Do B cells play a role in the pathogenesis of juvenile idiopathic arthritis?

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in childhood and adolescents and encompasses a heterogeneous group of diseases. The role of B cells (BC) in autoimmune diseases has been put in a new perspective due to the promising results of BC depleting therapies in RA. Experiments in mouse models have shed new light on the Ab-independent role of BC in the pathogenesis of autoimmune diseases. We discuss whether BC play a role in the pathogenesis of JIA appraising the question for an immunological basis of BC directed therapy.     

The role of Natural Killer cells in the pathogenesis of rheumatoid arthritis: major contributors or essential homeostatic modulators?

Natural Killer (NK) cells are lymphocytes of the innate immune system, originally described by their capacity to control tumour cells and eliminate virus-infected cells. However accumulating evidence suggests that NK cells can interact with various components of the immune system and play a critical role in autoimmune diseases by limiting or exacerbating immune responses. Rheumatoid arthritis is a chronic inflammatory disease characterised by joint inflammation and cartilage and bone destruction. NK cells are enriched within the joints of patients with rheumatoid arthritis but how they contribute to disease pathology is currently not fully elucidated. This review will outline the current understanding of NK cell biology and how these cells may modulate disease pathogenesis in rheumatoid arthritis through interactions with other immune cells.     

Regulatory T cells: which role in the pathogenesis and treatment of allergic disorders?

Several recent data suggest the importance of different types of cells in the regulation of T-cell effector-mediated immune responses. However, a unique specific marker for these cells has not yet been identified. Moreover, in addition to a dedicated functional lineage, even a 'plastic' phenotype of regulatory T cells seems to exist. The lack of a unique specific marker for regulatory T cells, as well as their heterogeneity, make it difficult to determine whether a defect of regulatory T cells plays a role in the pathogenesis of common allergic disorders. Novel therapeutic strategies based on the induction or potentiation of regulatory T cells able to hamper allergic inflammatory reactions are desirable, but their possible efficacy and safety are not yet known. At present, therapeutic strategies able to induce an immune deviation of allergen-specific type 2 T-helper responses to a less polarized phenotype rather than a general immune suppression appear more realistic.     

What is the role of rituximab in the treatment of rheumatoid arthritis?

Rituximab is a monoclonal antibody against CD20 that was developed for the treatment of relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). Recent controlled trials have shown that B cell-targeted therapy with rituximab is effective in RA (which suggest that B lymphocytes may be critical in its pathogenesis of RA) and early exposure data suggest that the tolerability and safety profile of rituximab may be even better in RA than in NHL patients. Rituximab is generally well tolerated, with a low incidence of serious adverse events, including serious infections. Available evidence suggests that its clinical benefits depend on effective B cell depletion, and the fact that its novel mode of action leads to the depletion of B cells makes it distinct from other biological therapies for RA that target T cells and their related cytokines. Although complete peripheral B cell depletion is regularly seen in RA and other autoimmune diseases, especially systemic lupus erythematosus (SLE), incomplete depletion has been reported in a subset of patients, even after full dosing with rituximab.     

Circulating IFN-γ producing CD4+ T cells and IL-17A producing CD4+ T cells,HLA-shared epitope and ACPA may characterize the clinical response to therapy in rheumatoid arthritis patients

This study analyzed the association between peripheral distributions of helper T cell subsets, HLA shared-epitope (SE), anti-cyclic citrullinated peptide antibody (ACPA) and clinical response to therapy in rheumatoid arthritis (RA) patients. Frequencies of IFN-γ-producing CD4+T (Th1) and IL-17A-producing CD4+T (Th17) cells were determined by flow cytometry in 167 patients (114 cases with good-response (GR) and 53 poor-response (PR) based on DAS28). HLA-DRB1 alleles for patients and 150 healthy controls were determined by PCR-SSP. We observed that 65.2% of RA patients were SE⁺, 63.4%ACPA⁺, 43.7%SE⁺ACPA⁺ and 14.9% were SE⁻ACPA⁻. Higher significantly proportions of Th1 and Th17 cells were found in RA patients than controls (P < 0.05) as well as in the SE⁺ or ACPA⁺RA patients compared to SE⁻ and ACPA⁻ patients. Increased frequencies of both Th subsets were found in SE⁺ACPA⁺ versus SE⁻ACPA⁻ patients (P < 0.001) and in the PR versus GR group (P < 0.001). We showed significant differences for Th cells frequencies between SE⁺ and SE⁻ patients in both groups, and between ACPA⁺ and ACPA⁻ cases in the PR group. Our findings suggest a close link between Th1 and Th17 cells proportions and HLA-SE/ACPA in the RA patients and remarkably in the PR group which could be indicative for the importance of immune monitoring for evaluation of response to therapy.     

