David T. Y. Yu

Glucocorticoids Administered In Vivo Inhibit Human Suppressor T Lymphocyte Function and Diminish B Lymphocyte Responsiveness in In Vitro Immunoglobulin Synthesis

The effects of corticosteroid given in vivo on human lymphocyte subpopulation function were investigated using an in vitro system of pokeweek mitogen-stimulated immunoglobulin production. Peripheral blood lymphocytes were obtained from normal volunteers before and 4 h after the intravenous administration of methylprednisolone. Unfractioned peripheral blood lymphocytes showed a consistent decrease (mean congruent with 50%) in immunoglobulin and total protein synthesis after steroid administration. Utilizing separated thymus-derived (T) and bone marrow-derived (B) lymphocyte fractions, the pathophysiology of this alteration in immunoglobulin production was elucidated. B lymphocytes obtained after steroid treatment showed a markedly diminished immunoglobulin response (20% of normal) to normal T lymphocytes and to normal T cells that had been irradiated to remove suppressor T lymphocyte function. All major classes of immunoglobulin (IgG, IgM, and IgA) were affected. T lymphocytes procured after steroid administration were capable of providing normal amounts of T cell help for B cells in immunoglobulin production. However, suppressor T lymphocyte activity, observed with normal T lymphocytes at high T to B cell ratios, was absent from the post-steroid T lymphocytes. This loss of suppressor T lymphocyte function was not due to the presence of excess help as irradiated pre- and poststeroid T cells provided equal amounts of helper activity. On recombining the poststeroid treatment B cells, which are hyporesponsive in immunoglobulin synthesis, with the posttreatment T lymphocytes, which lack suppressor activity, diminished amounts of immunoglobulin were produced which correlate well with the effects observed with unseparated cells. Thus, corticosteroids have differential effects on the lymphocyte populations involved in immunoglobulin biosynthesis. B cell responsiveness is diminished, suppressor T lymphocyte activity is removed, and helper T lymphocyte function is unaffected.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis

To provide evidence‐based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA).

Pathogenesis of ankylosing spondylitis

Ankylosing spondylitis (AS) is a potentially disabling form of seronegative spondyloarthritis. The main symptom of AS is inflammatory spinal pain; with time, some patients develop ankylosis and spinal immobility. The pathology mainly affects the entheses, where ligaments, tendons and capsules are attached to the bone. Three processes are observed at the entheses: inflammation, bone erosion and syndesmophyte (spur) formation. Tumor necrosis factor is an important mediator of the inflammatory processes, but this proinflammatory cytokine is not closely involved in bone erosion or syndesmophyte formation. The major causative factors of AS are genetic, with the gene encoding HLA-B27 being the most important genetic factor. Several other susceptibility genes have also been identified. An enormous number of papers have been published and many diverse hypotheses have been generated regarding the pathogenesis of AS. This Review outlines the key areas of current research in this field, describes several hypotheses regarding the pathogenesis of AS, which are under intense investigation, and concludes with a dissection of the processes involved in bone erosion and syndesmophyte formation.

Anti-Inflammatory Effects of Sphingosine Kinase Modulation in Inflammatory Arthritis

Sphingosine kinase (SphK) is a key enzyme in the sphingolipid metabolic pathway responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P). SphK/S1P play a critical role in angiogenesis, inflammation, and various pathologic conditions. Recently, S1P1 receptor was found to be expressed in rheumatoid arthritis (RA) synovium, and S1P signaling via S1P1 enhances synoviocyte proliferation, COX-2 expression, and prostaglandin E2 production. Here, we examined the role of SphK/S1P in RA using a potent SphK inhibitor, N,N-dimethylsphingosine (DMS), and a molecular approach against one of its isoenzymes, SphK1. We observed that levels of S1P in the synovial fluid of RA patients were significantly higher than those of osteoarthritis patients. Additionally, DMS significantly reduced the levels of TNF-α, IL-6, IL-1β, MCP-1, and MMP-9 in cell-contact assays using both Jurkat-U937 cells and RA PBMCs. In a murine collagen-induced arthritis model, i.p. administration of DMS significantly inhibited disease severity and reduced articular inflammation and joint destruction. Treatment of DMS also down-regulated serum levels IL-6, TNF-α, IFN-γ, S1P, and IgG1 and IgG2a anti-collagen Ab. Furthermore, DMS-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Moreover, similar reduction in incidence and disease activity was observed in mice treated with SphK1 knock-down via small interfering RNA approach. Together, these results demonstrate SphK modulation may provide a novel approach in treating chronic autoimmune conditions such as RA by inhibiting the release of pro-inflammatory cytokines.

