Cell Depletion Therapy Research Articles

COVID-19 clearance among patients with cancer during the Delta and Omicron waves.

42 Background: COVID-19 presents a particular challenge in oncology, as in-person visits and treatments can be delayed during infection and patients are at risk for prolonged viral shedding. Our center uses two consecutive negative PCR tests for patients to return to clinic. As vaccination rates increase, we questioned the need for this strategy vs a time-based clearance approach. Methods: We identified cancer patients who tested positive for COVID-19 from 10/1/2021 to 3/31/2022 at a single tertiary care center and performed chart review under an IRB-approved protocol. Subgroups were compared using the Welch’s t-test and Welch’s ANOVA for 2 or > 2 groups, respectively. Results: 169 patients were identified. 153 had documented clearance defined as two consecutive negative PCR tests. The mean clearance time was 35.7 days (95% CI 32.3-39.0). There was a trend toward longer clearance time in patients with hematologic vs solid tumors (39.6 vs 33.2, p =.06) and a significant increase in patients treated with B cell depletion (58.0) vs chemo/targeted therapy (35.7, p =.01) or immunotherapy (29.0, p =.004). No significant difference was found by vaccination status or between the Delta and Omicron waves. If defined as one negative test, mean clearance time was 25.9 days (95% CI 23.6-28.1), and there was a significant difference in patients with hematologic vs solid tumors and in those treated with B cell depletion vs other therapies. However, 16.0% (27/169) of patients had a subsequent positive test after a first negative result, with increased incidence in patients with hematologic malignancy (26.2%, 16/61) and stem cell/adoptive cell transplant (46.2%, 6/13). Conclusions: COVID-19 is a significant barrier to oncologic care, and clearance times remain longer than reported for the general population. In this single center study, clearance time was > 1 month and further increased in patients with hematologic malignancy or on B cell depleting therapy. While adjusting clearance criteria to a single negative test or specific timeframe may be an attractive option to reduce delays, a large proportion of patients may have further positive PCR testing.[Table: see text]

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.

Antibody-mediated cell depletion therapies in multiple sclerosis.

Development of disease-modifying therapies including monoclonal antibody (mAb)-based therapeutics for the treatment of multiple sclerosis (MS) has been extremely successful over the past decades. Most of the mAb-based therapies approved for MS deplete immune cell subsets and act through activation of cellular Fc-gamma receptors expressed by cytotoxic lymphocytes and phagocytes, resulting in antibody-dependent cellular cytotoxicity or by initiation of complement-mediated cytotoxicity. The therapeutic goal is to eliminate pathogenic immune cell components and to potentially foster the reconstitution of a new and healthy immune system. Ab-mediated immune cell depletion therapies include the CD52-targeting mAb alemtuzumab, CD20-specific therapeutics, and new Ab-based treatments which are currently being developed and tested in clinical trials. Here, we review recent developments in effector mechanisms and clinical applications of Ab-based cell depletion therapies, compare their immunological and clinical effects with the prototypic immune reconstitution treatment strategy, autologous hematopoietic stem cell transplantation, and discuss their potential to restore immunological tolerance and to achieve durable remission in people with MS.

Unmet Needs and Treatment of Relapsing-Remitting Multiple Sclerosis in Saudi Arabia: Focus on the Role of Ofatumumab.

Treatment-pattern data suggest that some patients with multiple sclerosis (MS) in the Kingdom of Saudi Arabia (KSA) may not be receiving optimal treatment. A virtual meeting of ten expert Saudi neurologists, held on October 23, 2020, discussed unmet needs in relapsing–remitting MS (RRMS), and the role of ofatumumab as a suitable treatment in the KSA. Multiple unmet needs were identified: poor quality of life, with high rates of depression and anxiety; a negative impact of MS on work ability; treatment choices that may compromise efficacy for safety or vice versa; inconvenient or complex dosage regimens; and limited access to patient education and support. Early use of highly effective disease-modifying treatments (DMTs) results in better patient outcomes than starting with less effective treatments and downstream escalation, but this strategy may be underutilized in the KSA. B cells are important in MS pathogenesis, and treatments targeting these may improve clinical outcomes. Ofatumumab differs from other B cell–depleting therapies, being a fully human monoclonal antibody that binds to CD20 at a completely separate site from the epitope bound by ocrelizumab, and being administered by subcutaneous injection. When compared with teriflunomide in two randomized, phase 3 clinical trials in patients with RRMS, ofatumumab was associated with significant reductions in annualized relapse rates, rates of confirmed disability worsening, and active lesions on magnetic resonance imaging. The incidence of adverse events, including serious infections, was similar with the two treatments. Ofatumumab is a valuable first- or second-line treatment option for RRMS in the KSA, particularly for patients who would benefit from highly effective DMTs early in the disease course, and for those who prefer the convenience of self-injection. Future research will clarify the position of ofatumumab in RRMS treatment, and comparative cost data may support the broad inclusion of ofatumumab in formularies across the KSA.

