Tocilizumab and rituximab for systemic sclerosis interstitial lung disease: a real-world cohort analysis.

Objectives: Systemic sclerosis (SSc)-interstitial lung disease (ILD) is one of the leading causes of mortality in SSc. Data from randomised controlled trials (RCTs) supports rituximab and tocilizumab monotherapy but there is limited data regarding their use for those who fail standard immunomodulatory therapies.

Methods: SSc patients treated with rituximab or tocilizumab were retrospectively identified in a single centre cohort.

Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance.

The mechanisms of endotoxin tolerance (ET), which down-regulate inflammation, are well described in response to exogenous toll-like receptor ligands, but few studies have focused on ET-associated mechanisms in inflammatory disease. As blocking TNF can attenuate the development of ET, the effect of anti-TNF on the expression of key ET-associated molecules in inflammatory auto-immune disease was measured; changes in inflammatory gene expression were confirmed using an ET bioassay. The expression of immunomodulatory molecules was measured in a murine model of arthritis treated with anti-TNF and the expression of ET-associated molecules was measured in whole blood in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients, before and after therapy.

Dysregulated B cell function and disease pathogenesis in systemic sclerosis.

Systemic sclerosis (SSc) is a complex, immune-mediated rheumatic disease characterised by excessive extracellular matrix deposition in the skin and internal organs. B cell infiltration into lesional sites such as the alveolar interstitium and small blood vessels, alongside the production of defined clinically relevant autoantibodies indicates that B cells play a fundamental role in the pathogenesis and development of SSc. This is supported by B cell and fibroblast coculture experiments revealing that B cells directly enhance collagen and extracellular matrix synthesis in fibroblasts.

Metabolic requirements of Th17 cells and of B cells: Regulation and defects in health and in inflammatory diseases.

The immune system protects from infections and cancer through complex cellular networks. For this purpose, immune cells require well-developed mechanisms of energy generation. However, the immune system itself can also cause diseases when defective regulation results in the emergence of autoreactive lymphocytes.

Disease status in human and experimental arthritis, and response to TNF blockade, is associated with MHC class II invariant chain (CD74) isoform expression.

Splice variants of CD74 differentially modulate the activity of cathepsin L (CTSL). As CD74 and CTSL participate in the pathogenesis of inflammatory diseases such as rheumatoid arthritis (RA), we determined whether splice variants of CD74 could be biomarkers of disease activity. Gene expression was measured in mice with collagen-induced arthritis using quantitative PCR (qPCR).

TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis.

The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease status in rheumatoid arthritis (RA), ankylosing spondylitis (AS), and in experimental arthritis. TLR gene expression was measured in whole blood and monocytes, before and after TNF blockade.

TNFα inhibitors reduce bone loss in rheumatoid arthritis independent of clinical response by reducing osteoclast precursors and IL-20.

Objectives: About half of RA patients treated with TNFα inhibitors either do not respond or lose their initial therapeutic response over time. The clinical response is measured by reduction in DAS28, which primarily reflects inflammation. However, other effects of TNFα inhibitors, such as impact on bone erosion, are not assessed by DAS28.

Functional and phenotypic heterogeneity of Th17 cells in health and disease.

Background: Th17 cells have nonredundant roles in maintaining immunity, particularly at mucosal surfaces. These roles are achieved principally through the production of cytokines and the recruitment of other immune cells to maintain the integrity of mucosal barriers and prevent the dissemination of microorganisms. Th17 cells are heterogeneous and exhibit a considerable degree of plasticity.

Association of Defective Regulation of Autoreactive Interleukin-6-Producing Transitional B Lymphocytes With Disease in Patients With Systemic Sclerosis.

Objective: Systemic sclerosis (SSc) has the highest case-specific mortality of any rheumatic disease, and no effective therapy is available. A clear manifestation of SSc is the presence of autoantibodies. However, the origin of autoantibody-producing B lymphocytes, their mechanisms of activation and autoantibody production, and their role remain unclear.

Response to Treatment with TNFα Inhibitors in Rheumatoid Arthritis Is Associated with High Levels of GM-CSF and GM-CSF T Lymphocytes.

Biologic TNFα inhibitors are a mainstay treatment option for patients with rheumatoid arthritis (RA) refractory to other treatment options. However, many patients either do not respond or relapse after initially responding to these agents. This study was carried out to identify biomarkers that can distinguish responder from non-responder patients before the initiation of treatment.

Intracellular B Lymphocyte Signalling and the Regulation of Humoral Immunity and Autoimmunity.

B lymphocytes are critical for effective immunity; they produce antibodies and cytokines, present antigens to T lymphocytes and regulate immune responses. However, because of the inherent randomness in the process of generating their vast repertoire of antigen-specific receptors, B cells can also cause diseases through recognizing and reacting to self. Therefore, B lymphocyte selection and responses require tight regulation at multiple levels and at all stages of their development and activation to avoid diseases.

TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases.

TNFα is a principal pro-inflammatory cytokine vital for immunity to infections. However, its excessive production is involved in chronic inflammation and disease pathology in autoimmune diseases. Evidence for its pathogenic role is validated by the fact that its neutralisation by therapeutic agents in vivo is beneficial in ameliorating disease and controlling symptoms.

