ABSTRACT
Survivin is a protein functionally important for cell division, apoptosis, and possibly, for micro-RNA biogenesis. It is an established marker of malignant cell transformation. In non-malignant conditions, the unique properties of survivin make it indispensable for homeostasis of the immune system. Indeed, it is required for the innate and adaptive immune responses, controlling differentiation and maintenance of CD4+ and CD8+ memory T-cells, and in B cell maturation. Recently, survivin has emerged as an important player in the pathogenesis of autoimmune diseases. Under the conditions of unreserved inflammation, survivin enhances antigen presentation, maintains persistence of autoreactive cells, and supports production of autoantibodies. In this context, survivin takes its place as a diagnostic and prognostic marker in rheumatoid arthritis, psoriasis, systemic sclerosis and pulmonary arterial hypertension, neuropathology and multiple sclerosis, inflammatory bowel diseases and oral lichen planus. In this review, we summarise the knowledge about non-malignant properties of survivin and focus on its engagement in cellular and molecular pathology of autoimmune diseases. The review highlights utility of survivin measures for clinical applications. It provides rational for the survivin inhibiting strategies and presents results of recent reports on survivin inhibition in modern therapies of cancers and autoimmune diseases.
Subject(s)
Autoimmune Diseases/immunology , Inhibitor of Apoptosis Proteins/immunology , Adaptive Immunity , Animals , Hematopoiesis , Humans , Hypoxia/immunology , Immunity, Innate , Inflammation/immunology , Inhibitor of Apoptosis Proteins/chemistry , Inhibitor of Apoptosis Proteins/metabolism , Protein Conformation , Smoking/immunology , Sunlight , SurvivinABSTRACT
B cells are an important part of both innate and adaptive immune system. Their ability to produce antibodies, cytokines and to present antigen makes them a crucial part in defence against pathogens. In this study, we have in naïve Naval Medical Research Institute mice functionally characterized a subpopulation of splenic B cells expressing CD25, which comprise about 1% of the total B cell compartment. Murine spleen cells were sorted into two highly purified B cell populations either CD19(+) CD25(+) or CD19(+) CD25(-). We found that CD25(+) B cells secreted higher levels of IL-6, IL-10 and INFgamma in response to different TLR-agonists, and were better at presenting alloantigen to CD4(+) T cells. CD25 expressing B cells spontaneously secreted immunoglobulins of IgA, IgG and IgM subclass and had better migratory ability when compared with CD25(-) B cells. In conclusion, our results demonstrate that CD25(+) B cells are highly activated and functionally mature. Therefore, we suggest that this population plays a major role in the immune system and may belong to the memory B-cell population.
Subject(s)
B-Lymphocyte Subsets/immunology , B-Lymphocytes/immunology , Interleukin-2 Receptor alpha Subunit/immunology , Animals , Antigen Presentation/immunology , Cell Movement , Cell Separation , Cytokines/biosynthesis , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Lymphocyte Activation/immunology , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred C57BLABSTRACT
We have shown that human CD20(+)25(+) B cells display immunomodulatory properties. The aim of this study was to investigate if CD25(+) B cells are found within the CD27 memory B cell population, and to analyse pattern of their cytokine production. B cells isolated from healthy subjects, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients were analysed regarding the frequency of CD25(+) B cells within certain B cell subsets. Purified CD25(+) B cells from healthy subject were used in vitro to evaluate their production of immunomodulatory cytokines. In healthy subjects the majority (60%) of memory B cells (CD20(+)27(+)) also co-expressed CD25 while only 10-20% of the naïve B cells (CD20(+)27(-)) and plasmablasts (CD20-27(+)) expressed CD25. In RA and SLE patients, we found that 51% and 48%, respectively, co-expressed CD25 in the memory population, whereas only 11% and 9% co-expressed CD25 in the naïve B cell population. Phenotypic analysis of the CD20(+)25(+)27(+) and CD20(+)25(+)27(-) cells using CD10, CD24, CD38, CD45, CD71, CD80, CD86, CD95, CD138, BAFF-R, TACI, IgA, IgD, IgG and IgM showed that CD20(+)25(+)27(+) B cells preferentially represent highly activated, Ig class switched memory B cells. Cytokine profile analysis showed that CD25(+) B cells secreted significantly higher levels of IL-10 versus CD25(-) B cells. In contrast, TGF-beta1 secretion was similar between the CD25(+) and CD25(-) sub-populations. In conclusion, CD20(+)25(+) B cells constitute a unique subpopulation preferentially occurring among CD20(+)27(+) memory B cells. We suggest that CD25 can be used as a marker for a memory B cell subset.
