Cells In Autoimmune Diseases Research Articles

Preclinical characterization of MTX-101: a novel bispecific CD8 Treg modulator that restores CD8 Treg functions to suppress pathogenic T cells in autoimmune diseases.

Regulatory CD8 T cells (CD8 Treg) are responsible for the selective killing of self-reactive and pathogenic CD4 T cells. In autoimmune disease, CD8 Treg may accumulate in the peripheral blood but fail to control the expansion of pathogenic CD4 T cells that subsequently cause tissue destruction. This CD8 Treg dysfunction is due in part to the expression of inhibitory killer immunoglobulin-like receptors (KIR; KIR2DL isoforms [KIR2DL1, KIR2DL2, and KIR2DL3]); these molecules serve as autoimmune checkpoints and limit CD8 Treg activation. Here we describe the pre-clinical characterization of MTX-101, a bispecific antibody targeting inhibitory KIR and CD8. Using human peripheral blood mononuculear cells (PBMC) derived from healthy donors and autoimmune patients, humanized mouse models, and human derived tissue organoids, we evaluated the molecular mechanisms and functional effects of MTX-101. By binding to KIR, MTX-101 inhibited KIR signaling that can restore CD8 Treg ability to eliminate pathogenic CD4 T cells. MTX-101 bound and activated CD8 Treg in human peripheral blood mononuclear cells (PBMC), resulting in increased CD8 Treg cytolytic capacity, activation, and prevalence. Enhancing CD8 Treg function with MTX-101 reduced pathogenic CD4 T cell expansion and inflammation, without increasing pro-inflammatory cytokines or activating immune cells that express either target alone. MTX-101 reduced antigen induced epithelial cell death in disease affected tissues, including in tissue biopsies from individuals with autoimmune disease (i.e., celiac disease, Crohn's disease). The effects of MTX-101 were specific to autoreactive CD4 T cells and did not suppress responses to viral and bacterial antigens. In a human PBMC engrafted Graft versus Host Disease (GvHD) mouse model of acute inflammation, MTX-101 bound CD8 Treg and delayed onset of disease. MTX-101 induced dose dependent binding, increased prevalence and cytolytic capacity of CD8 Treg, as well as increased CD4 T cell death. MTX-101 selectively bound CD8 Treg without unwanted immune cell activation or increase of pro-inflammatory serum cytokines and exhibited an antibody-like half-life in pharmacokinetic and exploratory tolerability studies performed using IL-15 transgenic humanized mice with engrafted human lymphocytes, including CD8 Treg at physiologic ratios. Collectively, these data support the development of MTX-101 for the treatment of autoimmune diseases.

Potential and pitfalls of repurposing the CAR-T cell regimen for the treatment of autoimmune disease

Chimeric antigen receptors (CARs) are synthetic proteins designed to direct an immune response toward a specific target and have been used in immunotherapeutic applications through the adoptive transfer of T...

Hyaluronidase 2 induces pathogenicity in Th17 cells

Abstract Autoreactive Th17 cells express high levels of inflammatory cytokine IL-17A promoting the development and progression of autoimmune diseases. Previous studies show that differentiation of Th17 cells with IL-1 and IL-23 or TLR2 activation drives their aggressive proliferation, making them pathogenic to induce experimental autoimmune encephalomyelitis (EAE). We aim to study a previously undefined role of hyaluronic acid (HA) and its modulation in influencing inflammatory potential and pathogenicity of Th17 cells in autoimmune diseases. Our in vitro differentiation experiments with HA and its modifying enzymes show that a baseline level of HA is essential for the normal differentiation and proliferation of Th17 cells. The overexpression of hyaluronidase 2 (Hyal2) that cleaves HA in Th17 cells decreases IL-17A production but increases cell proliferation in vitro, and adoptive transfer of these cells is sufficient to induce EAE in mice. Furthermore, flow cytometric analysis of infiltrated CD4+ T cells in the CNS of EAE mice indicates lower levels of inflammatory cytokines. Our findings suggest that Hyal2 itself exhibits a level of pathogenicity challenging the prevailing paradigm that these cells can induce the disease only when producing higher levels of encephalitogenic cytokines. Future experiments will delve into the regulation and mechanisms underlying the impact of HA on pathogenic Th17 cells, potentially identifying target molecules to treat autoimmune disorders.

