the factors that impact the post-fire behavior of concrete structures. In this paper, an extensive review was conducted and focused on the effect of concrete constituents on the overall behavior of concrete when exposed to elevated temperature. It was evident that utilizing fibers can improve the tensile capacity of concrete after exposure to higher temperatures. However, there is an increased risk of spalling due to the induced internal stresses. In addition, supplementary cementitious materials such as metakaolin and silica fume enhanced concrete strength, the latter proving to be the most effective. In terms of the heating process, it was clear that several constituents, such as silica fume or fly ash, that decrease absorption affect overall workability, increase the compressive strength of concrete, and can yield an increase in the strength of concrete at 200 °C. Most of the concrete types show a moderate and steady decrease in the strength up until 400 °C. However, the decrease is more rapid until the concrete reaches 800 °C or 1000 °C at which it spalls or cannot take any applied load. This review highlighted the need for more research and codes’ provisions to account for different types of concrete constituents and advanced construction materials technology. Fires around the world are more frequent than expected and occur due to several reasons. Civil engineering structures are always at risk of catching fire especially during the construction phase . The useWithin the last two decades there have been many advances in concrete technology and research. Fibers of different types, shapes, and sizes are being implemented into the concrete mix. In addition, modern concrete such as self-compacting (1980s) or self-healing (2000s) concrete are becoming points of interest when it comes to understanding how their constituents can affect their behavior when exposed to a fire or elevated temperature. One of the main topics under investigation is the effects of fire on concrete and how different constituents can improve the mechanical properties of concrete during and after fire. Since concrete has many different types, it is difficult for code developers and researchers to create a generalized equation that encompasses the fire and post-fire behavior of concrete. The current ACI and Eurocode codes ,5 only dMany research efforts indicated that there is a difference in the mechanical properties of concrete after being exposed to high temperatures based on the method of cooling ,17,18. TMoreover, there are three types of testing regimes that are followed in the literature, namely “stressed”, “unstressed”, and “residual”. In the stressed method, a preload is applied to the concrete specimen and then maintained during the heating phase. Then, when the target temperature is reached, the temperature is sustained and the load is applied further until the concrete fails. This method, being the most representative of real life due to the preloading, is significantly less represented than the other two since it can be more difficult to conduct, as the load has to be constant while the sample is inside the furnace and then increased when the temperature is reached. This needs a certain setup and procedure that are not required for the other two regimes. With the unstressed experiment, there is no preloading of the concrete samples. The samples are placed directly in the oven and heated to a target temperature. Once the temperature is reached, the load is applied to the concrete until it reaches failure. This method is highlighted under the “no cooling” sections of this study. Lastly, in the residual test regime, the concrete specimen is heated with or without preloading. Then, when the target temperature is reached, the concrete is then cooled to ambient temperature before the load is applied until failure. This method is the most present in the literature since it is the easiest to conduct in the lab while at the same time highlighting the effects of cooling on concrete. These experiments are illustrated in The current review focuses on the effect of concrete constituents on the behavior of concrete exposed to elevated temperature and different cooling methods; therefore, the discussion and comparisons will be mainly directed towards concrete of the same type that follow the same cooling method. For example, studies on normal strength concrete that is cooled in air will be compared with others of its type and so on. This will make it easier to isolate the effect of the aggregates and will in turn having fewer variables. The comparison of the results is split into two or three parts depending on the cooling method. These methods are naturally cooling outside of the furnace, naturally cooling inside the furnace, and water cooling. This study will present and analyze the different equations from the codes and the literature regarding the mechanical properties of concrete. Other reviews on the subject of concrete exposed to elevated temperature effects ,20,21, a2O3•3CaSO4•32H2O) takes place between a 50 °C and 110 °C [2 → CaO + H2O↑). This process leads to an endothermic peak and consequently to further loss of mass [It is important to note that the physical and chemical changes in concrete are essential to discuss when concrete is subjected to high temperatures. When the heating process is still in the early stage, the concrete undergoes a decrease in mass around 100 °C. This decrease is caused by evaporation of water from the macro pores. Decomposition of ettringite  emissions. The use of more sustainable supplementary cementitious materials could reduce the CO2 emissions by 12% [2 from cement production [Moreover, using pulverised fly ash (PFA) and slag in Portland cements (PC) can improve the concrete behavior at higher temperatures and allow it to sustain its mechanical properties. Furthermore, PCs blended with PFA and slag also exhibit a high resistance to spalling at high temperatures ,30,31,32s by 12% . China aoduction . ConsequNormal strength concrete (NSC) matrix can yield from different combinations of constituents, and changing their percentages can result in a variety of mixes with different microstructure, strength, cracking behavior, bond, and mass loss. Loss of compressive strength is a common behavior of NSC when exposed to high temperatures; however, in some cases, 20% or 60% increase in the compressive strength was reported, as shown in The use of nanomaterials as a replacement of cement affected the impact strength (resistance of sudden load or shock) of NSC after exposure to elevated temperature. This effect is influenced by the type and percentage of the nanomaterial used in the mixtures. The impact strength tends to increase at 250 °C when 10% of the cement is replaced with nano cement due to the extra gel it creates when reacting again at that temperature. The results vary and there is a difference in the percentage of impact energy retained by each percentage of each nanomaterial. The difference could sometimes be small but there are some exceptions. For instance, the 30% Nano metakaolin replacement lost all of its impact strength at 750 °C unlike the nano silica fume, nano fly ash, and nano cement . This coFor this type of cooling, the concrete is expected to yield similar results to natural cooling outside of the furnace since there is no shock (sudden change in temperature) such as in water cooling. However, the rate of cooling becomes slower since the concrete is not exposed to air. All the results shown in Unlike naturally cooled concrete, water cooled concrete shows no increase in strength between 200 °C and 400 °C. In fact, most of the tested samples retain around 50% of their compressive strength followed by a continuous drop in strength at temperatures above 400 °C ,45,50,51LWC is common within the construction industry because there are many design scenarios where LWC can be more cost effective than NSC. Especially when designing high-rise buildings and floating structures like pontoons and floating bridges ,53,54,55Since 2012, researchers have tried improving the properties of LWC using different constituents ,57,58,59Studying the residual properties involves applying different cooling methods to the samples after exposure to different heating rates. Studies found in the literature on the residual properties are limited and cannot be directly compared since they either use a different cooling method or add fibers. The results will be generally discussed.After an investigation of the behavior of LWC under fire, it was found that LWC could easily undergo an increase at 300 °C. This happens when free water evaporates forcing the cement gel layers to move closer together and strengthening the overall cement paste. It could also be due to the improved hydration and increase of C-S-H content. Moreover, many studies implement fly ash into the LWC mix in order to replace cement. When