Subject(s)
Autoimmune Diseases/immunology , B-Lymphocyte Subsets/metabolism , B-Lymphocytes/immunology , Immunologic Memory , Interleukin-2 Receptor alpha Subunit/metabolism , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/immunology , B-Lymphocyte Subsets/immunology , B-Lymphocytes/metabolism , Cytokines/biosynthesis , Female , Humans , Interleukin-2 Receptor alpha Subunit/immunology , Lupus Erythematosus, Systemic/immunology , Male , Middle Aged , Phenotype , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolismABSTRACT
B cells play an important role in the development of autoimmune diseases due to their production of autoantibodies, antigen-presenting capacity and production of pro-inflammatory cytokines. The purpose of the present study was to analyse B cells from rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients, with respect to their expression of the IL-2 receptor (IL-2R) subunit CD25. Using flow cytometry, we found that CD25(+) B cells from RA patients expressed significantly higher frequencies of CD122 and CD132 than CD25(+) B cells from control subjects, indicating a fully functional IL-2R. These CD25(+) B cells also expressed higher frequencies of the co-stimulatory molecule CD80, whereas IgM and IgA expression was decreased compared with CD25(+) B cells from healthy controls. In addition B cells from SLE patients co-expressed CD25 together with CD80, CD122, and CD132, but to a lower degree IgD and IgM, when compared with healthy controls. Taken together, our results indicate that CD25(+) B cells from RA and SLE patients are in a highly activated state, display a more mature phenotype and suggest that this B cell subset may be involved in the pathogenesis of RA and SLE.
Subject(s)
Arthritis, Rheumatoid/immunology , B-Lymphocytes/immunology , Interleukin-2 Receptor alpha Subunit/analysis , Lupus Erythematosus, Systemic/immunology , Adult , Aged , Female , Humans , Immunoglobulin A/immunology , Immunoglobulin M/immunology , Interleukin Receptor Common gamma Subunit/analysis , Interleukin-2 Receptor beta Subunit/analysis , Lymphocyte Activation , Male , Middle Aged , PhenotypeABSTRACT
B cells are in analogy with T cells capable of expressing functional IL-2 receptors. IL-2R alpha-chain (CD25) positive T cells have been studied in detail but not much is known about CD25 positive B cells. The aim of this study was to examine the phenotypic properties of the CD25 expressing B cells collected from different lymphoid organs in mice. Samples were stained for various cell surface markers and analysed using flow cytometry. We found that approximately 49% of B cells in bone marrow, 16% in peritoneal cavity, 2% in spleen and 1% in lymph nodes express CD25. In contrast, CD25 expressing B cells were not found in the blood or in Peyer's patches. Phenotypic characterization showed that CD25+ B cells in spleen, lymph nodes and peritoneal cavity have higher expression of AA4.1, CD5, CD69, CD80, CD86, CD122, CD132, IgA, IgG and IgM on their surface in comparison with CD25- B cells. In contrast, expression of IgD and IA-IE was lower on CD25+ B cells in spleen and lymph nodes. In bone marrow, the expression of CD5, CD80, CD86, CD122, CD132, IgA, IgD and IgM was lower, while the expression of AA4.1, IgG and IA-IE was increased on CD25+ B cells compared with CD25- B cells. In conclusion, our results indicate that B cells expressing CD25 are phenotypically distinctly different from those that are CD25 negative. Our findings suggest that CD25+ B cells are more prone to efficient antigen presentation and display a more mature phenotype.
Subject(s)
Antigens, CD/metabolism , B-Lymphocytes/metabolism , Interleukin-2 Receptor alpha Subunit/metabolism , Lymphoid Tissue/metabolism , Animals , Antigen Presentation/immunology , Female , Genes, MHC Class II , Immunoglobulin D/metabolism , Immunoglobulin G/metabolism , Immunoglobulin M/metabolism , Lymphoid Tissue/cytology , MiceABSTRACT
Helicobacter pylori infection is one of the most common gastrointestinal infections worldwide. Although the majority of the infected individuals remain asymptomatic carriers of the bacteria, approximately 15% develop peptic ulcers, which are most prevalent in the duodenum. H. pylori induce a vigorous immune response which, however, fails to clear the infection. Instead, the chronic inflammation that arises in the infected gastroduodenal mucosa may be involved in the development of H. pylori-associated peptic ulcers. We have previously shown that duodenal ulcer (DU) patients have a significantly lower epithelial cytokine, e.g. IL-8, response in the duodenum than asymptomatic (AS) carriers. In this study we have further investigated the mechanisms behind this finding, i.e. whether it can be explained by bacterial factors, down-regulation of epithelial cytokine production by regulatory T cells, or an impaired ability of the duodenal epithelium in DU patients to produce cytokines. Gastric AGS, and intestinal T84 epithelial cell lines were stimulated with H. pylori strains isolated from DU patients and AS carriers, respectively. All strains were found to induce comparable cytokine and cytokine receptor expression in epithelial cells. Regulatory T cells (CD4+ CD25(high)), isolated from human peripheral blood and cocultured with H. pylori stimulated AGS cells, were found to slightly suppress H. pylori-induced epithelial cytokine production. Furthermore, primary cultures of duodenal epithelial cells from DU patients were found to produce markedly lower amounts of cytokines than epithelial cells isolated from AS carriers. These results suggest that the lower epithelial cytokine responses in the duodenum of DU patients, which may be of importance for the pathogenesis of H. pylori-induced duodenal ulcers, most likely can be explained by host factors, i.e. mainly a decreased ability of the duodenal epithelium to produce cytokines, but possibly partly also down-regulation by regulatory T cells.