S100A4 (Mts1): is there any relation to the pathogenesis of rheumatoid arthritis?

S100A4 (Mts1) belongs to the S100 family of calcium binding proteins, which are involved in diverse biological regulatory activities. An association between S100A4 and tumor progression has been demonstrated in several studies. S100A4 binds to distinct intracellular target proteins and regulates specific functions involved in tumor progression such as cell motility, proliferation and apoptosis as well as remodelling of the extracellular matrix. Once released from the tumor or tumor-activated stromal cells, it may influence certain functions of target cells towards a more aggressive phenotype. Extracellular S100A4 has been demonstrated to contribute to angiogenesis and the increased production of matrix-degrading enzymes by both endothelial and tumor cells. Moreover, S100A4 might be responsible for TCRgammadelta T-cell mediated lysis and negative regulation of matrix mineralization. Increased expression of S100A4 mRNA has recently been found in proliferating rheumatoid arthritis synovial fibroblasts and synovial tissues from rheumatoid arthritis patients. Synovial hyperplasia in rheumatoid arthritis consists of inflammatory cells and activated synovial lining cells which contribute to the progressive destruction of the joints during the disease. Since several phenomena are similar between rheumatoid arthritis and malignant tumors it can be hypothesized that S100A4 contributes to the invasive and tumor-like behavior of rheumatoid arthritis synovium.     

2-Gy whole-body irradiation significantly alters the balance of CD4+CD25? T effector cells and CD4+CD25+Foxp3+ T regulatory cells in mice

CD4⁺CD25⁺ T regulatory (Treg) cells are critical in inducing and maintaining immunological self-tolerance as well as transplant tolerance. The effect of low doses of whole-body irradiation (WBI) on CD4⁺CD25⁺Foxp3⁺ Treg cells has not been determined. The proportion, phenotypes and function of CD4⁺CD25⁺ Treg cells were investigated 0.5, 5 and 15 days after euthymic, thymectomized or allogeneic bone marrow transplanted C57BL/6 mice received 2-Gy γ-rays of WBI. The 2-Gy WBI significantly enhanced the ratios of CD4⁺CD25⁺ Treg cells and CD4⁺CD25⁺Foxp3⁺ Treg cells to CD4⁺ T cells in peripheral blood, lymph nodes, spleens and thymi of mice. The CD4⁺CD25⁺ Treg cells of the WBI-treated mice showed immunosuppressive activities on the immune response of CD4⁺CD25⁻ T effector cells to alloantigens or mitogens as efficiently as the control mice. Furthermore, 2-Gy γ-ray WBI significantly increased the percentage of CD4⁺CD25⁺Foxp3⁺ Treg cells in the periphery of either thymectomized mice or allogeneic bone marrow transplanted mice. The in vitro assay showed that ionizing irradiation induced less cell death in CD4⁺CD25⁺Foxp3⁺ Treg cells than in CD4⁺CD25⁻ T cells. Thus, a low dose of WBI could significantly enhance the level of functional CD4⁺CD25⁺Foxp3⁺ Treg cells in the periphery of naive or immunized mice. The enhanced proportion of CD4⁺CD25⁺Foxp3⁺ Treg cells in the periphery by a low dose of WBI may make hosts more susceptible to immune tolerance induction.     

HIV-specific CD4+ T cells and viremia: who's in control?

It has been proposed that HIV-specific CD4+ T cells with a central memory phenotype might be involved in controlling HIV replication. Based on recent data (lack of protective effects of HIV-specific CD4+ T-cell responses in acutely infected patients undergoing treatment interruptions; loss of initially strong T-helper cell responses in progressors to AIDS; and lack of prognostic value of HIV-specific CD4+ T cells in a prospective study) we argue that the level of persistent viremia determines the fate of HIV-specific CD4+ T cells. We postulate that, rather than the absence of HIV-specific T cells, it is the viral and immune activation set points that are major determinants of progression to AIDS. This influences ideas about the type of cellular immunity a protective HIV vaccine should induce.     

Detection of a CD4+CD8−CD3− cell subpopulation during the differentiation of cord blood CD34+ cells into T cells in vitro

Introduction:  

Umbilical cord blood contains relatively abundant primitive CD34⁺ hematopoietic progenitor cells which can differentiate into T lymphocytes ex vivo     

Do regulatory T cells play a role in the control of homeostatic proliferation?