CD8+ T cells: An ineffective armor against prolonged COVID-19 in cancer patients

In a diverse cohort of cancer patients, Lyudovyk et al.1 show that persistent COVID-19 infection is associated with weaker humoral responses and increased CD8+ T cell responses that are ineffective in clearing virus, particularly in patients receiving B cell-depleting therapies.

Predictors of seroconversion after coronavirus disease 2019 vaccination

BackgroundVaccine nonresponse during the coronavirus disease 2019 (COVID-19) pandemic has considerable individual and societal risks. ObjectiveTo investigate the clinical characteristics of patients with lack of seroconversion after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MethodsDemographic and clinical data were collected from 805 patients who had validated antibody assays against the SARS-CoV-2 spike protein at least 14 days after completion of their COVID-19 vaccination. Clinical characteristics from patients with a negative (< 0.4 U/mL) antibody response were assessed and summarized. ResultsA total of 622 (77.3%) patients attained seroconversion as defined by a titer of greater than or equal to 0.4 U/mL, whereas 183 out of 805 (22.7%) patients exhibited no seroconversion after vaccination against SARS-CoV-2. Univariately, older age (P = .02) and male sex were associated with a lower likelihood of seroconversion (P = .003). Therapy with immunosuppressive drugs was noted in 93 (50.8%) of seronegative patients with most (n = 83/93, 89.2%) receiving ongoing immunosuppressive therapy at the time of vaccination. Among the 134 (73.2%) seronegative patients with immunodeficiency, 110 (82.1%) had primary immunodeficiency. Cancer (n = 128, 69.9%), B cell depletion therapy (n = 90/115, 78.3%), and immunosuppressant steroid use (n = 71/93 on immunosuppressants, 76.3%) were the other common characteristics among the vaccine nonresponders. More importantly, our study did not evaluate the actual efficacy of COVID-19 vaccination. ConclusionVaccine responses vary by age and sex, with men showing lower rates of seroconversion as compared with women. Primary immunodeficiency along with active malignancy and ongoing immunosuppression with steroids or B cell depletion therapy appeared to be the most common characteristics for those with a lack of vaccine seroconversion after COVID-19 vaccination.

Clinical Management of Patients With B-Cell Depletion Agents to Treat or Prevent Prolonged and Severe SARS-COV-2 Infection: Defining a Treatment Pathway.

IntroductionImmunocompromised patients with B-cell depletion agents are at risk for persistence and/or severe SARS-COV-2 infection. We describe a case series of 21 COVID-19 patients under B cell depletion therapy, mostly treated with a combined therapy based on intravenous remdesevir (RDV) and steroid associated with SARS-CoV-2 monoclonal antibodies against Spike glycoprotein and/or hyper-immune convalescent plasma.MethodsThis is a single-center longitudinal study. We retrospectively enrolled a total number of 21 B-cell depleted consecutive hospitalized patients with COVID-19 at the Lazzaro Spallanzani National Institute for Infectious Diseases, Rome, Italy, from November 2020 to December 2021. Demographic characteristics, medical history, clinical presentation, treatment, adverse drug reactions, and clinical and virological outcome were collected for all patients. In a subgroup, we explore immune T cells activation, T cells specific anti-SARS-COV-2 response, and neutralizing antibodies.ResultsTwenty-one inpatients with B-cell depletion and SARS-COV-2 infection were enrolled. A median of 1 B cells/mm3 was detected. Eighteen patients presented hypogammaglobulinemia. All patients presented interstitial pneumonia treated with intravenous RDV and steroids. Sixteen patients were treated with monoclonal antibodies against SARS-CoV-2 Spike protein, four patients were treated with SARS-CoV-2 hyper-immune convalescent plasma infusion, and three patients received both treatments. A variable kinetic of T cell activation returning to normal levels at Day 30 after immunotherapy infusion was observed. All treated patients recovered.ConclusionIn COVID-19 immunosuppressed subjects, it is mandatory to establish a prompt, effective, and combined multi-target therapy including oxygen, antiviral, steroid, and antibody-based therapeutics, tailored to the patient’s clinical needs.

