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Roles of basophils in immune regulation. Basophils present in the spleen and recruited to draining lymph nodes during immune responses are activated by cytokines, for example, IL-3 produced from CD4+ T helper cells, and by intact antigens that cross-link surface-bound immunoglobulins (IgG and IgE). Activated basophils express unidentified membrane-bound molecules and release soluble factors (for example, IL-4, IL-6, TSLP) that affect T- and B-cell function. CD4+ T cells differentiate into Th2 cells that gain the ability for B cell help and produce IL-4, IL-5, IL-10, IL-13, IL-21, and CD40L. Thereby basophils crucially support B-cell proliferation, differentiation into plasma cells, and immunoglobulin production. Immunoglobulins may be deposited in the kidney and drive auto- and alloimmunity in the case of autoantibodies or donor-specific antibodies. Immunoglobulins further enhance the reactivity of basophils to antigens. Cytokines released directly from basophils or from CD4+ T cells exposed to basophils may also affect renal diseases (for example, by inducing fibrosis). IgG, immunoglobin G; IL, interleukin.
Source publication
Until recently, basophils and mast cells were considered mainly effector cells with an innate immune response linked to allergy and parasite infection. Only in the past few years they were recognized as important regulators of adaptive immunity. The development of new methods and reagents has enabled detection and functional analysis of these rare...
Context in source publication
Context 1
... A memory-type immune response predominates in transplantation and many types of autoimmune diseases, where alloantigens/autoantigens are continuously present. These antigens, together with the specific antibodies, activate basophils, which may boost ongoing humoral immune responses and further enhance production of immunoglo- bulins ( Figure 1). Immune complexes deposited in various structures of the kidney and autoantibodies (for example, anti-neutrophil cytoplasmic antibody (ANCA), anti-DNA, anti-GBM) have a prominent role in many types of kidney diseases. ...
Citations
... They are activated by antigen-specific immunoglobulin (Ig) E via high-affinity receptors for IgE (FcεRI), leading to degranulation and release of mediators, including histamine (47). Furthermore, mast cell-derived cytokines and other mediators affect immune cells, such as dendritic cells, T cells, and B cells (48). A recent study showed that mast cell tryptase (MCT), which is relatively specific for histamine release, was significantly increased in participants who developed post-exercise hypotension compared with those who did not (49). ...
Heatstroke can cause multiple organ failure and systemic inflammatory response syndrome as the body temperature rises beyond the body’s ability to regulate temperature in a hot environment. Previous studies have indicated that heatstroke-induced acute kidney injury (AKI) can lead to chronic kidney disease. Therefore, there is an urgent need to elucidate the mechanism of heatstroke-induced AKI and to establish methods for its prevention and treatment. Recent reports have revealed that innate immunity, including neutrophils, macrophages, lymphocytes, and mast cells, is deeply involved in heat-induced AKI. In this review, we will discuss the roles of each immune cell in heat-induced renal injury and their potential therapeutic use.
... By manipulating models and controlling time, researchers can reveal the biologic responses that lead to inflammation, cell death/proliferation, kidney repair, and long-term fibrosis after the injury. Among the myeloid cells (Table 1), the roles of eosinophils and basophils in AKI have been reported in a small number of case reports and observational studies (102,103). In contrast, mast cells have been shown to not necessarily be involved in the development of kidney pathology, but could have a beneficial role in restoration of normal kidney homeostasis (104). ...
AKI remains highly prevalent, yet no optimal therapy is available to prevent it or promote recovery after initial insult. Experimental studies have demonstrated that both innate and adaptive immune responses play a central role during AKI. In response to injury, myeloid cells are first recruited and activated on the basis of specific signals from the damaged microenvironment. The subsequent recruitment and activation state of the immune cells depends on the stage of injury and recovery, reflecting a dynamic and diverse spectrum of immunophenotypes. In this review, we highlight our current understanding of the mechanisms by which myeloid cells contribute to injury, repair, and fibrosis after AKI.
... IgD is co-expressed with IgM and secreted IgD exists and has a function in blood, mucosal secretions and on the surface of innate immune effector cells such as basophils 49 . Basophils are white cells that fight viruses, bacteria, parasites and fungi and they have been shown to be involved in renal diseases and transplant rejection 50 . Thus, another evidence that relates the B-cell responses to the rejection process with viruses and bacteria. ...