The control of peripheral lymphocyte numbers is a fundamental aspect of the immune system. Regulatory T cells are involved in the suppression of autoimmune, antitumor, allergic, and other inflammatory responses, as well as in facilitating graft acceptance. In this paper, we discuss whether the control of homeostatic proliferation is another facet of the immune system that is controlled by regulatory T cells. A review of the published data connecting regulatory T cells with the control of homeostatic proliferation indicates that several key questions remain open. One of these relates to the stage at which regulatory T cells could play a role (i.e., T-cell proliferation vs. survival).     

Does IL-4 play a role in the expansion of V beta 8a T cell receptor-bearing cells?

BACKGROUND: Peripheral blood mononuclear cells (PBMC) of subjects allergic to the insect-derived allergen Chi t 1--9 are characterized by an allergen-induced pronounced proliferation and increased expression of activation markers (CD25, HLA-DR, CD23). T cell lines showed an elevated percentage of V beta 8a-positive cells following stimulation by Chi t 1--9. OBJECTIVE: The aim of the present study was to investigate whether V beta 8a dominance plays an important role in PBMC short-term cultures (24 h) as well. The role of exogenous added cytokines, especially IL-4, has been determined. METHODS: The T cell receptor repertoire was measured with 16 monoclonal antibodies to epitopes on the variable region of the beta chain by flow cytometry. Patients allergic to Chi t 1--9 were compared to nonallergic subjects as well as to subjects with other occupational allergies. In addition, cytokines were determined intracellulary by flow cytometry. Studies were performed with PBMC cultured for 24 h. RESULTS: After cultivation for 24 h without or with different stimuli (cytokines, allergen, phytohaemagglutinin), changes in the T cell receptor profile and the cytokine profile were measurable compared to the baseline value (without cultivation). Stimulation with IL-4 revealed increased percentages of V beta 8a-expressing cells in Chi t 1--9-sensitized patients. This IL-4-induced V beta 8a increase did not occur in PBMC from the two control subject groups (non-allergic and allergic to other allergens than Chi t 1--9). CONCLUSION In conclusion, the dominance of certain T cell receptor types seems to arise due to the exposure to specific allergens and cytokine production. Some T cell receptors are often affected, for example V beta 8a, whereas others only show minor variations. V beta 8a expression obviously plays an important role in Chi t 1-9 allergy.     

Chemokine receptor CCR9 suppresses the differentiation of CD4+CD8αα+ intraepithelial T cells in the gut

The chemokine receptor CCR9 equips T cells with the ability to respond to CCL25, a chemokine that is highly expressed in the thymus and the small intestine (SI). Notably, CCR9 is mostly expressed on CD8 but not on CD4 lineage T cells, thus imposing distinct tissue tropism on CD4 and CD8 T cells. The molecular basis and the consequences for such a dichotomy, however, have not been fully examined and explained. Here, we demonstrate that the forced expression of CCR9 interferes with the tissue trafficking and differentiation of CD4 T cells in SI intraepithelial tissues. While CCR9 overexpression did not alter CD4 T cell generation in the thymus, the forced expression of CCR9 was detrimental for the proper tissue distribution of CD4 T cells in the periphery, and strikingly also for their terminal differentiation in the gut epithelium. Specifically, the differentiation of SI epithelial CD4 T cells into immunoregulatory CD4⁺CD8αα⁺ T cells was impaired by overexpression of CCR9 and conversely increased by the genetic deletion of CCR9. Collectively, our results reveal a previously unappreciated role for CCR9 in the tissue homeostasis and effector function of CD4 T cells in the gut.     

In vitro autoreactivity against skin in rheumatoid arthritis: are peripheral blood mononuclear cells of patients with rheumatoid arthritis able to lyze autologous keratinocytes?

An in vitro explant model was originally developed to predict the occurrence and severity of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplants. In previous studies we reported that peripheral blood mononuclear cells of patients with rheumatoid arthritis were able to induce graft-versus-host-like histopathological changes when co-cultured in vitro with autologous skin explants. The aim of the present study was to verify if observed skin damage was really of autoimmune origin. Using a ⁵¹chromium release cytotoxic assay we found that peripheral blood mononuclear cells of patients lyzed autologous keratinocytes (n=5 patients with rheumatoid arthritis) but not autologous lymphoblasts (n=4 with rheumatoid arthritis, n=8 patients with juvenile idiopathic arthritis). No specific lysis of keratinocytes or lymphoblasts was observed in healthy controls (n=15). We hypothesize that autologous peripheral blood mononuclear cells might recognize similar autoantigen(s) expressed on epidermal cells, which gives rise to an autoimmune response in the synovium. Received: 23 November 2000 / Accepted: 30 May 2001