tested under fire, LWC with more than 20% fly ash is always better for maintaining the concrete’s compressive strength when compared to 0% fly ash concrete . As showDifferent results were reported by several studies, and the differences are not only due to the cooling or heating methods but due to the constituents used in the mix. For instance, it is shown in Several research efforts on LWC by the authors have shown different results when using normal and water cooling ,65. FiguAs shown in HSC is another type of concrete that mostly uses additional binding materials such as silica fume, metakaolin, and GGBS. It has an overall better strength, durability, and a higher modulus of elasticity than NSC. HSC relies on using a lower w/c ratio and making the matrix denser by increasing the volume of cementitious materials and fine aggregates. When compared to NSC under fire, HSC yields better results at the early stages of heating . In a nuResearch on HSC has shown diverse results in some sections and very limited results in others. HSC samples that were tested after being naturally cooled showed very unique results when changing their constituents. It was observed that HSC can be very weak and vulnerable to spalling when exposed to temperatures up to 300 °C. This is also true for those HSC samples that contain heavyweight magnetite as a coarse aggregate with 50% replacement ratio. The low permeability of HSC increases the built-up pressure within the concrete leading to very weak results, as shown in 3 or 6 kg/m3 quantities. However, the extent of these effects is still unclear. In addition, the current concrete codes, [3 and that the relative tensile strength was larger than the relative compressive strength. However, when using 6 kg/m3, the opposite effect could take place. This is mainly due to the increased pore content that is created at higher temperatures by the deteriorating PP fibers. In addition, the vapor pressure network created by the continuous channels of PP fibers could damage the concrete matrix [In terms of residual flexural or tensile strength of HSC, the use of Metakaolin or ground pumice proved to be the best at higher temperatures up to 600 °C, as shown in e codes, ,5, are ne matrix . Other te matrix . Surely,When it comes to natural cooling inside the furnace, the studies in the literature made it clear that there are differences in the behavior of HSC due to the use of different materials. Such differences are shown in Two studies indicated that there is a direct decrease in the compressive strength of HSC due to the negative effects that the thermal shock causes ,79. HoweDiscrete fibers from different materials and aspect ratios (length/diameter) with various volumetric ratios are dispersed separately or together (hybrid) in the concrete matrix to improve mechanical properties and durability of concrete structures. In addition, they can be used to enhance the post-fire properties. Different types of fibers can elongate in the early stages of heating improving crack control and enhancing the strength. However, at later stages, spalling and cracking are very prominent issues due to the excessive stresses created by the elongated fibers and the lack of concrete tensile strength to resist this elongation. It is important to note that American and European codes ,5 have nFRC specimens containing only Polypropylene (PP) or cellulose fibers reduced the tendency to spalling. The resistance to spalling was present in FRC when implementing hybrid fibers. This could be attributed to the relatively low melting point of the PP fiber. When the PP fiber decompose before 500 °C, the concrete develops small channels inside the concrete increasing the porosity and making it easier for vapor to move within the matrix without inducing high internal stresses . On the When PP fibers are used, the melting of the fibers at 170 °C and the slow cooling rate increase the concrete porosity and reduce the pore pressure, which lead to fewer cracks and overall similar results when compared to not using any fibers. There is no major change in the stress-strain curves of concrete with PP fibers and volumetric ratios of 1% or 2% . MoreoveRecycled rubber, better known as crumb rubber, is being studied as a viable option to become one of the modern constituents used in concrete that can improve thermal resistivity. Crumb rubber is used as replacement by volume fraction of fine aggregate which led to improvement of concrete behavior when exposed to elevated temperature. Concrete with 10% crumb rubber had about 20% increase in the residual compressive strength at 200 °C, as shown in Ongoing research on fiber reinforced LWC was also done regarding the residual flexural capacity of LWC using steel and synthetic fibers. The results presented in Another unique type of fibers are hemp fibers. These fibers are extracted from plants and can be integrated into the mix design to enhance the post-fire performance of concrete. Using PP or hemp fibers can increase the compressive strength by about 12%. This could be attributed to the increased bond present at lower temperatures before the disintegration of the fibers. With this type of fiber, the concrete did not benefit from the channel creation once the fibers disintegrate, since the water has already evaporated and the advantages of the channels by fiber disintegration are not significant. Nevertheless, hemp fibers were still able to improve fire resistance by reducing the propagation of cracks at 400 °C . FRC, usAlthough the water-cooling method is the most realistic, studies on the effects of water cooling on FRC are very limited. Water cooled concrete prepared using different percentages of PP fibers can lead to great variability in the overall behavior. It was found that water spraying the PP fiber samples for 5 min yielded different results than that quenching them in water. In fact, the longer the samples are sprayed with water, the weaker the concrete becomes. Concrete that was water sprayed for 30 or 60 min yielded the same results as water quenching. This result is different than that of naturally cooled PP fiber concrete due to the fact that water cooling leads to a thermal shock that creates additional tensile stresses that damages the integrity of the concrete matrix and leads to a weaker concrete . When coFrom the ongoing research on the subject, water cooled concrete having a combination of synthetic and steel fibers will yield the best results initially as shown in The studies summarized in UHPC is another unique type of concrete that is commonly used in bridge decks and other structures that require the concrete to have a high tensile strength. Here, it is important to note that fire in bridge decks is an entirely different scenario than fires in buildings. However, the studies in the literature use the common methods of conducting the experiment regardless. This type of concrete can yield a compressive strength between 100 and 150 MPa, which is significantly higher than all the other types of concrete. Designers could rely on this type of concrete to reduce the dimensions of the concrete elements without sacrificing durability or strength . UHPC prUnlike other concrete types, the high density of its matrix can be very detrimental at high temperatures. Naturally cooled UHPC specimens tend to undergo a general trend in which the concrete breaks off or spalls; usually, concrete spalls after 700 °C . However3 of natural jute fibers was the most efficient, as it can lead to a 40% increase at 200 °C. When jute fibers shrink, they leave behind pores but are still able to perform their intended use and improve the overall strength of concrete [Concrete that is subjected to high temperatures is expected to directly lose its strength. However, most of the studies in the literature reported an increase in strength between room temperature and 500 °C. This increase is mainly attributed to the migration of excess water in the pores, which creates extra hydrates that improves the bond characteristics and creates shrinkage. It is also stated that cement rehydrates at 200 °C and creates additional gel that can enhance the bond as well. The increase of the compressive strength varied among the studies found in the literature, as shown in concrete . In addiconcrete . This coFor this regime, the UHPC samples have been heated to different temperatures under two different heating rates. SCC is a relatively new concrete in the world of civil engineering. Since SCC is highly workable and does not need vibration, civil engineers use SCC to reduce the construction time and make it easier for placing and finishing of congested formwork. However, SCC does increase the cost of construction and requires more quality control. In addition, SCC is made from a wide range of mixes, and there is no specific mix that represents it . TherefoNormal weight SCC (NWSCC):Natural