Cell Depletion Therapy Research Articles

B cells in Graves' Orbitopathy: more than just a source of antibodies?

B cells have multiple actions on different phases of an immune reaction, mainly resulting in B and T cell-interaction (help), production of cytokines, regulation of dendritic cells and downregulation of regulatory B cells. The effectiveness of B cell depletion therapy is probably due to blockade of the antigen-presenting function of B cells, occurring very early in the setting of autoimmune reactions. B cells undergo a maturation process from stem cells during which the CD 20 antigen, which is the target of rituximab (RTX), is expressed from the stage of pre-B cells to mature and memory B cells, but not on plasma cells. During the maturation process, the cytokine B cell stimulating factor (BAFF) induces maturation of B cells and expansion of clones to produce plasma cells and eventually antibodies. The effect of RTX in GO is rather rapid, with significant improvement of the disease already 4-6 weeks after the first RTX infusion. Based on the evidence of significant lymphocytic infiltration in the orbits of patients with active GO, it is reasonable to postulate that RTX may cause depletion of B cells and block their antigen-presenting cell mechanism. Since it has been reported that serum BAFF concentrations are elevated in hyperthyroid GD patients and that BAFF is expressed on the thyrocytes of patients with either autoimmune disease or nodular goiter, the hypothesis that belimumab, an anti-BAFF monoclonal antibody, may be effective in patients with active GO his currently being tested in a randomized controlled trial.

The long and the short of it: insights into the cellular source of autoantibodies as revealed by B cell depletion therapy.

High titers of pathogenic autoantibodies are a hallmark of many autoimmune diseases. However, much remains unknown about the self-reactive plasma cells that are key mediators of disease. We propose a model in which the varying efficacy of precursor B cell depletion for the treatment of humoral autoimmunity can be explained by differences in the relative contributions of pathogenic antibodies by short-lived versus long-lived plasma cells. Beyond therapeutic considerations, this model suggests that we can infer the cellular source of disease-associated autoantibodies by the durability of serum titers following B cell depletion. Data from clinical trials and animal models across different autoimmune diseases may provide useful insights into the lifespan, lifestyle and fate of autoreactive plasma cells.

Monitoring and Treatment of Patients Undergoing Immunotherapy With Anti-CD20 Who are Exposed to HBV

Reactivation of hepatitis B virus (HBV) is a potentially fatal complication of immunosuppressive therapy, and can occur in individuals who are hepatitis B surface antigen (HBsAg) negative but positive for hepatitis B core antibody (anti-HBc). While anti-HBc positivity indicates prior HBV exposure, it may also reflect clearance of HBsAg, but with viral persistence at low intrahepatic replicative and transcriptional levels.1 HBV reactivation can still occur during intense immunosuppression, including B cell-depleting therapy with anti-CD20 antibodies2 and hematopoietic stem cell transplantation.3 While prevention via antiviral prophylaxis is recommended, it remains uncertain, from a global perspective, if this is an ideal and cost-effective strategy. An alternative is regular HBV DNA monitoring.4 However, this approach is problematic in resource-constrained regions, where the logistics of sample collection, transportation, and molecular analysis in dedicated facilities poses challenges.5 We aimed to evaluate the effectiveness of simple monitoring strategies using routine liver biochemistry and serum HBsAg in preventing HBV-related complications during anti-CD20 therapy.

Cryoglobulinaemia.

Cryoglobulinaemia refers to the serum presence of cryoglobulins, which are defined as immunoglobulins that precipitate at temperatures <37 °C. Type I cryoglobulinaemia consists of only one isotype or subclass of monoclonal immunoglobulin, whereas type II and type III are classified as mixed cryoglobulinaemia because they include immunoglobulin G (IgG) and IgM. Many lymphoproliferative, infectious and autoimmune disorders have been associated with mixed cryoglobulinaemia; however, hepatitis C virus (HCV) is the aetiologic agent in most patients. The underlying mechanism of the disorder is B cell lymphoproliferation and autoantibody production. Mixed cryoglobulinaemia can cause systemic vasculitis, with manifestations ranging from purpura, arthralgia and weakness to more serious lesions with skin ulcers, neurological and renal involvement. This Primer focuses on mixed cryoglobulinaemia, which has a variable course and a prognosis that is primarily influenced by vasculitis-associated multiorgan damage. In addition, the underlying associated disease in itself may cause considerable mortality and morbidity. Treatment of cryoglobulinaemic vasculitis should be modulated according to the underlying associated disease and the severity of organ involvement and relies on antiviral treatment (for HCV infection), immunosuppression and immunotherapy, particularly anti-CD20 B cell depletion therapies.