Studying immune repertoire in the context of organ transplant provides important information on how adaptive immunity may contribute and modulate graft rejection. Here we characterize the peripheral blood immune repertoire of individuals before and after kidney transplant using B cell receptor sequencing in a longitudinal clinical study. Individuals who develop rejection after transplantation have a more diverse immune repertoire before transplant, suggesting a predisposition for post-transplant rejection risk. Additionally, over 2 years of follow-up, patients who develop rejection demonstrate a specific set of expanded clones that persist after the rejection. While there is an overall reduction of peripheral B cell diversity, likely due to increased general immunosuppression exposure in this cohort, the detection of specific IGHV gene usage across all rejecting patients supports that a common pool of immunogenic antigens may drive post-transplant rejection. Our findings may have clinical implications for the prediction and clinical management of kidney transplant rejection.
... In addition, MCs producing inflammatory mediators activate fibroblasts and induce collagen synthesis causing inflammation and chemotaxis, recruiting other immune cells [33,34]. They are involved in initiation and regulation of innate and adaptive immune responses-pathways, and can participate in tissue transplantation, playing an important role in graft rejection [35]. ...
Objective:
The aim of this study was to evaluate the role of mast cells (MCs) in allograft rejection, eventually inhibited by IL-37. Immune cells including MCs participate in allograft rejection by generating IL-1, IL-33, TNF and other cytokines.
Methods:
We evaluated allograft rejection on the experience of our experimental data and using the relevant literature.
Results:
MCs are involved in initiation and regulation of innate and adaptive immune responses-pathways. MCs are important pro-inflammatory cells which express high-affinity receptor FceRI and can be activated by IgE and some pro-inflammatory cytokines, such as IL-1 and IL-33. The cross-linkage of high affinity IgE receptor on MCs by antigen ligation has a crucial role in allergy, asthma, anaphylaxis, cancer and allograft rejection. MCs mediate immunity in organ transplant, leading to the activation of allospecific T cells implicated in the rejection and generate pro-inflammatory cytokines/chemokines. IL-1 pro-inflammatory cytokine family members released by MCs mediate allograft rejection and inflammation. IL-37 is also an IL-1 family member generated by macrophage cell line in small amounts, which binds to IL-18Rα and produces an anti-inflammatory effect. IL-37 provokes the inhibition of TLR signaling, TLR-induced mTOR and (MyD88)-mediated responses, suppressing pro-inflammatory IL-1 family members and increasing IL-10.
Conclusion:
IL-37 inhibition offers the opportunity to immunologically modulate MCs, by suppressing their production of IL-1 family members and reducing the risk of allograft rejection, resulting as a potential good therapeutic new cytokine. Here, we report the relationship between inflammatory MCs, allograft rejection and pro-inflammatory and anti-inflammatory IL-37.
... To show that basophils contribute to the production of IL-4 we measured IL-4 levels in the allografts and spleens following depletion of basophils. Antibodies recognizing the highaffinity IgE receptor FcεRI (Clone: MAR-1) or the orphan receptor CD200R3 (Clone: Ba103) have been used to deplete basophils in different experimental settings (29,34,47,48). We used two different antibodies and appropriate isotype control antibodies to exclude off-target effects and non-specific effects of the antibodies. ...
Fibrosis is a major component of chronic cardiac allograft rejection. Although several cell types are able to produce collagen, resident (donor-derived) fibroblasts are mainly responsible for excessive production of extracellular matrix proteins. So far, it is unclear which cells regulate production of connective tissue elements in allograft fibrosis and how basophils, as potential producers of pro-fibrotic cytokines, are involved this process. We have studied this question in a fully MHC mismatched model of heart transplantation with transient depletion of CD4+ T cells to largely prevent acute rejection. The model is characterized by myocardial infiltration of leukocytes as well as development of interstitial fibrosis and allograft vasculopathy. Using depletion of basophils, IL-4 deficient recipients and IL-4-receptor deficient grafts we show that basophils and IL-4 play crucial roles for activation of fibroblasts and development of fibrotic organ remodelling. In the absence of CD4+ T cells, basophils are the predominant source of IL-4 in the graft and contribute to expansion of myofibroblasts, interstitial deposition of collagen and development of allograft vasculopathy. Our results indicate that basophils trigger the production of various connective tissue elements by myofibroblasts. Basophil-derived IL-4 may be an attractive target for treatment of chronic allograft rejection. This article is protected by copyright. All rights reserved.