Mesenchymal stem cells in autoimmune disease: A systematic review and meta-analysis of pre-clinical studies

Mesenchymal Stem Cells (MSCs) are of interest in the clinic because of their immunomodulation capabilities, capacity to act upstream of inflammation, and ability to sense metabolic environments. In standard physiologic conditions, they play a role in maintaining the homeostasis of tissues and organs; however, there is evidence that they can contribute to some autoimmune diseases. Gaining a deeper understanding of the factors that transition MSCs from their physiological function to a pathological role in their native environment, and elucidating mechanisms that reduce their therapeutic relevance in regenerative medicine, is essential. We conducted a Systematic Review and Meta-Analysis of human MSCs in preclinical studies of autoimmune disease, evaluating 60 studies that included 845 patient samples and 571 control samples. MSCs from any tissue source were included, and the study was limited to four autoimmune diseases: multiple sclerosis, rheumatoid arthritis, systemic sclerosis, and lupus. We developed a novel Risk of Bias tool to determine study quality for in vitro studies. Using the International Society for Cell & Gene Therapy's criteria to define an MSC, most studies reported no difference in morphology, adhesion, cell surface markers, or differentiation into bone, fat, or cartilage when comparing control and autoimmune MSCs. However, there were reported differences in proliferation. Additionally, 308 biomolecules were differentially expressed, and the abilities to migrate, invade, and form capillaries were decreased. The findings from this study could help to explain the pathogenic mechanisms of autoimmune disease and potentially lead to improved MSC-based therapeutic applications.

THE ROLE OF VASPIN IN RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS

Background: Adipo(cyto)kines are substances derived from adipose tissue that influence central processes in the body like inflammation, in addition to their effect on metabolism. Adipocytokines are implicated in inflammatory pathways that affect different types of cells in autoimmune disorders. Many rheumatic disorders, such as rheumatoid arthritis and psoriatic arthritis, are classified as autoimmune diseases. A chronic inflammatory environment develops as a result of autoimmune reactions, affecting the entire body, notably adipose tissue. Vaspin, an adipocytokine, is a visceral serpin protease inhibitor produced by subcutaneous adipose tissue, skeletal muscle, skin and stomach. Objectives: The present review summarizes the structure, mechanism of action and role of vaspin in the pathophysiology and development of rheumatoid arthritis and osteoarthritis. Methodology: The data was collected through the electronic search of several scientific sources including, Science Direct, PubMed, and Google scholar. Results: Because of changes in systemic vaspin levels, its potential role as a biomarker in the diagnosis of rheumatic diseases has been suggested. Furthermore, vaspin induction by adipose tissue may produce a compensatory response to obesity and its inflammatory consequences. Recent studies have shown that vaspin levels are lower in osteoarthritis and higher in rheumatoid arthritis and psoriatic arthritis compared to healthy control. Moreover, vaspin elevation may assist in predicting who is at risk of developing rheumatoid arthritis. Conclusion: Vaspin inhibitors can attenuate the pathological processes of rheumatoid arthritis and improve the outcome of treatment when used in combination with other inflammatory mediator inhibitors.

Abstract 6726: Costimulatory IgM T-cell engagers with enhanced and durable cytotoxicity