Reversing Autoimmunity Combination of Rituximab and Intravenous Immunoglobulin.

In this concept paper, the authors present a unique and novel protocol to treat autoimmune diseases that may have the potential to reverse autoimmunity. It uses a combination of B cell depletion therapy (BDT), specifically rituximab (RTX) and intravenous immunoglobulin (IVIg), based on a specifically designed protocol (Ahmed Protocol). Twelve infusions of RTX are given in 6–14 months. Once the CD20+ B cells are depleted from the peripheral blood, IVIg is given monthly until B cells repopulation occurs. Six additional cycles are given to end the protocol. During the stages of B cell depletion, repopulation and after clinical recovery, IVIg is continued. Along with clinical recovery, significant reduction and eventual disappearance of pathogenic autoantibody occurs. Administration of IVIg in the post-clinical period is a crucial part of this protocol. This combination reduces and may eventually significantly eliminates inflammation in the microenvironment and facilitates restoring immune balance. Consequently, the process of autoimmunity and the phenomenon that lead to autoimmune disease are arrested, and a sustained and prolonged disease and drug-free remission is achieved. Data from seven published studies, in which this combination protocol was used, are presented. It is known that BDT does not affect check points. IVIg has functions that mimic checkpoints. Hence, when inflammation is reduced and the microenvironment is favorable, IVIg may restore tolerance. The authors provide relevant information, molecular mechanism of action of BDT, IVIg, autoimmunity, and autoimmune diseases. The focus of the manuscript is providing an explanation, using the current literature, to demonstrate possible pathways, used by the combination of BDT and IVIg in providing sustained, long-term, drug-free remissions of autoimmune diseases, and thus reversing autoimmunity, albeit for the duration of the observation.

Standard Induction Immunosuppression Interferes with the Role of Vascularized Bone Marrow in Vascularized Composite Allograft Protection

Introduction Clinical induction therapies have been demonstrated to interfere with the development of immunologic tolerance in experimental models. Vascularized bone marrow (VBM) has been demonstrated to provide immunologic protection to vascularized composite allografts (VCA). We utilized a non-human primate (NHP) model of facial transplantation to investigate the effects of recipient T cell depletion and steroid therapy on VBM-mediated graft protection. Materials and Methods We utilized a well-established model of heterotopic facial subunit VCA in a NHP model. Recipients (N=3) were administered 50 mg/kg of anti-thymocyte globulin (ATGAM) on Day -2, -1, and 0 and transplanted Day 0. Steroids were administered with an initial 20 mg/kg dose and tapered over 21 days and maintained on tacrolimus (Tac) and mycophenylate mofetil (MMF). Chimerism was determined using flow cytometry from peripheral blood samples and final tissues. Comparison was made to historical cohorts, VCA + VBM (n=4) and VCA (no VBM, n=3) treated with Tac/MMF. Results and Discussion Mean survival in the ATGAM with steroid taper group was 28.3 ±8.02 days, as compared to VCA + VBM group 348.2±85.9 days, and VCA (no VBM) 24.7±16.6 days (p=0.008). NHP receiving induction therapies developed early Banff 4 rejection, as well as histopathologic evidence of thrombophlebitis and muscle necrosis. In contrast to the VCA + VBM group, chimerism was undetected in peripheral blood and graft bone marrow was nearly acellular, with an average of 91.5%±2.4 (range 89.8-93.2%) of the lymphocytes present recipient in origin (n=2). Also in contrast to VCA + VBM but comparable to VCA (no VBM), the development of IgM and IgG donor specific antibodies was noted in the ATGAM with steroid taper group, with a mean of 357.5 and 180.5 MFI respectively.Conclusion Presumptive VBM cell populations that regulate immune responses are susceptible to T cell depleting and steroid therapies. The observed interference of standard induction therapies on the protective value of VBM highlights relationships between pharmacologic and biologic mechanisms of VCA graft protection. Henry Jackson Foundation, Department of Defense Award # W81XWH-13-2-0056. Astellas Pharma US, Inc.