Transitioning From S1P Receptor Modulators to B Cell-Depleting Therapies in Multiple Sclerosis: Clinical, Radiographic, and Laboratory Data.

Background and ObjectivesPatients with multiple sclerosis (MS) transition from oral sphingosine-1-receptor (S1P) modulators to anti-CD20 therapies for several circumstances. Optimal timing of this transition is uncertain, given competing concerns of rebound disease activity and ensuring immune reconstitution. The objective of this study was to evaluate the relationship between inflammatory activity and the transition period from fingolimod to anti-CD20 therapies in a real-world MS cohort.MethodsMedical records were reviewed for all patients at our center transitioning from fingolimod to rituximab or ocrelizumab between 2010 and October 2020. Time periods reviewed were the following: before fingolimod discontinuation, interval between fingolimod and anti-CD20 treatments, and after the first anti-CD20 infusion. The primary outcome was clinical relapses; MRI activity, time to absolute lymphocyte count (ALC) recovery, and infections were secondary. Clinical and demographic factors significant in univariable analyses were included in multivariable analyses.ResultsTransition data were available for 108 patients (68.5% women, 68.5% relapsing-remitting MS, mean age 44.6 years). The median (interquartile range) interval between fingolimod and anti-CD20 therapy was 28 (1–115.2) days. Six of 51 patients (11.8%) with intervals >1 month and 0/57 patients with shorter intervals experienced a relapse (MRI confirmed) within 6 months of fingolimod discontinuation. In the year following anti-CD20 initiation, 4/108 patients (3.7%) experienced a relapse (median 214.5 days after infusion). An additional 7% of those undergoing contrast-enhanced MRIs developed Gd+ lesions. ALC normalized following treatment switch in 89/92; the interval between treatments was unrelated to ALC recovery or infection.DiscussionDelaying anti-CD20 start to monitor ALC after S1P modulator discontinuation may not be necessary and could increase rebound risk. ALC monitoring could instead occur after a rapid switch to anti-CD20 treatment.

Impact of B-cell depletion therapy on respiratory viral infection

Abstract B cell depletion therapy with anti-CD20 antibodies ameliorates autoimmune diseases such as multiple sclerosis, rheumatoid arthritis as well as haematological malignancies. Anti-CD20 antibodies deplete pre-B cells, mature B cells and malignant B cells but do not reduce plasma cells. Recently, studies have associated anti-CD20 therapy with severe manifestation of SARS-CoV2 infection. However, the mechanism of this adverse effect of anti-CD20 therapy remains unclear. This study was undertaken to investigate the effect of anti-CD20 therapy on respiratory viral infection. C57BL/6 mice were treated with anti-CD20 antibody to induce B cell depletion and then were infected intratracheally with H1N1 Influenza A mouse-adapted A/Puerto Rico/8/1934 virus (IAV). Our results show that B cell depletion therapy worsens lung infection with more severe and prolonged weight loss. Higher viral titers were found in the lungs of anti-CD20 treated mice, indicating impairment in virus clearance. Flow cytometry analysis showed no difference between groups in CD4+ and CD8+ PR8 antigen specific T cells on day 9 post-infection. However, higher numbers of inflammatory, SiglecF+ neutrophils were found in B cell depleted mice. In summary, our data show that anti-CD20 therapy exacerbates the viral pathology in respiratory lung infections. We further have identified that B cell depletion therapy affects viral clearance and inflammatory neutrophils but has no effect on T cell numbers in the lung at the peak of infection. Our future studies will identify the mechanisms driving the severe pathology in influenza infection with B cell depletion. Supported by grants from NIH (R01AI137047 and R01EY027346) A grant awarded to Dr. Kovatz and Dr Axtell from the Presbyterian Health Foundation

B cell-mediated antigen presentation is required to induce functional pathogenicity of CD4 T cells in a proteolipid protein mouse model of multiple sclerosis.