cooling outside the furnace is the common cooling method used by most of the studies found in the literature. Moreover, there is a variety of SCC types that are studied. These types cannot be compared directly because each of them has an entirely different composition and different proportions of materials. Therefore, mixtures within the same category were included in the discussion. Behavior of NWSCC is represented in Lightweight SCC (LWSCC):A quick comparison between LWSCC and NWSCC would show that NWSCC performs better before 600 °C. This is because lightweight aggregates absorb water at a faster rate. During the heating process the water evaporates and the bonds between aggregates is significantly damaged. However, after 600 °C the NWSCC matrix starts to deteriorate and develop many internal cracks that weaken the compressive strength of the concrete. Nonetheless, in terms of spalling, using lightweight aggregates yields better results since they add much less internal pressures at higher temperatures than normal weight aggregates. Constituents used in making LWSCC change its behavior in several ways, as shown in Fiber reinforced SCC (FRSCC)The addition of fibers to the SCC matrix yielded distinct results, as shown in Geopolymer concrete is a modern type of cementitious material that relies on the use of industrial by-products such as slag, rice husk ash, silica fume, or fly ash. It has excellent resistance to fire, durability, and thermal properties due to its stable chemical structure. The gels produced through the polymerization and pozzolanic reactions control the quality of the geopolymer composite. Geopolymer concrete is able to yield higher stresses on the stress strain diagrams when compared to NSC ,109. ThiWhen naturally cooled, GPC is likely to show a strength increase in the compressive strength between 200 °C and 400 °C as shown in Water cooled GPC specimens yield lower results than those naturally cooled ones. However, there is an abnormal increase in strength behavior, as shown in The elastic modulus of concrete varies depending on the type of concrete as well as several other factors. From the literature, data regarding each type of concrete is relatively scarce when compared to the data on residual compressive or tensile strength. It is also clear that most of the studies discussing the residual elastic modulus do so when naturally cooling their specimens. This is highlighted in the following figures. For NSC concrete that is naturally cooled, the data presented in When it comes to the discussion of the effects of fire on concrete, there are many technical reports, codes, and standards that provide guidance for the designers. Several documents regarding this topic are presented in The heating of such samples mainly follows certain heating curves provided by different standards . Curves Possible strength gain of concrete in the cooling phase should not be taken into account” [Although there are several codes that provide guidance on the design of concrete against fire, the ACI 216-14  are the account” . This goaccount”  does notaccount”  sheds liaccount”  is more The development of design rules that correctly represent the wide range of aggregates, cementitious materials, fibers, and the different cooling methods is very difficult to accomplish. This is because there are many variables that govern the behavior of concrete under elevated temperatures. There is a movement toward the development of machine learning (ML) in order to ease the solution of any civil engineering problems. One study has created a large database containing information on the frequency of identified features of selected certain RC columns under fire . The datIn light of the proposed models done in the literature, it is very difficult to compare them directly because there are very few and for different types of concrete. They rely on mainly one variable (the variation in temperature) to obtain the relative strength. Moreover, they are very general. For instance, SCC can be made from different materials that can have led to extremely different behaviors. Even in Recent civil engineering development aims to enhance concrete properties and to achieve durable and sustainable goals. Such advancements improve the efficiency of a wide range of applications related to structural health monitoring or the overall construction process. In addition, advancements in material science, construction materials, and methods highlight the need for research to investigate performance of these materials when exposed to elevated temperature ,138,139.Using 7% silica fume in NSC can improve its post-fire properties and yield around 60% increase in compressive strength at 300 °C. Furthermore, using air entrainers can prove to be beneficial in terms of reducing the built-up pressures within the concrete specimens.Adding 15% of fly ash can resist the negative effects of water cooling. However, water cooled NSC specimens will always yield worse results than naturally cooled ones.In lightweight concrete, using 60% fly ash as cement replacement yields the best results. A higher w/c ratio with a lower cement content will provide better results in terms of strength and cracking at every temperature. Moreover, an increase in residual strength of LWC is clear when adding fly ash or basalt furnace slag.Using PP fibers, plastic, or crumb rubber in higher strength concrete types such as HSC, UHPC, and FRC could reduce the risk of spalling. However, they could also reduce the overall strength of the concrete at higher percentages.Cracking and spalling are more significant issues in concrete that uses steel fibers. This is due to the fiber elongation and the additional stresses they have created as a consequence.SCC is heavily affected by the use of different binders as well as different aggregates such as limestone and can have increases in strength of up to 25%. GPC can have up to 80% increase at 400 °C due to the different reactors being implemented in the mix design and the lack of cement.The present models in the literature are few and still cannot be relied on. However, they do show that there is a difference in behavior of concrete. This lack of models calls for an increased focus on the topic of elevated temperatures in order to develop concrete that can behave well under fire.The current codes only discuss NSC and HSC using a very narrow range of aggregate types. They also neglect other types of concrete along with the effect of different cooling methods.Constituents such as Silica fume or Fly Ash which affect the setting time, as well as increase the long-term strength gain, have an overall positive effect on the residual properties of concrete as they provide a more compact matrix that has a higher compressive strength.Concrete has many different types, all of which have unique mechanical properties and their performance when exposed to elevated temperature/fire; every one of these concrete types yields a unique behavior in terms of strength, cracking, spalling, and durability. For instance, NSC will not behave similar to LWC or UHPC; in addition, SCC will not yield an exact behavior to HSC or GPC. It becomes more complicated when there is a change within the concrete type itself. For instance, it is clear from the literature that varying the constituents within the concrete mix will result in a different behavior at elevated temperatures. In fact, using additional binders or air entraining agents can enhance the properties of concrete under fire. However, they could also not provide the concrete with any benefits depending on their percentages in the mix and on the other constituents they are used with. For example, adding fibers to a mix that already has silica fume can enhance the performance of concrete initially but can increase the risk of spalling later on. Moreover, applying different cooling methods is clearly another variable that affects the post-fire properties of concrete. It is shown that water cooling results in the worse outcome for any type of concrete when compared to natural cooling inside or outside the furnace. However, the researchers still favor studying the properties of concrete under natural cooling outside the furnace. Although this is not representative of the most extreme case, it is safer to study than water cooling and it can provide the engineering community with a good understanding of different constitutive behaviors under fire. Also, the codes are still underdeveloped and are not representative of concrete under fire. This is because the variety in the mixes, cooling methods, heating rates, and new materials add many challenges to address these varieties. These varieties make it difficult to conduct studies that are representative of all concrete types. Some major conclusions found in the literature are:Finally, it is a fact that changing the materials in a concrete mix will change its post-fire behavior. Nonetheless, the extent of these changes is still not thoroughly investigated and more research should be done focusing on the behavior of concrete with different types of aggregates, cementitious materials, and different constituents under fire while implementing different cooling methods.