CD5 expression promotes IL-10 production through activation of the MAPK/Erk pathway and upregulation of TRPC1 channels in B lymphocytes.

CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia (CLL). Important functional properties are associated with CD5 expression in B cells, including signal transducer and activator of transcription 3 activation, IL-10 production and the promotion of B-lymphocyte survival and transformation. However, the pathway(s) by which CD5 influences the biology of B cells and its dependence on B-cell receptor (BCR) co-signaling remain unknown.

Favorable therapeutic response of osteoporosis patients to treatment with intravenous zoledronate compared with oral alendronate.

Objectives: To evaluate the efficacy of orally-administered alendronate compared with intravenously-administered zoledronate.

Methods: This prospective study was carried out at Barts Health HNS Trust between April 2010 and March 2012. This study compares changes in bone mineral density (BMD) in 234 patients treated with 2 bisphosphonates: alendronate taken orally, and zoledronate administered intravenously.

In-depth characterization of CD24(high)CD38(high) transitional human B cells reveals different regulatory profiles.

Background: CD24(high)CD38(high) transitional B cells represent cells at a key stage in their developmental pathway. In addition, these B cells have been widely ascribed regulatory functions and involvement in the control of chronic inflammatory diseases. However, the phenotypic and functional overlap between these cells and regulatory B cells remains controversial.

Harnessing the Therapeutic Potential of Th17 Cells.

Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods.

Bone loss in osteoporosis and arthritis. Pathogenesis and therapeutic strategies.

Bone makes up a framework that provides protection for internal body organs. The homeostasis of bone is maintained by balanced old bone resorption and new bone formation. However, this balance can be altered such as in postmenopausal women, patients with some cancers, and patients with chronic inflammatory conditions such as rheumatoid arthritis.

B-lymphocyte signalling abnormalities and lupus immunopathology.

Lupus is a complex autoimmune rheumatic disease of unknown aetiology. The disease is associated with diverse features of immunological abnormality in which B-lymphocytes play a central role. However, the cause of atypical B-lymphocyte responses remains unclear.

Aberrant B-lymphocyte responses in lupus: inherent or induced and potential therapeutic targets.

Background: Lupus is a prototype autoimmune disease of unknown aetiology. The disease is complex; manifest diverse clinical symptoms and disease mechanisms. This complexity has provided many leads to explore: from disease mechanisms to approaches for therapy.

Th17 lymphocytes in respiratory syncytial virus infection.

Infection by respiratory syncytial virus (RSV) affects approximately 33 million infants annually worldwide and is a major cause of hospitalizations. Helper T lymphocytes (Th) play a central role in the immune response during such infections. However, Th lymphocytes that produce interleukin 17 (IL-17), known as Th17 lymphocytes, in addition to been protective can also cause pathology that accompany this type of infection.

Altered patterns of epigenetic changes in systemic lupus erythematosus and auto-antibody production: is there a link?

The prominent feature of immunological defects in systemic lupus erythematosus (SLE) is the production of autoantibodies (auto-Abs) to nuclear antigens including DNA, histones and RNP. In addition, there is growing evidence that epigenetic changes play a key role in the pathogenesis of SLE. Autoreactive CD4(+) T cells and B cells in patients with SLE have evidence of altered patterns of DNA methylation as well as post-translational modifications of histones and ribonucleoproteins (RNP).

Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway.

Objectives: To establish if changes in Th1/Th17 cell populations previously reported in experimental arthritis occur in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor α (TNFα) agents, and whether the therapeutic response to anti-TNFα is compromised in patients and mice because of elevated Th17/IL-17 levels. Finally, to assess the efficacy of combined blockade of anti-TNFα and anti-IL-17 in experimental arthritis.

Methods: A longitudinal study of two independent cohorts (cohort 1, n=24; cohort 2, n=19) of patients with RA treated with anti-TNFα biological agents was carried out to assess their Th17/IL-17 levels before and after the start of anti-TNFα therapy.

CD5 expression promotes multiple intracellular signaling pathways in B lymphocyte.

CD5(+) B lymphocytes have distinct functional properties compared with B lymphocytes that lack CD5. However, it remains unclear if and how the CD5 molecule modulates B lymphocyte biology and responses. Our recent studies have revealed that CD5 promotes constitutive activation of multiple signaling pathways including extracellular signal-regulated kinases (ERK1/2), phosphatidylinositol 3-kinase (PI-3K)/mammalian target of rapamycin (mTOR) and calcineurin-NFAT signaling pathways.

CD5 promotes IL-10 production in chronic lymphocytic leukemia B cells through STAT3 and NFAT2 activation.

B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 containing the known exon 1 (E1A) and other CD5 transcripts containing the new exon 1 (E1B). These malignant B cells, as well as B cell lines transfected with cDNA for E1A-cd5 or with cDNA for E1B-cd5 produce IL-10, raising the possibility that CD5 participates in the secretion of IL-10. We identified transcription factors involved in this production in CD5(+) B lymphocytes from CLL patients and in E1A-cd5-transfected or E1B-cd5-transfected Jok cells.