Phenotype and Function of CD25-Expressing B Lymphocytes Isolated from Human Umbilical Cord Blood

Background. We have shown that approximately 30% of human peripheral blood B-cells express CD25. B cells expressing CD25 display a mature phenotype belonging to the memory B-cell population and have a better proliferative and antigen-presenting capacity. The aim of the present study was to characterize the CD25-expressing subset of B cells in human cord blood. Material and Methods. Mononuclear cell fraction from human cord blood (n = 34) and peripheral adult blood (n = 22) was sorted into CD20+CD25+ and CD20+CD25− B-cell populations. Phenotype and function of these B-cell populations were compared using flow cytometry, proliferation, cytokine production, and immunoglobulin secretion. Results. CD25-expressing B cells are a limited population of cord blood mononuclear cells representing 5% of the CD20+ B cells. They are characterised by high expression of CD5 in cord blood and CD27 in adult blood. CD25-expressing B cells express a functional IL-2 receptor and high levels of CC-chemokine receptors and spontaneously produce antibodies of IgG and IgM subclass. Conclusions. CD25 expression is a common denominator of a specific immunomodulatory B-cell subset ready to proliferate upon IL-2 stimulation, possibly ready to migrate and home into the peripheral tissue for further differentiation/action

Immunomodulatory therapeutic strategies in stroke

The role of immunity in all stages of stroke is increasingly being recognised, from the pathogenesis of risk factors to tissue repair, leading to the investigation of a range of immunomodulatory therapies. In the acute phase of stroke, proposed therapies include drugs targeting pro-inflammatory cytokines, matrix metalloproteinases, and leukocyte infiltration, with a key objective to reduce initial brain cell toxicity. Systemically, the early stages of stroke are also characterised by stroke-induced immunosuppression, where downregulation of host defences predisposes patients to infection. Therefore, strategies to modulate innate immunity post-stroke have garnered greater attention. A complementary objective is to reduce longer term sequelae, by focusing on adaptive immunity. Following stroke onset, the integrity of the blood-brain barrier is compromised, exposing central nervous system (CNS) antigens to systemic adaptive immune recognition, potentially inducing autoimmunity. Some pre-clinical efforts have been made to tolerise the immune system to CNS antigens pre-stroke. Separately, immune cell populations which exhibit a regulatory phenotype (T and B regulatory cells) have been shown to ameliorate post-stroke inflammation and contribute to tissue repair. Cell-based therapies, established in oncology and transplantation, could become a strategy to treat the acute and chronic stages of stroke. Furthermore, a role for the gut microbiota in ischemic injury has received attention. Finally, the immune system may play a role in remote ischemic preconditioning-mediated neuroprotection against stroke. The development of stroke therapies involving organs distant to the infarct site, therefore, should not be overlooked. This review will discuss the immune mechanisms of various therapeutic strategies, surveying published data and discussing more theoretical mechanisms of action that have yet to be exploited

Short- and long-term effects of anti-CD20 treatment on B cell ontogeny in bone marrow of patients with rheumatoid arthritis

It has been known for a long time that B cells play a role in rheumatoid arthritis (RA). By production of autoantibodies, presentation of auto-antigens and by producing cytokines B cells may contribute to the pathogenesis of RA. In recent years it has been shown that anti-B cell therapy is a powerful tool in the treatment of RA. The aim of this thesis was to a) investigate the effect on B cell ontogeny following B cell depletion therapy, b) during B cell depletion therapy evaluate serological and humoral immune responses and finally, c) try to establish a connection between Epstein-Barr virus (EBV) infection, CD25+ B cells and outcome of B cell deletion therapy. In paper I we could show that in bone marrow of RA patients following anti-CD20 treatment with rituximab (RTX) IgD expressing naïve cells are depleted whereas immature and memory B cells where still detectable. However, the long-term effects clearly showed a reduction of memory B cells in bone marrow. The examination of rheumatoid factor (RF) production revealed that RFs decline short after treatment but returned to baseline levels concurrently with the IgD expressing B cells when patients where subjected to an additional course. In paper II the cellular and humoral immune responses were evaluated by immunisation of RA patients before or during RTX treatment with a protein vaccine against influenza and a pneumococcal polysaccharide vaccine. The results suggest that both cellular and humoral immune responses are affected in patients receiving RTX treatment and we therefore suggest that immunisation should be performed before RTX treatment. In paper III we investigate the effects of EBV on selected B cell subsets and how infection may affect the clinical response to RTX treatment. The phenotypical study showed that B cells are more mature in EBV infected patients and the CD25+ B cell subset was more mature as compared to the CD25- B cell population. The evaluation of clinical response to RTX treatment with regard to B cell subsets showed that non-responding EBV+ patients had a significantly larger CD25+ plasma cell population. When investigating the effects of EBV stimulation in vitro we found that the CD25+ B cell population developed into antibody-producing cells to a higher extent than did the corresponding CD25- B cell population. The results of our studies indicate that that B cells play an essential role in the pathogenesis of RA. During RTX treatment we suggest that the IgD expressing population may harbour the autoantibody producing B cells. We also claim that that there are subsets of B cells (i.e. CD25+ B cells) that may have significant impact on the pathogenesis of RA, and the clinical outcome following RTX treatment