Abstract T-cell engagers (TCEs) have established therapeutic effect in treatment of various cancers by harnessing the power of the immune system against tumors in a targeted manner. IgM-based TCEs may offer high avidity, specificity, and safety advantages over other modalities because of their multivalent architecture and unique positioning of the CD3 binding domain on the J-chain. We have built a costimulatory IgM TCE platform that engages both signal 1 and signal 2 on T-cells, with the goal of enabling their optimal activation and survival for more robust and durable cytotoxic activity. Multiple antigen targeting costimulatory IgM TCEs were generated and activity was evaluated both in vitro and in vivo to assess the role of CD28 co-stimulation. Costimulatory IgM TCEs engaged both CD3 and CD28 on the T-cell surface, enhancing in vitro cytotoxicity and T-cell activation. Levels of IL-2 increased significantly with dual signal engagement promoting proliferation and survival of T-cells. In long-term culture assays, costimulatory IgM TCEs promoted better T-cell proliferation and survival compared to IgM TCEs with only a CD3 binder, and was even more pronounced at low E:T ratios. In the absence of CD3 engagement, CD28 binding alone did not induce any T-cell activation, cytotoxicity, or cytokines. Activation of T-cells was also fully dependent on the presence of target cells, underscoring the safety profile of the platform. In Hu-PBMC xenograft tumor models, costimulatory IgM TCEs exhibited stronger in vivo anti-tumor activity compared to TCEs only engaging CD3. Tumor growth inhibition was maintained for longer after dosing was stopped with costimulatory IgM TCEs, indicating the durability of responses. Costimulatory IgM TCEs suppressed tumor growth in xenograft studies using cell lines that expressed both high and low target copy numbers suggestive of their broad utility against multiple tumor types. Enhanced in vivo anti-tumor activity of costimulatory IgM TCEs was associated with significant increases in intra-tumoral CD8/CD3+T-cells.Both peripheral and intra-tumoral T-cells exhibited enhanced anti-apoptotic and cytotoxic phenotypes indicative of the costimulatory activation. IgM-based costimulatory TCEs provide enhanced cytotoxicity through optimal T-cell activation and proliferation/survival. This dual engagement of T-cell activation signals, along with the high avidity target binding offered by IgM platform, could enable the creation of effective therapeutics targeting pathogenic cells in autoimmune diseases and solid tumors that will maintain activity even in conditions with low T-cell counts. Citation Format: Jie Xue, Keyu Li, Poonam Yakkundi, Palak Chadasama, Tina Mao, Zee Malik, Vidhya Rao, Madhura Joglekar, Kristene Mai, Gene Li, Deepal Pandya, Rodnie Rosete, Zhongde Ye, Leyla Tahrani, Jinqiu Wang, Nardeen Hanna, Elizabeth Perez, Yue Wang, Sachi Ahmed, Lusiana Widjaja, Paul Hinton, Krzysztof Bzymek, Bruce Keyt, Miho Oyasu, Liqin Liu, Angus Sinclair, Umesh S. Muchhal. Costimulatory IgM T-cell engagers with enhanced and durable cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6726.

B-Cell Receptor Repertoire: Recent Advances in Autoimmune Diseases.

In the field of contemporary medicine, autoimmune diseases (AIDs) are a prevalent and debilitating group of illnesses. However, they present extensive and profound challenges in terms of etiology, pathogenesis, and treatment. A major reason for this is the elusive pathophysiological mechanisms driving disease onset. Increasing evidence suggests the indispensable role of B cells in the pathogenesis of autoimmune diseases. Interestingly, B-cell receptor (BCR) repertoires in autoimmune diseases display a distinct skewing that can provide insights into disease pathogenesis. Over the past few years, advances in high-throughput sequencing have provided powerful tools for analyzing B-cell repertoire to understand the mechanisms during the period of B-cell immune response. In this paper, we have provided an overview of the mechanisms and analytical methods for generating BCR repertoire diversity and summarize the latest research progress on BCR repertoire in autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), multiple sclerosis (MS), and type 1 diabetes (T1D). Overall, B-cell repertoire analysis is a potent tool to understand the involvement of B cells in autoimmune diseases, facilitating the creation of innovative therapeutic strategies targeting specific B-cell clones or subsets.

CD19-targeting CAR T cells protect from ANCA-induced acute kidney injury

ObjectivesAnti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are life-threatening systemic autoimmune diseases manifesting in the kidneys as necrotizing crescentic glomerulonephritis (NCGN). ANCA antigens are myeloperoxidase (MPO) or proteinase 3. Current treatments...

T Cell Repertoire in Lupus: Autoreactive T Cells in Central and Peripheral Selection

Systemic lupus erythematosus (SLE) is an immune disorder characterized by the presence of T and B cells which drive a pathogenic autoimmune response. Autoreactive T effector cells naturally arise during the process of development in the thymus, but most are removed by several self-tolerance mechanisms. Self-antigen recognizing T cells emigrating from the thymus are normally prevented from causing cellular or tissue damage by peripheral tolerance mechanisms. While we understand much about how self-antigens are presented to T cells and the mechanisms to remove those T cells or convert them into regulatory T cells in thymus and peripheral lymphoid organs, we understand much less about the derivation of potentially pathogenic self-reactive T cells in autoimmune disease. It is not clear whether individuals with autoreactive T cell activation have an altered T cell receptor repertoire of naïve T cells that have matured to immunocompetence as effector cells or whether the pathogenic process involves altered activation of immunocompetent T cells in the periphery. There is increasing evidence that the autoantibodies that characterize SLE result from an interaction of B cells with self-reactive T cells. Here we summarize the evidence for autoreactive T cells in both lupus mouse models and in patients with SLE and discuss the evidence for either altered T cell selection or altered T cell activation in SLE, which has implications for both pathogenesis and treatment