Abstract Given the success of B cell depletion therapy in multiple sclerosis (MS), deeper understanding of pathogenic B cells will be key in developing novel treatments. Notably, B cell depletion therapy leaves plasma cells and immunoglobulin levels largely intact, indicating that B cells provide pathogenic functions beyond antibodies. To better understand this, we recently developed a novel B cell-dependent, antibody-independent experimental autoimmune encephalomyelitis (EAE) mouse model of MS featuring immunoreactivity to the extracellular domains of myelin proteolipid protein (PLPECD). In contrast to a B cell-independent EAE model, we demonstrate here that PLPECD induced EAE in WT but not B cell-depleted mice, and that established disease was ameliorated by B cell depletion. We tested antigen presentation by B cells through mixed bone marrow chimeras and demonstrate that mice in which MHC II deficiency is restricted to B cells alone failed to exhibit EAE compared to MHC II sufficient mice. Given that HLA class II is the largest molecular link to MS incidence and CD4 T cells are causative in EAE, we tested B cells’ influence on CD4 T cells. In the absence of B cells, we observed not only lower activation and proliferation of CD4 T cells, but also noted a lower proinflammatory functional profile amongst the activated cells. Further, adoptively transferred CD4 T cells derived from B cell-depleted donors induced significantly less EAE compared to those from B cell-sufficient donors. These results demonstrate that antigen presentation by B cells plays a critical role in the activation, proliferation, function and pathogenicity of autoreactive CD4 T cells in demyelinating disease. Supported by grants from NIAID/NIH AI156123 and US Veterans Affairs I01BX003677.

Immunosuppression and SARS-CoV-2 breakthrough infections.

Within a year of the introduction of vaccines against SARS-CoV-2, global research efforts had identified that subsets of patients with immune-mediated inflammatory diseases have suboptimal humoral responses after vaccination. Specifically, B cell-depleting therapies, mycophenolate mofetil, and glucocorticoids were found to confer the greatest risk of poor humoral immunity,1,2 suggesting that patients on these therapies will have the highest risk and severity of breakthrough infections.

Effectiveness of COVID-19 vaccination in immune-mediated inflammatory diseases.

The rapid development of safe and effective COVID-19 vaccines was a hallmark achievement in the pandemic. However, patients with immune-mediated inflammatory diseases were excluded from vaccine clinical trials and might be vulnerable to SARS-CoV-2 breakthrough infection due to immunosuppression and altered immunity.1,2 Indeed, studies showed lower humoral responses after COVID-19 vaccination in these patients than in healthy controls.3,4 Although most patients who are immunosuppressed had only a slightly reduced humoral response after COVID-19 vaccination, some medications, such as B cell-depleting therapies, are associated with severely reduced response.

B Cells on the Stage of Inflammation in Juvenile Idiopathic Arthritis: Leading or Supporting Actors in Disease Pathogenesis?

Juvenile idiopathic arthritis (JIA) is a term that collectively refers to a group of chronic childhood arthritides, which together constitute the most common rheumatic condition in children. The International League of Associations for Rheumatology (ILAR) criteria define seven categories of JIA: oligoarticular, polyarticular rheumatoid factor (RF) negative (RF-), polyarticular RF positive (RF+), systemic, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. The ILAR classification includes persistent and extended oligoarthritis as subcategories of oligoarticular JIA, but not as distinct categories. JIA is characterized by a chronic inflammatory process affecting the synovia that begins before the age of 16 and persists at least 6 weeks. If not treated, JIA can cause significant disability and loss of quality of life. Treatment of JIA is adjusted according to the severity of the disease as combinations of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and/ or biological disease modifying anti-rheumatic drugs (DMARDs). Although the disease etiology is unknown, disturbances in innate and adaptive immune responses have been implicated in JIA development. B cells may have important roles in JIA pathogenesis through autoantibody production, antigen presentation, cytokine release and/ or T cell activation. The study of B cells has not been extensively explored in JIA, but evidence from the literature suggests that B cells might have indeed a relevant role in JIA pathophysiology. The detection of autoantibodies such as antinuclear antibodies (ANA), RF and anti-citrullinated protein antibodies (ACPA) in JIA patients supports a breakdown in B cell tolerance. Furthermore, alterations in B cell subpopulations have been documented in peripheral blood and synovial fluid from JIA patients. In fact, altered B cell homeostasis, B cell differentiation and B cell hyperactivity have been described in JIA. Of note, B cell depletion therapy with rituximab has been shown to be an effective and well-tolerated treatment in children with JIA, which further supports B cell intervention in disease development.