The immune system and stroke: from current targets to future therapy

Stroke is a major cause of morbidity and mortality worldwide. Despite the intensive search for new therapies, hundreds of agents targeting various pathophysiological mechanisms have failed clinical trials, and the thrombolytic agent tissue plasminogen activator is currently the only FDA-approved medication for the treatment of acute ischaemic stroke (AIS). The immune system is involved in all stages of stroke, from the pathogenesis of risk factors to neurotoxicity, to tissue remodelling and repair. There is a bi-directional interaction between the brain and the immune system, with stroke-induced immunosuppression and subsequent infection a principal source of patient mortality. Newer work also points to a role for the gut microbiota in the immune response to stroke, while clinical sequelae such as dementia might now also be explained in immune terms. However, the exact roles of innate and adaptive components have not been fully elucidated, with studies reporting both detrimental and beneficial functions. Time is a key determinant in defining whether immunity and inflammation are neuroprotective or neurotoxic. The local inflammatory milieu also has a clear influence on many proposed treatments. This review examines the individual components of the immune response to stroke, highlighting the most promising future stroke immunotherapies

Frequency and phenotype of B cell subpopulations in young and aged HIV-1 infected patients receiving ART

BACKGROUND: Aged individuals respond poorly to vaccination and have a higher risk of contracting infections in comparison to younger individuals; whether age impacts on the composition and function of B cell subpopulations relevant for immune responses is still controversial. It is also not known whether increased age during HIV-1 infection further synergizes with the virus to alter B cell subpopulations. In view of the increased number of HIV-1 infected patients living to high age as a result of anti-retroviral treatment this is an important issue to clarify. RESULTS: In this work we evaluated the distribution of B cell subpopulations in young and aged healthy individuals and HIV-1 infected patients, treated and naïve to treatment. B cell populations were characterized for the expression of inhibitory molecules (PD-1 and FcRL4) and activation markers (CD25 and CD69); the capacity of B cells to respond to activation signals through up-regulation of IL-6 expression was also evaluated. Increased frequencies of activated and tissue-like memory B cells occurring during HIV-1 infection are corrected by prolonged ART therapy. Our findings also reveal that, in spite of prolonged treatment, resting memory B cells in both young and aged HIV-1 infected patients are reduced in number, and all memory B cell subsets show a low level of expression of the activation marker CD25. CONCLUSIONS: The results of our study show that resting memory B cells in ART-treated young and aged HIV-1 infected patients are reduced in number and memory B cell subsets exhibit low expression of the activation marker CD25. Aging per se in the HIV-1 infected population does not worsen impairments initiated by HIV-1 in the memory B cell populations of young individuals. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12977-014-0076-x) contains supplementary material, which is available to authorized users

The Synthetic Cannabinoid R(+)WIN55,212-2 Augments Interferon-β Expression via Peroxisome Proliferator-activated Receptor-α

We have demonstrated that R()WIN55,212-2, a synthetic cannabinoid that possesses cannabimimetic properties, acts as a novel regulator of Toll-like receptor 3 (TLR3) signaling to interferon (IFN) regulatory factor 3 (IRF3) activation and IFN- expression, and this is critical for manifesting its protective effects in a murine multiple sclerosis model. Here we investigated the role of peroxisome proliferator-activated receptor- (PPAR) in mediating the effects of R()WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN- expression and R()WIN55,212-2 enhances TLR3-induced IFN- expression in a stereoselective manner via PPAR. R()WIN55,212-2 promotes increased transactivation and expression of PPAR. Using the PPAR antagonist GW6471, we demonstrate that R()WIN55,212-2 acts via PPAR to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN- promoter. Furthermore, GW6471 ameliorated the protective effects of R()WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPAR as an important mediator in manifesting the effects of R()WIN55,212-2 on the signaling cascade regulating IFN- expression. The study adds to our molecular appreciation of potential therapeutic effects of R()WIN55,212-2 in multiple sclerosis

Impaired B cells survival upon production of inflammatory cytokines by HIV-1 exposed follicular dendritic cells

Additional file 3. Activation of B and T cells upon different stimuli. The frequency of activated CD69 + cells among PBMCs (A), B cells (B) and T cells (C) are shown when PBMCs were exposed to different activation stimuli

Mice Chronically Fed High-Fat Diet Have Increased Mortality and Disturbed Immune Response in Sepsis

BACKGROUND: Sepsis is a potentially deadly disease that often is caused by gram-positive bacteria, in particular Staphylococcus aureus (S. aureus). As there are few effective therapies for sepsis, increased basic knowledge about factors predisposing is needed. METHODOLOGY/PRINCIPAL FINDINGS: The purpose of this study was to study the effect of Western diet on mortality induced by intravenous S. aureus inoculation and the immune functions before and after bacterial inoculation. Here we show that C57Bl/6 mice on high-fat diet (HFD) for 8 weeks, like genetically obese Ob/Ob mice on low-fat diet (LFD), have increased mortality during S. aureus-induced sepsis compared with LFD-fed C57Bl/6 controls. Bacterial load in the kidneys 5-7 days after inoculation was increased 10-fold in HFD-fed compared with LFD-fed mice. At that time, HFD-fed mice had increased serum levels and fat mRNA expression of the immune suppressing cytokines interleukin-1 receptor antagonist (IL-1Ra) and IL-10 compared with LFD-fed mice. In addition, HFD-fed mice had increased serum levels of the pro-inflammatory IL-1beta. Also, HFD-fed mice with and without infection had increased levels of macrophages in fat. The proportion and function of phagocytosing granulocytes, and the production of reactive oxygen species (ROS) by peritoneal lavage cells were decreased in HFD-fed compared with LFD-fed mice. CONCLUSIONS: Our findings imply that chronic HFD disturb several innate immune functions in mice, and impairs the ability to clear S. aureus and survive sepsis