The role of Siglec-G on B cells in autoimmune disease and leukemia

BackgroundB-cell activation is triggered by the B-cell receptor, but is also controlled by inhibitory receptors, which limit the BCR signaling. CD22 (Siglec-2) and Siglec-G are such inhibitory receptors expressed on B cells. CD22- or Siglec-G deficient mice show enhanced B cell activation. ObjectivesIt was the objective of our study to investigate the role of these inhibitory receptors in autoimmune disease and leukemia. ResultsAgeing Siglec-G deficient or CD22 x Siglec-G deficient mice develop an SLE-like autoimmune disease with autoantibodies and kidney nephritis. In a mouse model for chronic lymphocytic leukemia (CLL), Siglec-G deficient mice show an earlier and more severe disease. Author's conclusionsThese results show that Siglec-G and CD22 are both involved in preventing autoimmune diseases and leukemia delevopment and could therefore be attractive new targets.

Tfh and Tfr Cells in Autoimmune Diseases

An immunological condition known as autoimmunity causes the excessive generation of autoantibodies against self-antigen and is characterized by enhanced T-cell activation and extra-stimulated B-cells. The development of lymphatic follicle germinal centers (GCs), the maturation of B cells, and differentiation into plasma cells are all significantly aided by follicular helper T cells (Tfh). Tfh cells express the transcriptional regulator B cell lymphoma 6 (BCL-6), C-X-C chemokine receptor 5 (CXCR5), inducible T cell co-stimulator (ICOS), and programmed cell death protein 1 (PD-1). The production of interleukin (IL)-21 and low expression of the chemokine (C-C motif) receptor 7 (CCR7) define Tfh cells. Additionally, Tfh cells are a diverse population of cells with the potential to co-express minute quantities of transcription factors, such as T-box expressed in T cells (T-bet), GATA-binding protein 3 (GATA-3), and retinoic acid receptor-related orphan receptor (ROR-t). Tfh cells that also produce IL-21, IL-4, IL-17, and IFN-γ are referred to as Tfh1, Tfh2, and Tfh17 cells, respectively. The control of humoral immunity is carried out by follicular regulatory (Tfr) cells that express Forkhead box protein 3 (Foxp3). Tfr cells can, however, decrease T-B cell interactions through the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) while promoting B cell maturation through IL-10. In the context of autoimmunity, the role of Tfh and Tfr cells is still not fully understood. We intend to present the most recent data on the characteristics and function of Tfh and Tfr cells under conditions of autoimmunity in this review.

Content of myeloid-derived suppressor cells in autoimmune diseases in children

Myeloid-derived suppressor cells (MDSCs) play an important role in regulation of immune response. An increase in their number in adult patients with autoimmune diseases has been reported. G-MDSCs, M-MDSCs, and MDSCs(M-G-) at different stages of autoimmune disease may both activate T cell proliferation, leading to disease progression, or inhibit it, thus promoting Treg differentiation. Arginase-1 (Arg- 1) is an enzyme in MDSCs that reduces the concentration of arginine required for T lymphocyte proliferation. Our aim was to evaluate the content of MDSCs populations and functional activity of MDSCs in children with autoimmune diseases. 75 children with inflammatory bowel diseases (IBD), 60 children with multiple sclerosis (MS), 69 children with psoriasis (PS), 62 healthy age-matched children were included into the study. The content of MDSCs ((CD3, CD19, CD56, HLA-DR)-, CD11b+ and CD33+), subpopulations of MDSCs (M-MDSCs, G-MDSCs expressing CD14 and CD15), assessment of Arg-1 activity were performed by flow cytometry techniques. The content of MDSCs in patients with IBD, MS and PS was significantly higher than in the comparison group and depended on the state of exacerbation/remission. In exacerbation and remission of IBD, MS and PS, a significant increase of MDSCs was revealed when compared with healthy children; the highest values were found in children in exacerbation of MS (Me-3.5 (2.5-5.6) % MNC against Me-1.6 (0.9-2.5) % MNC, p 0.001). In patients with MS, the content of G-MDSC, M-MDSC was significantly higher, and MDSC(M-G-) was lower than in healthy children. An increase in absolute amounts of G-MDSCs was shown in MS exacerbation compared to the disease remission state (p = 0.022). For patients with IBD, a significant increase in percentage of MDSCs and M-MDSCs (p = 0.014 and p = 0.045, respectively) was obtained in exacerbation of the disease relative to remission state. In patients with IBD, MS, and PS, a significant increase in Arg-1 activity in MDSCs was found, with a decreased number of MDSCs in patients in remission compared to exacerbation phase of the disease. In children with autoimmune diseases, an increase in the MDSC populations was found. The activity of arginase-1 in MDSCs is increased in remission, along with a decrease in their numbers.