B cells are capable of independently eliciting rapid reactivation of encephalitogenic CD4 T cells in a murine model of multiple sclerosis.

Recent success with B cell depletion therapies has revitalized efforts to understand the pathogenic role of B cells in Multiple Sclerosis (MS). Using the adoptive transfer system of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, we have previously shown that mice in which B cells are the only MHCII-expressing antigen presenting cell (APC) are susceptible to EAE. However, a reproducible delay in the day of onset of disease driven by exclusive B cell antigen presentation suggests that B cells require optimal conditions to function as APCs in EAE. In this study, we utilize an in vivo genetic system to conditionally and temporally regulate expression of MHCII to test the hypothesis that B cell APCs mediate attenuated and delayed neuroinflammatory T cell responses during EAE. Remarkably, induction of MHCII on B cells following the transfer of encephalitogenic CD4 T cells induced a rapid and robust form of EAE, while no change in the time to disease onset occurred for recipient mice in which MHCII is induced on a normal complement of APC subsets. Changes in CD4 T cell activation over time did not account for more rapid onset of EAE symptoms in this new B cell-mediated EAE model. Our system represents a novel model to study how the timing of pathogenic cognate interactions between lymphocytes facilitates the development of autoimmune attacks within the CNS.

B cells in multiple sclerosis.

Although it is becoming increasingly clear that B cells play important roles in multiple sclerosis (MS) pathogenesis, it is incompletely understood how they contribute. The purpose of this review is to provide an overview of the current knowledge about B cells in MS taking into account MS heterogeneity. The efficacy of B cell-depleting therapies has provided strong evidence for the involvement of these cells in MS pathogenesis. Although pathogenic antibodies were found in some MS patients, the observation that plasma cells and antibodies remain largely unchanged after B-cell depletion suggests that B cells are involved in MS by other mechanisms than antibody production. MS is an autoimmune disease, in which T and B cells play a crucial role. B cells can be involved in MS by different mechanisms such as presentation of antigens to T cells, transport of antigens from tissues to secondary lymphoid organs, secretion of pro-inflammatory or anti-inflammatory cytokines and in a subgroup of patients also production of pathogenic antibodies. As several B-cell/antibody-directed therapies are available, it is important to understand how these different functions of B cells and antibodies vary among patients in order to identify which could benefit best from the different therapies.

B cell depletion reduces T cell activation in pancreatic islets in a murine autoimmune diabetes model

Aims/hypothesisType 1 diabetes is a T cell-mediated autoimmune disease characterised by the destruction of beta cells in the islets of Langerhans, resulting in deficient insulin production. B cell depletion therapy has proved successful in preventing diabetes and restoring euglycaemia in animal models of diabetes, as well as in preserving beta cell function in clinical trials in the short term. We aimed to report a full characterisation of B cell kinetics post B cell depletion, with a focus on pancreatic islets.MethodsTransgenic NOD mice with a human CD20 transgene expressed on B cells were injected with an anti-CD20 depleting antibody. B cells were analysed using multivariable flow cytometry.ResultsThere was a 10 week delay in the onset of diabetes when comparing control and experimental groups, although the final difference in the diabetes incidence, following prolonged observation, was not statistically significant (p = 0.07). The co-stimulatory molecules CD80 and CD86 were reduced on stimulation of B cells during B cell depletion and repopulation. IL-10-producing regulatory B cells were not induced in repopulated B cells in the periphery, post anti-CD20 depletion. However, the early depletion of B cells had a marked effect on T cells in the local islet infiltrate. We demonstrated a lack of T cell activation, specifically with reduced CD44 expression and effector function, including IFN-γ production from both CD4+ and CD8+ T cells. These CD8+ T cells remained altered in the pancreatic islets long after B cell depletion and repopulation.Conclusions/interpretationOur findings suggest that B cell depletion can have an impact on T cell regulation, inducing a durable effect that is present long after repopulation. We suggest that this local effect of reducing autoimmune T cell activity contributes to delay in the onset of autoimmune diabetes.

Ofatumumab for B cell depletion in patients with systemic lupus erythematosus who are allergic to rituximab.