... However, the mechanisms of MCNS are not fully understood. Certain studies have proposed that MCNS is a T helper (Th)2-dominated disease that may be associated with a circulating factor from MCNS T cells (2,3). ...
... Laurent et al also observed frequent positivity of the HBDT in individuals with INS (minimal glomerular changes and segmental and focal glomerulosclerosis) (40). Furthermore, Mack and Rosenkranz stated that basophils, which are not frequently studied, should be analyzed when investigating the pathogenesis of MCNS (3). ...
A number of studies have verified that minimal change nephrotic syndrome (MCNS) may result from the dysfunction of T cells and B cells, although the precise mechanisms are yet to be elucidated. It is widely recognized that MCNS is a T helper (Th)2-dominant glomerular disease caused by an imbalanced Th1/Th2 immune response. Increased levels of the Th2 cytokines, interleukin (IL)-4 and IL-13, have been demonstrated to be closely associated with disease activity. In addition, basophils can affect the Th1/Th2 balance by enhancing the Th2 response and impairing the Th1 response, which are then involved in the development of numerous diseases. However, whether basophils are vital in the pathogenesis of MCNS remains unknown. Frequent positivity of the human basophil degranulation test in patients with MCNS has been observed. Thus, basophils should be analyzed in order to determine their role in the pathogenesis of MCNS.
... Biopsy samples have revealed a positive correlation between the accumulation of mast cells and the degree of renal interstitial fibrosis, 76 but the functional role of mast cells in fibrosis remains controversial. 77 Mast-cell deficient Kit W-sh / W-sh ) mice show reduced infiltration of CD4 + T cells and macrophages as well as reduced renal fibrosis in the UUO model; both reductions are restored by the adoptive transfer of bone-marrow-derived mast cells from wild-type mice. 78 Furthermore, administration of disodium cromoglycate, which stabilizes mast cells and, therefore, impairs degranulation, significantly attenuated renal fibrosis in wild-type UUO mice. ...
Many types of kidney injury induce inflammation as a protective response. However, unresolved inflammation promotes progressive renal fibrosis, which can culminate in end-stage renal disease. Kidney inflammation involves cells of the immune system as well as activation of intrinsic renal cells, with the consequent production and release of profibrotic cytokines and growth factors that drive the fibrotic process. In glomerular diseases, the development of glomerular inflammation precedes interstitial fibrosis; although the mechanisms linking these events are poorly understood, an important role for tubular epithelial cells in mediating this link is gaining support. Data have implicated macrophages in promoting both glomerular and interstitial fibrosis, whereas limited evidence suggests that CD4(+) T cells and mast cells are involved in interstitial fibrosis. However, macrophages can also promote renal repair when the cause of renal injury can be resolved, highlighting their plasticity. Understanding the mechanisms by which inflammation drives renal fibrosis is necessary to facilitate the development of therapeutics to halt the progression of chronic kidney disease.
... Basophil has been known to play a central role for the allergic and parasitic diseases. However, numbers of recent works suggest the basophil is a key factor in the acquired and innate immune responses involving the expression of Toll-like receptors (TLRs) and the immunoregu-latory roles via not only the release of cytokines and chemokines, but also its antigen presenting properties [9][10][11]. ...
... In several recent reports, the basophil was issued as an important regulator in the pathogenesis of various non-allergic diseases. For examples, infiltration of basophils in the gastric mucosa has been reported at the sites of Helicobacter pylori infection [12] and basophil has been issued as a key factor for the chronic inflammatory damage of kidney diseases [9]. It is interesting that a recent report suggested that the commensal bacteria derived signals regulated basophil hematopoiesis [13], which reminds us the reaction http://jsms.sch.ac.kr between commensal and pathogenic bacteria involving TLR pathways seems to be essential in the pathogenesis of NEC [1]. ...