Role of stem cell-like memory T cells in autoimmune diseases.

Stem cell-like memory T (TSCM) cell is a memory T cell subset with characteristics of long life span, consistent self-renewing, and the multipotent capacity to reconstitute the memory and effector T cell subsets. TSCM cell is the least differentiated cell in the memory T lymphocyte system, endowed with the stem cell-like ability, and it is essential for maintaining functional immunity. In addition, owing to its robust potential for immune reconstitution, it is central player in many physiological and pathological human processes. TSCM cell plays an important role in the occurrence and development of various autoimmune diseases. The specific role of TSCM cell in autoimmune diseases may make it a potential target for the treatment of multiple autoimmune diseases, driving effective immune reconstitution in therapy.

Endoplasmic reticulum stress in T cell-mediated diseases.

T cells synthesize a large number of proteins during their development, activation, and differentiation. The build-up of misfolded and unfolded proteins in the endoplasmic reticulum, however, causes endoplasmic reticulum (ER) stress. Thus, T cells can maintain ER homeostasis via endoplasmic reticulum-associated degradation, unfolded protein response, and autophagy. In T cell-mediated diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, type 1 diabetes and vitiligo, ER stress caused by changes in the internal microenvironment can cause disease progression by affecting T cell homeostasis. This review discusses ER stress in T cell formation, activation, differentiation, and T cell-mediated illnesses, and may offer new perspectives on the involvement of T cells in autoimmune disorders and cancer.

Addressing the key issue: Antigen-specific targeting of B cells in autoimmune diseases

Autoimmune diseases are heterogeneous pathologies characterized by a breakdown of immunological tolerance to self, resulting in a chronic and aberrant immune response to self-antigens. The scope and extent of affected tissues can vary greatly per autoimmune disease and can involve multiple organs and tissue types. The pathogenesis of most autoimmune diseases remains unknown but it is widely accepted that a complex interplay between (autoreactive) B and T cells in the context of breached immunological tolerance drives autoimmune pathology. The importance of B cells in autoimmune disease is exemplified by the successful use of B cell targeting therapies in the clinic. For example, Rituximab, a depleting anti-CD20 antibody, has shown favorable results in reducing the signs and symptoms of multiple autoimmune diseases, including Rheumatoid Arthritis, Anti-Neutrophil Cytoplasmic Antibody associated vasculitis and Multiple Sclerosis. However, Rituximab depletes the entire B cell repertoire, leaving patients susceptible to (latent) infections. Therefore, multiple ways to target autoreactive cells in an antigen-specific manner are currently under investigation. In this review, we will lay out the current state of antigen-specific B cell inhibiting or depleting therapies in the context of autoimmune diseases.

Single-cell Spatial Phenotyping of Immune and Metabolic Landscapes in Systemic Lupus Erythematosus

Abstract Autoimmune diseases like systemic lupus erythematosus (SLE) affect the health of multiple organ systems including the central nervous system, skin, joints, and kidneys. The heterogeneity of clinical profiles observed with SLE reflects a complex dysregulation of cellular processes, including metabolism, apoptotic clearance, and inflammation. Diagnosis and treatment of SLE is thus challenging, and few new treatments have been approved over the past 60 years. In this study, we aimed to characterize the spatial immune and metabolic profiles of SLE at single cell resolution. To do so, we profiled a cohort of human FFPE SLE tissues with an ultrahigh-plex panel of >50 oligo-conjugated antibodies representing immune, apoptotic, metabolic and stress markers. Whole-slide, spatial phenotyping was performed using the PhenoCycler ®-Fusion system, followed by deep bioinformatic analyses to determine the cellular phenotypes, spatial neighborhoods, and metabolic determinants of SLE. By combining immune cell lineage information with expression of key proteins involved in glycolysis, amino acid metabolism, lipid metabolism, hypoxia, oxidative stress, and apoptosis, we elucidated the functional dysregulation in key immune subsystems that may contribute to development of autoimmunity and inflammation associated with SLE. Spatial phenotyping also revealed a high degree of inter- and intra-sample heterogeneity, confirming the complexity of the SLE clinical profile. Collectively, our data amount to new insights into metabolic reprogramming of immune cells in autoimmune diseases and may aid in the identification of novel therapeutic biomarkers within the tissue microenvironment of SLE patients.