SARS-CoV-2 breakthrough infections among vaccinated individuals with rheumatic disease: results from the COVID-19 Global Rheumatology Alliance provider registry

ObjectiveWhile COVID-19 vaccination prevents severe infections, poor immunogenicity in immunocompromised people threatens vaccine effectiveness. We analysed the clinical characteristics of patients with rheumatic disease who developed breakthrough COVID-19 after vaccination...

Treating Patients With ANCA-Associated Vasculitis and Very Severe Renal Injury With an Intensified B Cell Depletion Therapy: Comparison With a Control Cohort Receiving a Conventional Therapy.

Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown to be an effective induction treatment for small-vessel vasculitides associated with antineutrophil cytoplasm antibodies (AAV) in both newly diagnosed and relapsing patients. However, the role of RTX in the management of the most severe cases of AAV remains to be fully elucidated. The aim of this study was to assess both safety and efficacy of an intensified B-cell depletion therapy (IBCDT) protocol, including RTX, cyclophosphamide (CYC), and methylprednisolone pulses without additional maintenance immunosuppressive therapy in a cohort of 15 AAV patients with the most severe features of AVV renal involvement (as <15 ml/min GFR and histological findings of paucimmune necrotizing glomerulonephritis with more than 50% crescents of non-sclerotic glomeruli at the renal biopsy). Results of the IBCDT regimen have been compared to those obtained in a control cohort of 10 patients with AAV treated with a conventional therapy regimen based on oral CYC and steroids followed by a prolonged maintenance therapy with azathioprine (AZA). Plasma exchange was equally employed in the study and the control group. Complete clinical remission (BVAS 0) was observed at 6 months in 14 of 15 patients treated with IBCDT (93%). All cases who achieved a complete clinical remission experienced a depletion of peripheral blood B cells at the end of therapy. Of the 10 dialysis dependent patients at onset, 6 subjects (60%) experienced a functional recovery allowing the suspension of dialysis treatment. When compared to the control group, no statistically significant difference was observed in patients treated with IBCDT in terms of overall survival, 6-month therapeutic response rate, and 6-, and 12-month functional renal recovery. The cumulative total dose of CYC in the case group was on average 1 g/patient while in the control group on average 8.5 g/patient (p = 0.00008). Despite the retrospective design and relative limited sample size, IBCDT appeared to be safe and had the same efficacy profile when compared to the conventional therapy with CYC plus AZA in the management of the most severe patients with AAV. Additionally, this avoided the need of prolonged maintenance therapy for long, and limited the exposure to CYC with consequent reduced toxicity and drug-related side effect rates.

Sulfasalazine: a risk factor for severe COVID-19?

Sulfasalazine, a disease-modifying antirheumatic drug (DMARD), has a well established role in the treatment of patients with rheumatoid arthritis, spondyloarthritis, and inflammatory bowel disease—diseases in which therapeutic benefit may primarily derive from the drug's inhibitory effect on tumour necrosis factor (TNF) and prostaglandin synthesis. In view of this mechanism, it is of note that several independent studies identified baseline treatment with sulfasalazine or mesalamine as a major risk factor (second only to rituximab and other B cell-depleting therapies) for severe COVID-19 in patients with autoimmune and rheumatic diseases.

Response to Vaccines in Patients with Immune-Mediated Inflammatory Diseases: A Narrative Review.

Patients with immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis and inflammatory bowel disease, are at increased risk of infection. International guidelines recommend vaccination to limit this risk of infection, although live attenuated vaccines are contraindicated once immunosuppressive therapy has begun. Biologic therapies used to treat IMIDs target the immune system to stop chronic pathogenic process but may also attenuate the protective immune response to vaccines. Here, we review the current knowledge regarding vaccine responses in IMID patients receiving treatment with biologic therapies, with a focus on the interleukin (IL)-12/23 inhibitors. B cell-depleting therapies, such as rituximab, strongly impair vaccines immunogenicity, and tumor necrosis factor (TNF) inhibitors and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) fusion protein abatacept are also associated with attenuated antibody responses, which are further diminished in patients taking concomitant immunosuppressants. On the other hand, integrin, IL-6, IL-12/23, IL-17, and B-cell activating factor (BAFF) inhibitors do not appear to affect the immune response to several vaccines evaluated. Importantly, treatment with biologic therapies in IMID patients is not associated with an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or developing severe disease. However, the efficacy of SARS-CoV-2 vaccines on IMID patients may be reduced compared with healthy individuals. The impact of biologic therapies on the response to SARS-CoV-2 vaccines seems to replicate what has been described for other vaccines. SARS-CoV-2 vaccination appears to be safe and well tolerated in IMID patients. Attenuated but, in general, still protective responses to SARS-CoV-2 vaccination in the context of certain therapies warrant current recommendations for a third primary dose in IMID patients treated with immunosuppressive drugs.