Expression of arthritis-causing HLA-B27 on Hela cells promotes induction of c-fos in response to in vitro invasion by Salmonella typhimurium.

HLA-B27 confers a very strong genetic predisposition to development of a reactive arthritis after infection by bacteria such as Salmonella typhimurium. This study examines the role of HLA-B27 in the initiation of the earliest host activities after exposure to Salmonella, namely activation of the immediate early genes in the epithelial cells. Our major finding is that in Hela cells, the expression of c-fos was induced by Salmonella invasion only when the cells expressed the transfected HLA-B27 gene, but not the HLA-A1 gene or a truncated HLA-B27 gene lacking the exons encoding the cytoplasmic domain. C-fos is potentially capable of complexing with members of the c-jun family to become the AP-1 transcription complex. Parallel to c-fos expression, we found that only with the HLA-B27 transfectant was there expression of AP-1. AP-1 potentially controls the expression of a large number of genes. On screening a panel of proinflammatory molecules, we found that Salmonella invasion induced expression of monocyte chemoattractant protein-1 in the HLA-B27 cells. Since each of these separate positive findings belong to the same cascade of events after cell activation, together they reinforce the hypothesis that HLA-B27 plays a modulatory role in the early signal transduction events induced by Salmonella invasion. This hypothesis adds another item to the list of allele-specific activities carried out by HLA class I molecules. If similar activation also occurs in the joints, it may play a major role in arthritis.

Cellular Immunological Aspects of Rheumatoid Arthritis

arthritis. Rheumatoid arthritis has been regarded as an autoimmune disease largely because of its association with antiimmunoglobulin antibody. Since the concept of immune surveillance and autoimmunity was first proposed by Burnett in 1959,” much information on cellular autoimmunity has been gained. We shall attempt to review this information and outline the various ways in which a breakdown in the self-recognition system can result in disease. We would like to admit first of ail that a single coherent hypothesis for the cellular pathogenesis of rheumatoid arthritis is not possible at the moment. This is primarily because many new insights into lymphocyte function and pathology gained in laboratory animals have not yet been satisfactorily extended to the human lymphocyte. Although rheumatoid arthritis is a systemic disease,9 arthritis is usually the predominant factor and the only factor shared by all patients. Thus in this review we shall confine discussion to those pathological processes leading to joint inflammation that are of special interest to cellular immunologists for the following reasons: 1. There is evidence suggesting that cell-mediated immunity (CMI)* may play a role in the pathogenesis of rheumatoid arthritis. 2. The science of cellular immunology is concerned first with CMI, which includes the production of mediators of cellular immunity and direct toxicity of lymphocytes on target cells, and second with the characteristics of all the cells

A case report: Thoracic duct lymphocyte drainage in rheumatoid arthritis

Abstract A 24-year-old woman with severe rheumatoid arthritis was treated by removing 170 × 109 lymphocytes through a thoracic duct fistula which drained continuously for 46 days. Marked clinical improvement occurred during the first 2 weeks of drainage and persisted until about 6 weeks after the fistula was discontinued, when articular inflammation recurred. Serum immunoglobulin concentrations and cell-mediated, transplantation, and humoral immune responses were suppressed in varying degrees after 4–6 weeks of drainage, but serum complement, inflammatory responses, and bone marrow granulocyte reserves were not adversely affected. Although the mechanisms responsible for the clinical response are not known; it is possible that cells contained in the thoracic duct lymph may have been continuously required in order to sustain the synovial inflammation of this patient.