T follicular helper cells and T follicular regulatory cells in autoimmune diseases.

T follicular helper (Tfh) cells are heterogeneous and mainly characterized by expressing surface markers CXCR5, ICOS, and PD-1; cytokine IL-21; and transcription factor Bcl6. They are crucial for B-cell differentiation into long-lived plasma cells and high-affinity antibody production. T follicular regulatory (Tfr) cells were described to express markers of conventional T regulatory (Treg) cells and Tfh cells and were able to suppress Tfh-cell and B-cell responses. Evidence has revealed that the dysregulation of Tfh and Tfr cells is positively associated with the pathogenic processes of autoimmune diseases. Herein, we briefly introduce the phenotype, differentiation, and function of Tfh and Tfr cells, and review their potential roles in autoimmune diseases. In addition, we discuss perspectives to develop novel therapies targeting Tfh/Tfr balance.

A Comprehensive Review on T Cells, B Cells, Natural Killer Cells, and Dendritic Cells Exhaustion: From Main Concepts to Clinical Use

During chronic infections, a distinct physiological condition named “exhaustion” arises that is associated with the dysfunctionality in immune cells and their eventual removal from the environment, which evidently help the progress of infection or tumors in human or animal bodies. This state of immune cells could be under the control of different elements such as the antigen load, help from inhibitory cells, lack of costimulatory signals and etc. Exhaustion that has been found in different immune system cells, is usually accompanied by impaired effector function and proliferation of immune cells, poor memory recall, upregulation of inhibitory molecules, compromised metabolism and altered transcription program, and is considered a reversible process, unlike other physiological states like anergy or senescence, organized through the blockage of several factors. Although the emergence of these cells in viral infections and cancer is an undesirable event, the importance of the presence of exhausted cells in autoimmune diseases and organ transplantation is highlighted as a positive change. In this review, we aimed to determine the occurrence of this process in different immune cells, the characteristics obtained by these cells, effective and primitive factors on exhaustion, metabolic and transcriptional cell changes, and the use of these cells in autoimmune diseases and organ transplantation.

T peripheral helper cells in autoimmune diseases: What do we know?

The interactions between T cells and B cells are essential for antibody responses and the development of autoimmune diseases. Recently, a distinct subset of T cells capable of helping B cells was established in synovial fluid, and they were termed peripheral helper T (Tph) cells. PD-1hiCXCR5-CD4+ Tph cells express high levels of CXCL13, which drives the formation of lymphoid aggregates and tertiary lymphoid structures, ultimately facilitating the local production of pathogenic autoantibodies. Tph and T follicular helper cells share some key features but can be distinguished by their surface markers, transcriptional regulation, and migration capability. We summarize recent findings on Tph cells in this review and provide a perspective on their potential roles in a range of autoimmune diseases. More clinical and in-depth mechanistic investigations of Tph cells may help to improve the understanding of pathogenesis and further provide novel therapeutic targets in autoimmune diseases.

Development of a novel, highly sensitive assay for quantification of minimal residual B cells in autoimmune disease and comparison to traditional methods across B-cell–depleting agents

Targeted B-cell depletion is a useful therapy for many diseases, including autoimmune disorders and certain cancers. We developed a sensitive blood B-cell depletion assay, MRB 1.1, compared its performance with the T-cell/B-cell/NK-cell (TBNK) assay, and assessed B-cell depletion with different therapies. The empirically defined lower limit of quantification (LLOQ) for CD19+ cells in the TBNK assay was 10 cells/μL, and 0.441 cells/μL for the MRB 1.1 assay. The TBNK LLOQ was used to compare differences between B-cell depletion in similar lupus nephritis patient populations who received rituximab (LUNAR), ocrelizumab (BELONG), or obinutuzumab (NOBILITY). After 4 weeks, 10% of patients treated with rituximab retained detectable B cells vs 1.8% with ocrelizumab and 1.7% for obinutuzumab; at 24 weeks 93% of patients who received obinutuzumab remained below LLOQ vs 63% for rituximab. More-sensitive measurements of B cells may reveal differences in potency among anti-CD20 agents, which may associate with clinical outcomes.