B cell depletion, most commonly with rituximab, is an evolving therapeutic approach in SLE. Infusion reactions after rituximab are common, and may prevent re-treatment in patients who previously demonstrated beneficial response. We have used ofatumumab, a fully humanized anti-CD20 mAb, as an alternative B cell-depleting agent in patients with SLE who are rituximab-intolerant due to severe infusion reactions. A single-centre retrospective case series of 16 patients were treated with ofatumumab for SLE between 2012 and 2015. Ofatumumab infusion was well tolerated in 14/16 patients, in whom the median age was 34 (range 19-55) and the median duration of SLE 9.2 years (0.6-28.5). The cohort was heavily pre-treated, with 50% having prior CYC exposure, and a median cumulative dose of prior rituximab 4 g (1-6). Twelve patients were treated for LN, one for extra-renal flare and one for remission maintenance. B cell-depletion was achieved in 12/14 patients, with comparable reconstitution kinetics to a previous cohort treated with rituximab at our centre, and was associated with improvements in serological markers of disease activity, including ANA, anti-dsDNA antibody and complement levels. Half of the patients with LN achieved renal remission by 6 months. Progressive disease that was unresponsive to augmented immunosuppression with CYC was seen in five patients. During long-term follow-up (median 28 months), five grade III infections were reported, and there were no malignancies or deaths. In this pre-treated cohort with long-standing SLE, ofatumumab was a well-tolerated, safe and effective alternative to rituximab for B cell-depletion therapy.

B cells in multiple sclerosis therapy-A comprehensive review.

For decades, B cells were ignored in multiple sclerosis (MS) pathogenesis, and the disease was always regarded as a T cell-mediated disorder. Recent evidence shows that there is an antigen-driven B-cell response in the central nervous system of patients with MS, and memory B cells/plasma cells are detectable in MS lesions. The striking efficacy of B cell-depleting therapies in reducing the inflammatory activity of the disease highlights that B cells may play more pathogenetic roles than expected. B cells express several unique characteristic markers on their surface, for example, CD19, CD20 molecules, that provide selective targets for monoclonal antibodies. In this respect, several B cell-targeted therapies emerged, including anti-CD20 antibodies (rituximab, ocrelizumab, and ofatumumab), anti-CD19 antibody (inebilizumab), and agents targeting the BAFF/APRIL signaling pathway (atacicept, belimumab, and LY2127399). In this review, we discuss, in detail, the immunobiology of B cells and their protective and destructive roles in MS pathogenesis. In the second part, we list the completed and ongoing clinical trials investigating the safety and efficacy of B cell-related monoclonal antibodies in MS.

The Immunologic Paradoxes of IgG4-Related Disease.

IgG4-related disease (IgG4-RD), which usually occurs in middle-aged and elderly men, is a newly recognized fibroinflammatory condition characterized by swelling and sclerosis of involved organs, increased IgG4-positive plasma cell infiltration in lesions, and elevated IgG4 concentration in serum. Despite growing interest in the research, the pathophysiological mechanism remains elusive. Most IgG4-RD patients respond well to steroid therapy initially, but recurrent and refractory cases are common, especially in advanced fibrotic stage. Recent studies have documented the heterogeneity of the B cell lineages, which suggests their multiple functions in IgG4-RD beyond IgG4 production, such as cytokine secretion, antigen presentation, autoantibody production, and modulation of T and B cell interactions. Thus, a critical balance exists between pathogenic and regulatory B subsets to prevent immunopathology. A prompt response to B cell depletion therapy reported in recent cases strongly suggests the imbalance within B cell lineages in IgG4-RD. A more precise understanding of the pathogenesis of IgG4-RD will open up new perspectives for therapeutic strategy. With a particular emphasis on the novel B cell-targeted therapeutic strategies, this review highlights the immunologic features of IgG4-RD and the possible roles of B cell lineages in the pathogenesis of IgG4-RD.