Targeted Immunotherapy for Autoimmune Disease.

In the past few decades, biological drugs and small molecule inhibitors targeting inflammatory cytokines, immune cells, and intracellular kinases have become the standard-of-care to treat autoimmune diseases. Inhibition of TNF, IL-6, IL-17, and IL-23 has revolutionized the treatment of autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. B cell depletion therapy using anti-CD20 mAbs has shown promising results in patients with neuroinflammatory diseases, and inhibition of B cell survival factors is approved for treatment of systemic lupus erythematosus. Targeting co-stimulatory molecules expressed on Ag-presenting cells and T cells is also expected to have therapeutic potential in autoimmune diseases by modulating T cell function. Recently, small molecule kinase inhibitors targeting the JAK family, which is responsible for signal transduction from multiple receptors, have garnered great interest in the field of autoimmune and hematologic diseases. However, there are still unmet medical needs in terms of therapeutic efficacy and safety profiles. Emerging therapies aim to induce immune tolerance without compromising immune function, using advanced molecular engineering techniques.

Functional impairment of CD19+CD24hiCD38hi B cells in neuromyelitis optica spectrum disorder is restored by B cell depletion therapy.

The role of B cells in immune response regulation is context dependent. In some cases, bystander B cell activation leads to interleukin-10 (IL-10) production, suppressing inappropriate immune responses. However, the role of B cells in regulation of autoimmune diseases, including neuromyelitis optica spectrum disorder (NMOSD), is incompletely understood. NMOSD is an autoimmune disease of the central nervous system with a relapsing-remitting course in which acute attacks lead to severe disability. B cell depletion therapy (BCDT) has shown clinical efficacy in NMOSD by eliminating pathogenic B cells; however, its effect on regulatory B (Breg) cells remains elusive. Here, we evaluated the B cell subsets, Breg cell function, and the effect of BCDT on these cells in patients with NMOSD. We showed that CD24hiCD38hi B cells from patients with NMOSD did not inhibit CD4+ T cell production of interferon-γ (IFN-γ), IL-17, or IL-21 and failed to inhibit follicular helper T cell expansion or induce regulatory T cells. This cellular impairment in patients with NMOSD can be explained by deficient Breg cell numbers and Breg cell–intrinsic deficits in IL-10 production specifically in response to B cell bystander activation. Using cross-sectional and 3-year longitudinal studies, we showed that BCDT treatment restored the numerical deficiency of Breg cells. Moreover, the post-BCDT repopulated CD24hiCD38hi B cells restored IL-10 production and suppressed IFN-γ and IL-17 production by CD4+ T cells. Our results suggest that both numerical deficiency of CD24hiCD38hi B cells and their impaired regulatory function contribute to NMOSD pathophysiology, and function is restored after BCDT.

B cells in central nervous system disease: diversity, locations and pathophysiology.

B cells represent a relatively minor cell population within both the healthy and diseased central nervous system (CNS), yet they can have profound effects. This is emphasized in multiple sclerosis, in which B cell-depleting therapies are arguably the most efficacious treatment for the condition. In this Review, we discuss how B cells enter and persist in the CNS and how, in many neurological conditions, B cells concentrate within CNS barriers but are rarely found in the parenchyma. We highlight how B cells can contribute to CNS pathology through antibody secretion, antigen presentation and secretion of neurotoxic molecules, using examples from CNS tumours, CNS infections and autoimmune conditions such as neuromyelitis optica and, in particular, multiple sclerosis. Overall, understanding common and divergent principles of B cell accumulation and their effects within the CNS could offer new insights into treating these devastating neurological conditions.