Inappropriate antibiotic use may lead to antibiotic resistance, which has become a serious global crisis. Addressing suboptimal antibiotic use in the general population can play a significant role in the fight against antimicrobial resistance. This study aims to describe antibiotic use and sources of acquisition, and to identify factors influencing antibiotic access among rural community residents in Eastern China. A cross-sectional survey was conducted from July to August 2020, and 1494 participants from two villages in Eastern China were enrolled. Information was obtained using face-to-face interviews with a structured electronic questionnaire. Chi-squared and multinominal logistic regression analysis were used to explore possible determinants. In total, 1379 participants were eligible for the analysis. In the past 12 months, nearly half the respondents had taken any antibiotic (48.4%), and this proportion varied across marital status and age group. Two thirds of them (59.9%) obtained antibiotics from medical facilities with a prescription when they last took antibiotics, while 17.7% and 22.4% chose retail pharmacies and other sources, respectively. Multinominal analysis found that a higher proportion obtained antibiotics outside medical facilities among those aged 15 to 44 years, unmarried, non-white collar workers, with more years of education, lower annual household income per capita and lower levels of antibiotic knowledge. The antibiotic use behavior of rural community residents in Eastern China remains suboptimal. Antibiotic use and access behaviors need to be further addressed. Effective antibiotic stewardship in non-medical facility sources and training programs targeted for rural Chinese is warranted in future. Antimicrobial resistance (AMR) poses a major threat to human health around the world, which is a serious problem, especially in middle- and low-income countries including China ,2, and hThe spread of AMR is an urgent issue, requiring global and coordinated efforts to address ,10,11. IAlthough many measures have focused on antibiotic provision, including clinician training and financial compensation, few patient or resident-oriented interventions have been reported in China . CompareOf the 1379 eligible subjects, including 610 (44.2%) from Village A and 769 (55.8%) from Village B, more than half were female in the age range of 45–64 years. Most of them were married, with under nine years of education, and were blue-collar workers. Nearly half had an average annual household income per capita over 50,000 RMB (US $7470), and over half of them reported one or more chronic diseases. Two-fifths were classed as having a high level of antibiotic knowledge. Compared to Village A, residents in Village B had statistically higher proportions of female, blue-collar and high antibiotic knowledge level, but lower proportions of 45–64 years, under nine years of education and annual income over 50,000 .p > 0.05).Among all the 1379 participants, nearly half  reported having taken antibiotics in the last year. The proportions of antibiotic use were 18.4% in the past month and 40.5% within the past six months, respectively. No statistical difference was observed between the two villages, as shown in As The majority (59.9%) of participants obtained antibiotics from medical facilities with a prescription. Almost one fifth (17.7%) of respondents obtained antibiotics from pharmacies, and over one fifth (22.4%) reported obtaining antibiotics from other sources outside medical facilities and pharmacies. Among the other sources, the proportion of online purchasing was the highest in this survey . Higher proportions of participants who obtained antibiotics from medical facilities (with prescription) were seen among those who were married, with education levels of under nine years, white-collar workers, with per capita household income over 50,000 and a high level of antibiotic knowledge, without chronic disease history, and lived in Village A . After adjustment for possible covariates, residents aged 15–44 years, who were blue-collar workers, had an annual household income per capita of less than 10,000 RMB, or a low level of antibiotic knowledge, were significantly more likely to obtain antibiotics from pharmacies, while those with under nine years of education tended to choose medical facility access compared to those with a higher level of education. Those who were unmarried, unemployed, or blue-collar workers, with a low level of antibiotic knowledge or without a history of chronic disease were more likely to obtain antibiotics from other sources rather than medical facilities .Antibiotic resistance is one of the biggest threats worldwide and antibiotic misuse is accelerating the process. Since consumers play an important role in antibiotic use , improviIn this study, nearly half of the residents reported having used antibiotics within the past 12 months in July 2020, which is in line with results reported by other Chinese studies ,28. The Since 2011, accompanied by new healthcare reforms in China, many measures have been effectively implemented to ensure the appropriate use of antibiotics in public hospitals under the surveillance system  proposesOur study findings on the preferred sources for obtaining antibiotics generally reflects wider buying habits for antibiotics in the population. A multi-country survey in 2015 revealed that most respondents (81%) obtained antibiotics from a doctor or nurse, and the proportion was relatively consistent across the countries surveyed, which was 74% in China . In the The distribution of antibiotic acquisition also varied greatly across sociodemographic groups in this study. Compared with older people, young and middle-aged groups preferred to obtain antibiotics over the counter from pharmacies rather than via clinical consultations at medical facilities, which is contrary to findings from Central China . This diIn China, antibiotics are believed to be a panacea and are mistakenly taken for prophylaxis by the general public with limited medical knowledge . SupportAntibiotic over-prescription was previously thought to be more prevalent in the less developed areas of China , but thiOf course, there were some inevitable limitations in this study. One was that the cross-sectional study design has very limited ability in causal inference. Another was that the self-reported survey may lead to a degree of bias, with respondents providing the answer they believe is “expected”. Additionally, a notable fact is that seasonal fluctuations in morbidity affect the need for medicines, which may underestimate or overestimate the proportions of antibiotic use over one month or over the course of six months during the pandemic . A cross-sectional survey was conducted with a sample of the rural Chinese population in Eastern China between July and August 2020. Based on the per capita gross domestic product and antibiotic application in industry and agriculture, the research was carried out in Zhejiang and Jiangsu provinces. Given the antibiotic use rate of 50% in China over one year, the minimum sample size was estimated to be 400 with a 5% margin of error. Using the rapid cluster sample survey methodology recommended by the WHO , one viln = 20). Five individuals with missing sex variables, and 90 without socioeconomic answers were also excluded. A final total of 1379 participants were included in the analysis. This study received ethical approval from the Institutional Review Board of School of Public Health, Fudan University, China (number IRB#2019-03-0733). Written informed consent was obtained from all participants prior to any data collection. Questionnaires which had more than three of the knowledge items unfinished were excluded from further analysis  as well as a five-point Likert scale . For the antibiotic knowledge items, answers were coded as correct based on WHO recommendations, with each correct answer assigned a score of “1” and other responses  a score of “0”. In the five-point section, responses were given a corresponding score of 5, 4, 3, 2 and 1 for positive response to negative response . Then, tp < 0.05 and all analyses were performed in R software .Descriptive statistics were performed on the whole dataset and reported as frequency and percentages for qualitative variables. The Chi square test was performed to primarily explore the possible determinants of antibiotic use and its access. The multinominal logistic regression analysis was further performed to identify factors significantly associated with antibiotic access. In this multinomial model, access to antibiotics via medical facilities was used as the reference level. Adjusted odds ratios (adjusted ORs) and 95% confidence intervals (95% CIs) were estimated. The level of statistical significance was set at In summary, the antibiotic use behavior of rural community residents in Eastern China is suboptimal. Our findings help to address the scarcity of empirical evidence of antibiotic use behaviors. China still needs to make considerable efforts to effectively contain AMR, such as by constructing a supportive and supervised environment for rational antibiotic use and strengthening antibiotic information dissemination for the rural population to limit over-the-counter antibiotics. Given the complex relationship observed in this and other studies between education, economic status and antibiotic self-medication, further research into the reasons for non-prescribed antibiotic use in specific population groups would help to inform the development of appropriate and effective targeted interventions.