Objective: The pathophysiology of necrotizing enterocolitis (NEC) is incompletely understood. There were some reports that the pathogenesis of NEC involves intrauterine process and infants with fulminant NEC had low lymphocyte count. Thus, we investigated complete blood count (CBC) parameters of infants at birth and their mothers near delivery. Methods: We retrospectively reviewed the medical records of NEC patients and controls. The CBC parameters were compared between infants with NEC (modified Bell's criteria stage ≥ Ia, n= 82) and controls matched for gestational age, birth weight, gender, and race (n= 169). The blood test findings were obtained from infants within the first 2 hours of life and from mothers as the latest one before delivery. Results: Statistically different findings at birth were found in NEC infants; red cell distribution width (RDW) and basophil count. In the multiple logistic regression analysis after adjustment for gestational age, birth weight, and gender, several infantile independent risk factors were identified; basophil count < 40/μL (odds ratio [OR], 4.60; 95% confidence interval [CI], 2.18 to 9.73; P< 0.001) and low RDW (OR, 7.15; 95% CI, 2.93 to 17.41; P< 0.001). Conclusion: We found that NEC was associated with low infantile RDW and basophil count at birth. These findings might support roles of red blood cell and basophil in the pathogenesis of NEC, which might predict development of NEC with neonatal findings at birth.
... No difference in the mRNA expression of the TH1 and TH2 master regulator t-bet and GATA3, respectively, was detected between the two groups (Figure 3G). Since immune-regulation in NTS has been shown to be of importance [16], [26]–[28], cytokine profiling in the lymph nodes was performed. Only IL-6 mRNA expression was significantly changed in Lcn-2 KO mice as compared to WT mice 7 days after NTS induction. ...
Lipocalin-2 (Lcn-2) is involved in divergent processes such as acute kidney injury or bacterial host defence. Our study was designed to evaluate the functional role of Lcn-2 in nephrotoxic serum nephritis (NTS). Since Lcn-2 is expressed in tubular epithelial cells as well as in cells of innate immunity such as macrophages and polymorphonuclear neutrophils (PMN), we induced NTS in wild-type (WT), Lcn-2 knock-out (KO) mice and WT/Lcn-2 KO chimeras. Mice lacking Lcn-2 exhibited more glomerular damage with increased proteinuria and interstitial leukocyte accumulation compared to WT mice. Chimeras able to express Lcn-2 in macrophages and PMN but not in epithelial cells were found to develop NTS comparable to wild-type controls. In contrast, chimeras expressing Lcn-2 in tubular epithelial cells with no expression in innate immune cells developed increased NTS due to decreased concerted apoptosis but increased necrosis and formation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB-1) in the kidney. In vivo blockade of HMGB-1, a toll-like receptor (TLR)-2 agonist, significantly reduced inflammation and NTS in Lcn-2 knock-out mice. In parallel, TLR-2 signalling was found to drive Lcn-2 transcription in vitro. Taken together, Lcn-2 expressed in innate immune cells is protective in NTS by inducing concerted apoptosis and inhibiting the formation of HMGB-1 thereby limiting cytokine production via TLR-2 signalling. In parallel, TLR-2 dependent transcription of Lcn-2 is an endogenous inhibitor of inflammation in NTS.
... Our results confirm these observations and indicate that greater renal MC degranulation could be important in facilitating the occurrence of doxorubicin-induced renal injury in these animals. Clinically, abnormal MC function has been associated with the development of renal tissue fibrosis and renal deterioration in glomerular diseases (Mack and Rosenkranz 2009). ...
Clinically, girls appear to be more sensitive than boys to the cardiotoxic effects of doxorubicin, whereas the opposite may be true for adults. To identify and characterize potential sex-related differences, adult male and female spontaneously hypertensive rats (SHR; some ovariectomized [OVX]) received 1 mg/kg of doxorubicin or saline iv weekly for 9, 10, or 12 weeks. Weight gain was slower in treated males. Serum concentrations of cholesterol and triglycerides increased and those of albumin decreased in both sexes, but changes were more pronounced in treated males. Treated males had significantly more severe cardiomyopathy scores and higher serum levels of cTnT than females. The increased cardiotoxicity was accompanied by higher numbers of cardiac mast cells (MCs) and percentage of cardiac MCs undergoing degranulation. Doxorubicin-treated OVX animals had significantly increased numbers of cardiac MCs, more severe myocardial lesions, and elevated serum concentrations of cTnT compared to doxorubicin-treated normal female SHR. The severity of cardiac lesions in the OVX female was similar to that observed in doxorubicin-treated males. This study demonstrated the presence of sex-related differences in the cardiotoxic effects elicited by doxorubicin and identified variations in the level of cardiac MC activity as a factor which could possibly contribute to the male-female dissimilarity.