Pathogenic roles of B lymphocytes in systemic sclerosis

Systemic sclerosis (SSc) is a collagen disease characterized by autoimmunity and excessive extracellular matrix deposition in the skin and visceral organs. Although the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc remains unknown, SSc patients show a variety of abnormal immune activation including the production of disease-specific autoantibodies and cytokine production. Many recent studies have demonstrated that immune cells, including T cells, B cells, and macrophages, have a variety of immunological abnormalities in SSc. So far, several groups and our group reported that B cells play a critical role in systemic autoimmunity and disease expression through various functions, such as cytokine production, lymphoid organogenesis, and induction of other immune cell activation in addition to autoantibody production. Recent studies show that B cells from SSc patients demonstrate an up-regulated CD19 expression, a crucial regulator of B cell activation, which induces chronic hyper-reactivity of memory B cells and SSc-specific autoantibody production and also causes fibrosis of several organs. Furthermore, in SSc-model mice, such as tight-skin mice, bleomycin-induced SSc model mice, and DNA topoisomerase I and complete Freund’s adjuvant-induced SSc model mice, have abnormal B cell activation which associates with skin and lung fibrosis. Indeed, B cell depletion therapy using anti-CD20 Ab, Rituximab, is considered to one potential beneficial treatment for patients with SSc. However, there is no direct evidence which can explain how B cells, especially autoantigen-reactive B cells, progress or regulate disease manifestations of SSc. Collectively, B cell abnormalities in SSc is most likely participating in fibrosis and tissue damage of SSc. If the relationship between SSc-specific tissue damage and B cell abnormalities is revealed, these findings lead to novel effective therapy for SSc.

Recovery of hepatitis C specific T-cell responses after rituximab therapy in hepatitis C mixed cryoglobulinemic vasculitis.

Mixed cryoglobulinemic vasculitis is associated with monoclonal B cell expansion in patients with chronic hepatitis C (HCV) infection. B cell depletion therapy using rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from symptomatic disease. This study investigated whether B cell depletion therapy has an impact on activation of HCV-specific T cell phenotype and function. Nineteen patients with Hepatitis C mixed cryoglobulinemic vasculitis were treated with 4 cycles of rituximab (375 mg/m2 ) and variables were measured 6 months after therapy. Using flow cytometry and Enzyme-Linked Immunospot assay, the number of activated and tissue-like B cells and number of T cells expressing Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and multiple cytokines were measured before and after rituximab therapy. B cell depletion therapy is associated with a significant (P < 0.0001) decline in peripheral T cells with exhaustive phenotype, from pre-therapy to post-therapy-of rituximab (mean ± standard error): CD4+ (16.9 ± 0.9% to 8.9 ± 1.0%) and CD8+ (6.8 ± 0.6% to 3.0 ± 0.5%) T cells expressing PD-1 and CD4+ (11.0 ± 1.0% to 6.1 ± 0.8%) and CD8+ (12.7 ± 0.7% to 6.4 ± 0.4%) T cells expressing TIM-3. In addition, there was a significantly higher percentage of peripheral CD8+ T cells responding to HCV peptide stimulation in vitro secreting IFN-γ (4.55 ± 0.3 to 9.6 ± 1.0 IFN-γ/106 PBMCs, P < 0.0001), and more than one cytokine (1.3 ± 0.1% to 3.8 ± 0.2%, P < 0.0001) after therapy compared to pre-therapy. B cell depletion therapy results in recovery of T cell exhaustion and function in patients with HCV cryoglobulinemic vasculitis.

Mechanisms underlying B cell immune dysregulation and autoantibody production in MuSK myasthenia gravis.

Pathogenic autoantibodies to muscle-specific tyrosine kinase (MuSK) can be found in patients with myasthenia gravis (MG) who do not have detectable antibodies to the acetylcholine receptor. Although the autoantibody-mediated pathology is well understood, much remains to be learned about the cellular immunology that contributes to autoantibody production. To that end, our laboratory has investigated particular components associated with the cellular immunopathology of MuSK MG. First, we found that B cell tolerance defects contribute to the abnormal development of the naive repertoire, which indicates that dysregulation occurs before the production of autoantibodies. Second, both the naive and antigen-experienced memory B cell repertoire, which we examined through the application of high-throughput adaptive immune receptor repertoire sequencing, include abnormalities not found in healthy controls. This highlights a broad immune dysregulation. Third, using complementary approaches, including production of human monoclonal antibodies, we determined that circulating plasmablasts directly contribute to the production of MuSK-specific autoantibodies in patients experiencing relapse following B cell depletion therapy. These collective findings contribute to defining a mechanistic model that describes MuSK MG immunopathogenesis.

Effect of rituximab on a salivary gland ultrasound score in primary Sjögren’s syndrome: results of the TRACTISS randomised double-blind multicentre substudy

ObjectivesTo compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren’s syndrome (PSS) in a multicentre, multiobserver phase III trial substudy.MethodsSubjects consenting to SGUS were...