Identification of interleukin-7 as a candidate disease mediator in spondylarthritis.

OBJECTIVE Understanding of the molecular pathophysiology of spondylarthritis (SpA) remains largely elusive. This is related both to the complexity of the disease (axial versus peripheral disease, inflammation versus tissue remodeling) and to the difficulty in obtaining samples from primary disease sites. This study was undertaken to explore a gene expression approach for identifying novel candidate mediators of SpA. METHODS Sacroiliac joint fluid aspirates from 3 SpA patients with active sacroiliitis were studied by microarray analysis. The expression of selected candidate molecules in peripheral synovitis was confirmed by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS Microarray analysis identified 4 sacroiliitis gene clusters, containing a total of 47 messenger RNA (mRNA) transcripts. Two clusters contained genes expressed in all sacroiliitis samples, corresponding to both known and unsuspected candidate mediators of SpA pathology. These included proinflammatory molecules as well as molecules involved in tissue remodeling, such as transforming growth factor beta2. Of the novel candidate genes selected for confirmation, interleukin-7 (IL-7) mRNA expression was higher in SpA peripheral synovial fluid and synovial tissue samples than in osteoarthritis samples, and similar to expression in rheumatoid arthritis (RA) samples. At the protein level, synovial fluid IL-7 levels were even higher in SpA than in RA, despite lower levels of tumor necrosis factor alpha and IL-1beta. CONCLUSION In the present study, both known and unsuspected candidate mediators of SpA pathogenesis were identified, including IL-7. The specific overexpression of IL-7 at sites of peripheral synovitis in SpA suggests that further functional investigations of the role of this cytokine in SpA pathogenesis are warranted.

Human lymphocyte receptor movement induced by sheep erythrocyte binding: Effect of temperature and neuraminidase treatment

Abstract The formation of sheep red blood cells (SRBC) rosettes by human lymphocytes was promoted by incubation at 4 °C and by treatment of the lymphocytes or SRBC by neuraminidase. On incubating the untreated SRBC rosettes at 37 °C, the rosettes dissociated by capping in which rings were converted into horseshoes and then caps. This capping was inhibited by incubation of the rosettes at 4 °C and partially by treatment of the cells with neuraminidase. During rosette formation, the proportion of caps decreased progressively during 4 °C incubation. This decrease of capping was also promoted by neuraminidase treatment. We concluded that the main reason why 4 °C and neuraminidase treatment facilitated rosette formation was by inhibition of capping.

Matrix metalloproteinase expression in the spondyloarthropathies.

Purpose of reviewExpression of matrix metalloproteinases and their tissue inhibitors has been an active area of investigation in rheumatoid arthritis and osteoarthritis. Only recently have investigators started to study these factors in spondyloarthropathy. The purpose of this review is to summarize these recent findings. Recent findingsMultiple matrix metalloproteinases and their tissue inhibitors are expressed in the synovial fluid as well as serum samples of spondyloarthropathy patients. Their degrees of expression in the synovia correlate with parameters of arthritis activity such as cell infiltration. In the synovial fluids, the factor which is expressed in very high level is matrix metalloproteinase-3. Two separate cohorts demonstrate that serum levels of matrix metalloproteinase-3 correlate with disease activity in ankylosing spondylitis. Their usefulness appears to exceed those of erythrocyte sedimentation rate and C-reactive protein. Multiple studies also indicate that serum levels of matrix metalloproteinase-3 are suppressed when patients are treated with the anti-tumor necrosis factor-α antibody infliximab. SummaryNew biomarkers are in demand for spondyloarthropathy in deciding whether patients would benefit from treatment with tumor necrosis factorα blockers, monitoring response to treatment, or predicting potential of joint damage if untreated. Recent studies show that among the matrix metalloproteinase and their tissue inhibitors, serum MMP-3 is the one with potential usefulness.