The aim of this review is to discuss the proposed roles of different T cell subsets in the pathogenesis of IgG4-related disease focusing on their roles in immunopathogenesis of IgG4-related sialadenitis.IgG4-related disease is a multiorgan immunological fibroinflammatory disorder characterized by lymphoplasmacytic infiltration and fibrosis in multiple organs accompanied by high serum IgG4 levels. The salivary glands are the most common organs involved in this disease. Recently, chronic sclerosing sialadenitis affecting salivary glands, formerly known as Küttner's tumor, and Mikulicz's disease have been classified as a class of IgG4-related diseases. The etiopathobiology of IgG4-related disease is not fully understood. It has recently been hypothesized that the inflammatory and fibrotic process and the increased serum IgG4 At the beginning of the 21st century, IgG4-related disease (IgG4-RD), also known as IgG4-related sclerosing disease, was recognized as a multiorgan disease by Japanese physicians . The his+ cytotoxic T lymphocytes (CTLs), and CD8+ CTLs; these T cell subtypes could contribute to the immunopathogenesis of IgG4-RD through the activation of B cells and plasmacytes, enhancement of IgG4 class-switch recombination, development of ectopic germinal centers, and induction of fibrosis [The underlying pathogenesis of IgG4-RD remains largely unknown . In addifibrosis –10.+) plasma cells in both Küttner's tumor, a type of chronic sialadenitis, and the so-called Mikulicz's disease, a form of Sjögren's syndrome, resulted in their classification among IgG4-RD group that affects salivary gland tissues, designated as IgG4-related sialadenitis (IgG4-RS) and IgG4-related dacryoadenitis and sialadenitis (IgG4-RDS), respectively [Many medical conditions that have long been viewed as confined to single organs are now considered a part of the IgG4-RD spectrum . In the ectively , 14–17.This review focuses on the proposed and theoretical roles of T cells in the immunopathogenesis of IgG4-RS.+ plasma cells and fibrosis in the affected organs, this disorder was classified clinically and histopathologically as a single group of diseases known as IgG4-RD [IgG4-RD is a newly recognized multiorgan systemic immune-mediated disorder characterized by a chronic fibroinflammatory condition , 19. The IgG4-RD . Clinica IgG4-RD –24.IgG4-RD can involve any organ. The most commonly involved organs are the salivary glands, the lacrimal gland, and the pancreas; however, it can affect other organs such as the retroperitoneum, lymph nodes, aorta, arteries, breast, prostate, thyroid, pericardium, and skin , 25.A characteristic feature of IgG4-RD is the presence of similar histopathology findings across all of the affected organs –28.+ plasma cells with IgG4+ plasma cell/IgG+ plasma cells at a > 40% ratio; an irregularly whorled fibrotic pattern referred to as “storiform fibrosis;” obliterative phlebitis involving partial or complete obliteration of medium-sized veins by lymphoplasmacytic cell infiltration, which appear as an inflammatory nodule next to a patent artery; mild-to-moderate tissue eosinophilia with the absence of granuloma or tissue necrosis; and hyperplastic ectopic germinal centers [The typical and specific histopathological features are as follows: a dense lymphoplasmacytic infiltrate enriched in IgG4 centers .+ plasma cells within affected organs cannot be utilized as the sole diagnostic parameter for IgG4-RD, as the diagnosis should be based on clinical, serological, and histological findings [IgG4-RD is often associated with elevated serum IgG4 levels, though this feature must be present for the final definite diagnosis. Yet, elevated levels of serum IgG4 have also been reported in other conditions , 27. Higfindings .In 2019, a new 3-step classification process system was proposed for the classification of IgG4-RD. First, a potential IgG4-RD case must involve at least one of the 11 possible organs consistent with IgG4-RD criteria. Second, the exclusion criteria, consisting of a total of 32 clinical, radiologic, serologic, and pathologic items, must be applied; the presence of any exclusion criterion excludes the patient from IgG4-RD classification. Third, eight inclusion criteria, including clinical findings, radiology assessments, serologic results, and pathology interpretations, are applied. American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for IgG4-RD demonstrate excellent test performance and should contribute to future clinical, epidemiologic, and basic scientific investigations .The revised comprehensive diagnostic (RCD) criteria for IgG4-RD in any involved organ were proposed by Umehara et al., which depend on three critical items: clinical, serological, and pathological findings in IgG4-RD patients, as listed in Upon applying both the 2019 ACR/EULAR classification criteria and RCD criteria to a group of previously diagnosed IgG4-RD patients, Byung-Woo Y. (2020) proposed that there is agreement between these two sets of criteria for the diagnosis of IgG4-RD .The etiology and pathogenesis of IgG4-RD are not fully understood. Many factors seem to contribute to IgG4-RD development, including allergic, autoimmune, and genetic factors , 34. An Furthermore, researchers in the field of immunology identified that certain abnormal immunological mechanisms, derived from both innate and adaptive immunity, are involved in the pathogenesis of IgG4-RD , 36.+ T cells, maintain CD4+ memory T cells by providing antigen-independent factors, and promote the proliferation of pathogenic T cells [In the last decade, several pathophysiological mechanisms responsible for the development of IgG4-RD have been described. Some of these suggested mechanisms indicate that B lymphocytes might act as functional antigen-presenting cells to CD4 T cells .+ T cells are the most abundant and active cells within the lymphoplasmacytic infiltrate in the affected organ in IgG4-RD patients, suggesting that, in addition to B cells, T cells could be key players in IgG4-RD pathogenesis [Recent immunohistochemical studies showed that CD4ogenesis , 37–39.In patients treated with rituximab (RTX), B cell counts are effectively depleted; thus, apart from depleting B cells, RTX is likely to interfere with the more important B cell/T cell cross-talk processes through the elimination of a major B-cell type required for persistence of antigen presentation to T cells and for the maintenance of T cell activation, thereby indicating that B cell depletion during treatment ultimately revokes the production of proinflammatory and profibrotic cytokines such as IL-4, IL-13, and IL-10 by the pathogenically activated T cell populations . Thus, T+ T helper cells are the most abundant cells within disease-involved tissues and show increased levels in peripheral circulation [+ T helper cell subsets that play important roles in IgG4-RD pathogenesis include Th2 cells, Treg cells, Tfh cells, and CD4+ CTLs [In IgG4-RD, CD4culation . The CD4D4+ CTLs .Kamekura et al. suggested that subsets of T helper cells that play roles in IgG4-RD pathogenesis could be organized into two main groups according to their activity, intensity, and abundance in the affected tissue . The difγ producing cells, but in case of IgG4-RD conflicting results have been reported regarding the involvement of Th1 cells in producing IFN-γ in IgG4-RD pathophysiology [+ T cells or Tfh1 cells, rather than Th1 cells, are the most likely IFN-γ-producing cells in IgG4-RD [Th1 is the main IFN-ysiology . Recent  IgG4-RD , 43.IgG4 is a Th2-dependent isotype that has a low affinity for target antigens and represents the lowest and rarest fraction of the IgG subclasses. IgG4 is accounting for only 3–6% of total IgG in normal serum .Th2 cells, which produce interleukin-4 (IL-4), IL-5, IL-10, and IL-13, have the capacity to induce IgG4 class-switch recombination, thereby directing B cells to produce IgG4 –47.Most studies have indicated that IgG4-RD is characterized by the predominant activation of Th2 with the overexpression of their cytokines , 43–47.Conflicting results have been reported regarding the involvement of Th2 cells in IgG4-RD immunopathogenesis. Most studies revealed that Th2 cells accumulate only in the blood of IgG4-RD patients, whereas other studies showed that the levels of cytokines produced by Th2 are frequently increased in the affected tissues and peripheral blood of IgG4-RD patients , 48–52.Previous studies demonstrated that circulating Th2 memory cells accumulate in patients with IgG4-RD who have history of atopy but not among those without atopic disease , 48–54. + GATA3+ Th2 cells were found to be sparse in the salivary glands of patients with IgG4-RD, and the percentage of CD4+ GATA3+ Th2 cells in tissues in IgG4-RD does not seem to be correlated with other diagnostic parameters, such as serum IgG4 concentrations and the number of affected organs [CD4d organs , 55, 56.All these findings indicate the involvement of Th2 cell and its cytokines in the pathogenesis of IgG4-RDS , 48.