Transcriptional profiling of PBMCs unravels B cell mediated immunopathogenic imprints of HCV vasculitis.

B cell depletion therapy using rituximab has been shown to be effective in achieving remission in patients with HCV-mixed cryoglobulinemic (MC) vasculitis. Previously, we have demonstrated abnormalities in peripheral immune cells involving neutrophils, chemotaxis, and innate immune activation among patients with HCV-MC vasculitis when compared to HCV patients without vasculitis. In this study, we evaluated the effect of B cell depletion therapy on transcriptional profiles of peripheral blood mononuclear cells before and after riruximab therapy, in order to unravel the pathogenic mechanism involved in HCV-MC vasculitis induced by abnormal B cell proliferation. DNA microarray analysis was performed using RNA from PBMCs from seven patients with HCV-MC vasculitis and seven normal volunteers. DNA was hybridized to Affymetrix U133A chips. After normalization, differentially expressed gene list with treatment was generated using partitional clustering. RT-PCR, flow cytometry, and enzyme immunoassay (EIA) was used to validate DNA microarray findings. Differentially expressed genes included B cells and non-B cell genes. Validation of genes using purified cell subsets demonstrated distinct effect of B cell depletion therapy on non-B cells, such as monocytes, T cells, and NK cells. Notably, B lymphocyte stimulator (BLyS) levels were persistently elevated in patients who subsequently relapsed. In conclusion, pathogenesis of HCV-MC vasculitis is mediated by abnormal proliferation of B cells, driven by BLyS, leading to significant effects on non-B cells in mediating symptomatology. Future therapeutics using a combination approach of B cell depletion and proliferation may be desired to achieve long-term remission.

Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment

The clinical success of anti-CD20 monoclonal antibody (mAb)-mediated B cell depletion therapy has contributed to the understanding of B cells as major players in several autoimmune diseases. The first therapeutic anti-CD20 mAb, rituximab, is a murine–human chimera to which many patients develop antibodies and/or experience infusion-related reactions. A second generation of anti-CD20 mAbs has been designed to be more effective, better tolerated, and of lower immunogenicity. These include the humanized versions: ocrelizumab, obinutuzumab, and veltuzumab, and the fully human, ofatumumab. We conducted a literature search of relevant randomized clinical trials in the PubMed database and ongoing trials in Clinicaltrials.gov. Most of these trials have evaluated intravenous ocrelizumab or subcutaneous ofatumumab in rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus. Understanding how newer anti-CD20 mAbs compare with rituximab in terms of efficacy, safety, convenience, and cost is important for guiding future management of anti-CD20 mAb therapy in autoimmune diseases.

B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement.

The efficacy of B cell depletion therapies in diseases such as nephrotic syndrome and rheumatoid arthritis suggests a broader role in B cells in human disease than previously recognized. In some of these diseases, such as the minimal change disease subtype of nephrotic syndrome, pathogenic antibodies and immune complexes are not involved. We hypothesized that B cells, activated in the kidney, might produce cytokines capable of directly inducing cell injury and proteinuria. To directly test our hypothesis, we targeted a model antigen to the kidney glomerulus and showed that transfer of antigen-specific B cells could induce glomerular injury and proteinuria. This effect was mediated by IL-4, as transfer of IL-4-deficient B cells did not induce proteinuria. Overexpression of IL-4 in mice was sufficient to induce kidney injury and proteinuria and could be attenuated by JAK kinase inhibitors. Since IL-4 is a specific activator of STAT6, we analyzed kidney biopsies and demonstrated STAT6 activation in up to 1 of 3 of minimal change disease patients, suggesting IL-4 or IL-13 exposure in these patients. These data suggest that the role of B cells in nephrotic syndrome could be mediated by cytokines.

Dysregulation of T and B cells in myalgic encephalomyelitis/chronic fatigue syndrome

Background: Neurological manifestations such as cognitive impairment and sleep abnormalities are core symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that is a severely debilitating disease of unknown etiology. Various immune system abnormalities have been reported and recent studies revealed that two thirds of ME/CFS patients receiving B cell depletion therapy by rituximab had a clinical improvement. However, how the pathogenesis of ME/CFS is related to B cell is still unclear.