+FoxP3+ Treg cells play an important role in the regulation of self-tolerance and the maintenance of tissue homeostasis [β (TGF-β), which are the key cytokines involved in the differentiation of IgG4-producing B cells and in the fibrogenesis, respectively [CD4eostasis –59. Thesectively , 57, 58.+CD25+Foxp3−expressing Treg cells are significantly higher in the affected tissues and peripheral blood in comparison to the cell count in patients with other autoimmune and nonautoimmune diseases [In IgG4-RD patients, the numbers of CD4diseases , 60, 61.β has been reported [β is a fibrogenic cytokine that may be involved in the promotion of fibrosis in IgG4-RD [Regarding the levels of cytokines produced by Treg cells in IgG4-RD, an overexpression of the regulatory cytokines IL-10 and TGF-reported , 50, 62. IgG4-RD , 63, 64.+CD45RO+CD39+CD25+FoxP3+ Treg cells in IgG4-RD patients (T cells with CD45RO+ are considered memory types of CD4+ T cells) [A recent study revealed only a marginal increase in circulating Treg cells that were identified as CD4T cells) .(1) Immunobiological Function of Tfh Cells in IgG4-RD. Tfh cells can participate in B cell differentiation through IL-21 and promote the formation of germinal centers and the production of IgG4 Abs [hi Tfh2 cells), help naïve B cells differentiate into plasmablasts and initiate production of IgG4 [IgG4 Abs , 65–68.  of IgG4 , 66, 69. of IgG4 .γ; cTfh2 cells subset that secretes IL-4, IL-5, and IL-13; and cTfh17 cells subset that secretes primarily IL-17, IL-21, and IL-22, whereas the second set of Tfh cells is the tissue-infiltrating one [There are two sets of Tfh cells. The first set is the peripheral circulating cells which are of three subsets: cTfh1 cells that are known to secrete mostly IFN-ting one , 65–68.++Tfh in IgG4-RD(2) CD4. Generally, in IgG4-RD, these cells are significantly increased in both peripheral blood and disease-affected organs [d organs , 67, 70.(3) Circulating Tfh (cTfh) Cells in IgG4-RD. The number of cTfh cells is significantly higher in IgG4-RD patients than in healthy individuals [ividuals  and cTfhividuals , 71. Furividuals .Akiyama et al. showed that the numbers of circulating Tfh2 cells and plasmablasts were increased in patients with active, untreated IgG4‐related disease . Akiyama(4) Tissue-Infiltrating Tfh in IgG4-RD. The number of activated Tfh cells is increased in the salivary gland of IgG4-RD patients and is correlated with disease activity but not with serum IgG4 level [G4 level , 69, 70.(5) Tfh Cells and the Biological Treatment of IgG4-RD. Grados et al. showed that CD4+CXCR5+PD1+ Tfh cells were normalized under RTX treatment [β-producing cells remained in the blood of IgG4-RD patients, suggesting that these cells might be risk factors for incomplete resolution of the inflammatory process [reatment . However process .Recent studies showed that, in contrast to serum concentrations of IgG4 Abs and IL-4, cTfh2 cell counts do not decrease after glucocorticoid treatment; additionally, the persistently circulating activated cTfh2 cells might contribute to disease relapse after ceasing treatment , 72.(1) Tfr Characteristics and Functions in IgG4-RD. Recently, a subpopulation of T regulatory (Treg) cells named Tfr cells that coexpress markers of both Treg and Tfh cells has been identified. Similar to Treg cells, Tfr cells are regulated by regulatory molecules such as Bcl6, PD-1, ICOS, Foxp3, CD25, CTLA-4, TGF-β, and IL-10 which promote B cell differentiation and GC development [elopment –76. Simielopment –75. In celopment , 74, 77.(2) Tfr in Autoimmune Diseases and IgG4-RD. Studies have demonstrated that, in some immune-mediated diseases such as multiple sclerosis and systemic lupus erythematosus, there is a significant correlation between the percentage of Tfr cells and other clinical parameters [rameters .In IgG4-RD patients, the numbers of Tfr cells are significantly increased in both the blood and submandibular glands when compared with those levels in peripheral blood and tonsils from healthy individuals , 79. The(1) Characteristics and Functions of Tph in IgG4-RD. A recent study on some autoimmune diseases exposed an unidentified subset of CD4+ T cells, named Tph cells (PD-1hiCXCR5−CD4+ Tph cells) [h cells) . These ch cells) . CXCL13,h cells) , 81–84. h cells) , 83.(2) Tph Cells in IgG4-RD. In IgG4-RD patients, there are increased levels of the circulating PD-1high CXCR5−CD4+ Tph and the percentage of these PD-1hiCXCR5−CD4+ Tph cells is positively correlated with serum levels of IgG4 and soluble IL-2 receptors and with the number of involved organs in IgG4-RD patients [hiCXCR5−CD4+ Tph cells may play a more pathogenic role than their Tfh counterparts in IgG4-RD pathogenesis [patients , 40, 83.ogenesis . Treatme(1) Immunobiology of CD4+ SLAMF7+CTLs. Cytotoxic CD4+ T cells (CD4+CTLs) are classically known as the CD28low subpopulation among CD4+T cells [+T cells . These c+T cells , 43, 86.β, TGF-β1, and IFN-γ, suggesting their role in tissue inflammation and fibrosis in various immune responses [Moreover, these cells possess a surface protein called SLAMF7 and can secrete Th1-like proinflammatory and profibrotic cytokines, including IL-1esponses , 86, 87.+SLAMF7+ CTLs in IgG4-RD(2) CD4. In IgG4-RD, CD4+ CTLs infiltrate the affected tissue and increased in peripheral circulation and at these sites CD4+ CTLs show oligoclonal expansion [β, IL-1β, and IFN-γ secreted by CD4+ CTLs may play a role in tissue fibrosis in IgG4-RD [xpansion , 55. The+ CTLs and CD8+ CTLs, but not Th1 and Th2 cells, are significantly more abundant in the lesions of IgG4-RD, correlate with disease activity, and may contribute to the initiation of T cell-mediated apoptosis and tissue fibrosis in the disease-affected organs [Both CD4d organs , 88. Saed organs .+ CTLs and their suppression following glucocorticoid administration suggest that these cells may play a central role in disease development [In IgG4-RD patients, the clonally expanded populations of CD4elopment , 90.+PD-1+ CTLs(1) Immunobiology of CD8. Cytotoxic CD8+ T cells exert their cytotoxic activity by releasing two types of cytotoxic proteins. The first protein type is granzymes (A and B), which are able to induce apoptosis in any type of target cell, whereas the second protein type is the pore-forming protein perforin, which pierces holes in the target cell membrane, thus allowing the granzymes to enter the cell and exert their cytotoxic activity through apoptosis [poptosis .+PD-1+ CTLs in IgG4-RD(2) CD8. Little information exists in the literature regarding the role of CD8+ CTLs in the pathogenesis of IgG4-RD.γ+CD8+ T (Tc1) cells in peripheral blood, although there were no differences in the percentage of IL‐4-expressing CD8+ T (Tc2) subsets between patients with IgG4‐related sclerosing disease and healthy controls [Ohta et al. (2012) revealed a significant increase in the number of IFN-controls .+ CTLs are correlated with disease activity and may initiate T cell-mediated apoptosis and tissue fibrosis in the disease-affected organs [Perugino et al. found that CD8d organs .Generally, IgG4-RD are lymphoproliferative disorders associated with hyper-IgG4 (gammaglobulinemia) and IgG4-producing plasma cell expansion with fibrotic or sclerotic changes in the disease-affected organs. IgG4-RD include a wide variety of diseases, such as Mikulicz's disease, Küttner's tumor, autoimmune pancreatitis (AIP), interstitial nephritis, retroperitoneal fibrosis, and prostatitis .Mikulicz's disease and Küttner's tumor have been reported to be associated with elevated serum IgG4 levels and prominent infiltration of plasmacytes expressing IgG4 with occasional storiform fibrosis , 93, 94.+ plasma cells, whereas the fibrosis is less severe in Mikulicz's syndrome. Therefore, it is difficult to differentiate between the two diseases histologically [Küttner's tumor and Mikulicz's syndrome are two similar disorders that share common features and are now considered a type of IgG4-RD , 95–97. ogically , 96, 97.Recently, authors have suggested that Küttner's tumor and Mikulicz's disease may in fact represent two variants of IgG4-associated sialadenitis , 38.Küttner's tumor, sometimes identified as chronic sclerosing sialadenitis, is a fibroinflammatory process of underrecognized cause that involves the submandibular gland of patients with IgG4-RD , 98, 99.It is a relatively uncommon lesion that is considered an IgG4-RD because of its histologic features and elevated serum IgG4 levels . MoreoveAccording to the literature, unilateral submandibular gland involvement, previously known as Küttner's tumor, is now preferably termed as IgG4-RS of the submandibular gland , 93. In The exact etiology of this entity is unclear. There are several theories that have been presented to explain its origin , 104.The first theory identified sialolithiasis as an etiological factor. Sialolithiasis induces inflammation and fibrosis and has been demonstrated in 29%–83% of cases of chronic sclerosing sialadenitis . Some auThe second theory indicates that this disease is caused by infectious agents, such as ascending microbial infection of the oral cavity, or that it is a result of foreign bodies, such as duct obstruction by foreign bodies , 104.The third theory is that it is an active local immune reaction in which there is involvement of IgG4 Abs , 98.The fourth theory indicates a group of etiological factors and mechanisms which assume secretory dysfunction with ductal inspissation, duct abnormalities, or autoimmune reaction as a cause of Küttner's tumor .+ T helper cells significantly exceeds that of CD8+ cytotoxic T cells and the quantity of CD4+ and CD8+ cells is higher than that of CD3+ cells. Additionally, there is the formation of tertiary lymphoid follicles in which CD3+ T cells are located at of the follicle periphery [+ and CD20+) could be found in tertiary lymphoid follicles [Küttner's tumor shows features of immune compartment dysregulation, where the number of CD4eriphery , 105. FuIn the salivary glands of Küttner's tumor, there are abundant cytotoxic T cells that are found in the parafollicular zone of germinal centers and in interfollicular areas and centered mostly around ducts and between acini that are intimately related to epithelial cells. These cytotoxic T cells show monoclonal and oligoclonal expansion , 105. In+ plasmacytes), and the peripheral blood shows an increased level of serum IgG4 [Salivary gland specimens collected from Küttner's tumor patients show IgG4-producing cells  found that CD3tal area .+ T helper cells are predominantly infiltrate around the glandular ducts and acini [+ T helper cells localize to the lymphoid follicles in the affected gland, and the percentage of CD4+ T helper lymphocytes is larger than that of CD8+ CTLs [In the affected gland, CD4nd acini , 114. SoD8+ CTLs .+GATA3+ Th2 and CD4+FoxP3+ Treg cells are predominant and highly active in the affected gland [Both CD4ed gland –46, 125.In IgG4-RS, it is postulated that the inflammatory and fibrotic processes are derived by Th2 and Treg cells secreted cytokines. This is contrary to most autoimmune disorders, where polarized Th1 and/or Th17 subsets are responsible for the inflammatory process , 16, 125+SLAMF7+ CTL cells are found in the parafollicular zone of germinal centers and in interfollicular areas of the affected gland, especially near ducts and between acini that are intimately close to the epithelial cells [+ CTLs show monoclonal and oligoclonal expansion [CD4al cells , 108. Thxpansion .The presence of cytotoxic T cells intimately close to the ductal epithelial cells indicates that IgG4-RS may be the consequence of an immune process triggered by intraductal epithelial agents , 127.+ CTLs [+SLAMF7+ CTLs result in tissue inflammation and fibrosis [In stages 2 and 3 of disease progression, there is intensive infiltration by periductal and intraepithelial CD4+ CTLs , whereas+ CTLs . Finallyfibrosis .+ and granzyme B+ CD8+ T cells in the affected submandibular gland [There is an abundant infiltration of granzyme Aar gland , 128.In defining and differentiating Mikulicz's disease as an IgG4-RDS, Stone et al. suggested the disposal of the term “Mikulicz's disease” when referring to IgG4-RD patients with involvement of the lacrimal, parotid, and submandibular glands and to instead use terms that refer to the specific individual organ involved, such as IgG4-related parotitis for those with parotid gland disease, IgG4-RS or IgG4-related submandibular gland disease, which is also known as Küttner's tumor, for those with submandibular gland involvement, IgG4-RDS, which is also known as Mikulicz's disease, for those with bilateral and symmetrical enlargement of both lacrimal and salivary glands, and IgG4-related dacryoadenitis for those with lacrimal gland disease only .The etiology of Mikulicz's disease, similar to that of other IgG4-RDs, is still unclear, and little is known regarding its etiology and pathogenesis. Some authors consider its etiology and pathogenesis to be controversial , 130.+ cells in the affected glands and peripheral blood is polyclonal, revealing that Mikulicz's disease is an IgG4-RD involving multiple organs [In the pathogenesis of Mikulicz's disease, most of the infiltration of IgG4e organs .In Mikulicz's disease, some patients did not show typical symptoms involving the lachrymal, parotid, or submandibular glands, but they exhibited elevated serum IgG4 levels; therefore, a unified set of criteria have been approved for the diagnosis of Mikulicz's disease, which is shown in Mikulicz's disease was once considered a subtype of Sjögren's syndrome because of the histopathological similarities between the two diseases. However, recent studies demonstrated that Mikulicz's disease is a distinct entity and should be regarded as an IgG4-RD , 133.+ B cells in the lacrimal and salivary glands [Clinically, Mikulicz's disease is characterized by symmetrical, bilateral, painless swelling of the lacrimal, parotid, and submandibular glands. Furthermore, it is characterized by high serum IgG4 concentrations and abundant infiltration of IgG4y glands , 14, 21.Complications of Mikulicz's disease include AIP, retroperitoneal fibrosis, and tubular interstitial nephritis . Some pa+ plasmacytes in the nasal mucosa of Mikulicz's disease patients who complained of olfactory disturbance, suggesting that these disturbances could be related to this mucosal infiltration of IgG4+ B cells [Himi et al. found an abundance of IgG4 B cells .+ plasma cells, and storiform fibrosis [Similar to other IgG4-RDs, Mikulicz's disease is characterized by elevated serum IgG4 levels, tissue infiltration by IgG4fibrosis , 18, 19.fibrosis .The underlying pathogenesis of IgG4-RDS remains largely unidentified , 130.In IgG4-RDs, large numbers of T cells are present at the affected organs, including the salivary glands, indicating that T cells are involved in the pathogenesis of this disease. Evidence of the T cells involvement in all IgG4-RDs, including IgG4-RDS, has been increasing, and recently the roles of T cell subsets in IgG4-RD pathogenesis have been largely clarified .The cytokine profile of Mikulicz's disease shows that Th2 and Treg cells are predominant , 136. InMost previous studies on the contribution of T cells to the pathogenesis of IgG4-RDs have focused on Th2 and Treg cells as the dominant cells that infiltrate the affected tissue; thus, these two subtypes are considered as the major T cells that play a role in the pathogenesis of IgG4-RDS.+ CTLs, in the affected tissue that may also play a role in pathogenesis [Additionally, recent studies identified new subsets of T cells, such as T follicular cells and CD4ogenesis , 141.+ T helper cells and CD8+ CTLs [In Mikulicz's disease, the affected gland tissue shows infiltration of CD4D8+ CTLs .Immunobiologically, cytolytic T cells destroy tissue through perforin or Fas lytic pathways –144. In γ and IL-12 are utilized as indicators to study the activity of classical Th1 [The levels of Th1 cytokines IFN-ical Th1 . In the ical Th1 .Th17 cells, which primarily produce IL-17, have been suggested to play a critical role in the pathogenesis of autoimmune diseases. Th17 is a very flexible phenotype of T cells because it can easily shift to Th1 phenotype in inflammatory sites via the activity of proinflammatory cytokines, such as IL-12. This newly produced Th1 is designated as a Th17-derived Th1 cell or nonclassical Th1 that has the capacity to produce IL-17. Nonclassical Th1 cells play a more important role than classical Th1 and even Th17 cells in the persistence of chronic inflammation in several autoimmune disorders . Howeverγ/IL-4 ratio is very high in Mikulicz's disease, and the elevated IgG4 production is considered dependent upon the high level of IFN-γ/IL-4 [Yamamoto et al. reported that the IFN-N-γ/IL-4 .γ+, IFN-γ+IL-17+, and IL-17+ cells, which are proposed to be Th17/Th1 cells, suggesting that Th17/Th1 cells may be involved in the pathogenesis of Mikulicz's disease [In the submandibular salivary gland and the lymph node of Mikulicz's disease patients, Nanke et al. detected IFN- disease .+GATA3+ Th2 Cells in the Salivary Gland of IgG4-RDS(1) CD4. On comparing Mikulicz's disease patients with healthy individuals, CD4+GATA3+ Th2 cells are predominant and significantly increased in the affected salivary glands of Mikulicz's disease patients [+/IgG+ cells in tissues with IgG4-RDS indicating their close association with IgG4 production [patients , 145. Thpatients , 145. Zeoduction .γ from Th1 cells, which may prevent the destruction of the glandular acinar structure [Furthermore, predominant infiltration of Th2 cells and increased levels of their cytokines in the salivary glands of patients with Mikulicz's disease could suppress production of IFN-tructure .+GATA3+ Th2 Cells in Peripheral Circulation of IgG4-RDS(2) CD4. CD4+ Th2 cell represents the predominate phenotype of CD4+ in the peripheral circulation of IgG4-RDS [IgG4-RDS , 145.(3) Association of Th2 and Atopy in IgG4-RDS. Allergic immune responses are induced by allergen-specific Th2 cytokines, such as IL-4 and IL-13, which promote the secretion of IgG4 and IgE by B cells. In particular, IL-4 directs naïve B cells to switch to producing IgG4 and IgE [+GATA3+ Th2 cells were shown to be relatively rare in patients without associated allergic diseases [ and IgE , 148. Ig and IgE , 149. Indiseases . Mattoo diseases .Several studies have revealed that autoimmune diseases are caused by disruption of Th1/Th2 balance , 150.Most studies revealed that Th1/Th2 balance toward Th2 resulted in the overexpression of Th2 cytokines IL-4 and IL-10 along with IgG4 production in the labial salivary glands of patients with IgG4-RDS , 151.Contrary to previous studies, Ohta et al. (2012) reported a strong predominance of Th1 and cytotoxic type cells in the salivary glands of IgG4-RDS patients, suggesting that this disruption of the Th1/Th2 balance might be because of differences in the specimens examined or the severity of the disease .+ T cells of IgG4-RDS patients deviates toward Th2 and the expression of Th2-type cytokines is elevated, indicating that IgG4-RDS has a Th2-predominant phenotype [Generally, Th1/Th2 balance in peripheral CD4henotype , 145. Anhenotype , 50, 145Th17-related cytokines and molecules are rarely expressed in patients with Mikulicz's disease , 152.(1) Tissue Treg Cells in IgG4-RDS. In IgG4-RDS, the activation of Treg cells in IgG4-RD is reported to be based on the increased expression of FoxP3 messenger RNAs in the affected tissues when compared with its decreased expression in classic autoimmune diseases [diseases , 45, 47.+Foxp3+ Treg cells which are predominantly located around the acinar and ductal cells [In the affected gland in IgG4-RDS patients, most of the studies revealed that there are an increased number of CD4al cells , 153.(2) Circulatory Treg Cells in IgG4-RDS. Increased numbers of CD4+CD25high Treg cells are observed in the circulation of IgG4-RDS patients [patients , 64.(3) Treg Cell Molecules and Cytokine Levels and in IgG4-RDS. The expression levels of IL-4, IL-5, IL-10, TGF-β, and FoxP3 mRNA in labial salivary glands of patients with Mikulicz's disease have been shown to be higher than the levels in healthy persons [β level is upregulated and appears to play central fibrogenic roles in tissue fibrosis [ persons . IL-4, I persons , 154. Infibrosis .Corticosteroid treatment improving the disease activity of IgG4-RDS is accompanied by a decline in the frequency of circulating Treg cells . Akiyama+ Th phenotype, expressing high levels of the chemokine receptor CXCR5. These cells are reported to control the activity of CD4+ effector Th cells, B cell activation, and differentiation and promote ectopic germinal centers formation by IL-21, which is secreted by CD4+ Th cells, including Th2, Th17, and especially Tfh cells [Tfh cells are identified as a CD4fh cells –158.+CXCR5+ Tfh Cells in IgG4-RDS(1) Tissue CD4. In IgG4-RDS, Maehara et al. revealed that an increase in the expression of some Tfh cell-related genes in IgG4-RDS-affected tissue resulted from increased differentiation and activation of Tfh cells [fh cells .IgG4-RDS shows a high frequency of germinal center formation in the affected salivary glands as a result of increased differentiation and activation of Tfh cells .(2) Peripheral Circulation Tfh Cells in IgG4-RDS. In IgG4-RDS, there is positive correlation between circulating type of Tfh (cTfh2) and the number of plasmablasts because cTfh2 cells have the efficiency to induce differentiation of naïve B cells into plasmablasts [mablasts .(3) Tfh Cells and Their Cytokine Levels in IgG4-RDS. The increased level of Tfh molecules and cytokines supports the role of Tfh cells in the progression of disease as a lymphoproliferative disorder, particularly in the formation, growth, and activation of ectopic germinal centers in IgG4-RDS patients [patients .Tfh-related molecules, CXCR5, B cell lymphoma 6 protein (Bcl-6), and IL-21 are highly expressed on infiltrating lymphocytes in or around the ectopic germinal centers of labial salivary gland lesions from IgG4-RDS patients , 151.In IgG4-RDS, the serum level of IL-4 Tfh-related cytokine is increased and positively correlated with the serum IgG4 level or the IgG4 : IgG ratio .IL-21, which is one of the cytokines produced by Tfh, may be involved in the class-switching of IgG4, thus affecting the IgG4/IgG ratio in IgG4-RDS –161. TheIn IgG4-RDS patients that show the involvement of salivary glands, the numbers of Tfr cells in circulating peripheral blood and infiltrating the submandibular glands are significantly increased compared with those in healthy individuals .+GZMA+SLAMF7+ CTLs in IgG4-RDS(1) Tissue Infiltration of CD4. In IgG4-RDS tissues, nine genes associated with CD4+ CTLs are overexpressed; in particular, the mRNA expression of GZMA was shown to be significantly higher in submandibular specimens from patients with IgG4-RD compared with that in corresponding tissues from healthy individuals [ividuals .+GZMA+ CTLs, but not Th1 and Th2 cells, are significantly more abundant in the lesions of patients with IgG4-RDS than in healthy individuals, suggesting that the activity of IgG4-RDS is prominently linked to tissue infiltration by CD4+GZMA+ CTLs but not to Th1 and Th2 cells. Also, the increased IFN-γ expression in IgG4-RDS tissues is more likely from CD4+ CTLs not from Th1 cells [+GZMA+ CTLs in submandibular glands from patients with IgG4-RDS is positively correlated with serum IgG4 concentrations and the number of affected organs.Some studies revealed that CD4h1 cells , 55. Fur+TGF-β1+ cells are abundantly present in areas where fibrotic pathology is seen in IgG4-RDS [β and TGF-β, secreted by CD4+SLAMF7+ CTLs, may contribute to fibrogenesis in IgG4-RDS [Regarding the distribution of these cells within the specimen of affected organ, it has been found that CD4IgG4-RDS , 55. ThiIgG4-RDS , 55.(2) Circulating CD4+GZMA+CTLs in IgG4-RDS. Maehara et al. described clonally expanded circulating CD4+GZMA+ CTLs in IgG4-RDS with predominant infiltration in the affected tissues where they secrete IFN-γ, IL-1β, and TGF-β1 [d TGF-β1 , 55.+ CTLs have been shown to decrease in response to B cell depletion therapy, which may reflect the interaction between CD4+ CTLs and B cells in the pathogenesis of IgG4-RDS. This interaction may be explained by the potential of some activated B cells to present antigens to tissue-infiltrating CD4+ CTLs, causing their activation and subsequently exerting their cytotoxic activity [CD4activity , 141.+ CTLs, Tsubota et al. revealed increased numbers of these cells in the affected organs [+CD8+ CTLs are mostly located around the lymphoid follicles in IgG4-RDS [In relation of CD8d organs . Tabeya IgG4-RDS .The immunopathogenesis of IgG4-RS (Küttner's tumor and Mikulicz's disease) as a type of IgG4-RD has not yet been fully clarified. Immunohistological studies have revealed that IgG4-RS lesions are characterized by the abundant infiltration of different T cell subsets in the salivary tissues and peripheral blood.Recent studies have abundantly clarified that T cells and their interactions with and activation of B cells play key roles in the pathogenesis of IgG4-RS.Further research works are required to elucidate the roles of the T cell subsets and their secreted cytokines in the complex mechanisms of IgG4‐RS pathogenesis, which could lead to the development of novel pharmacological strategies aimed to control the overactivity of T and B cells and their cytokine network, thereby inhibiting the initiation and/or progression of IgG4‐RS.