Light chain skewing in autoantibodies and B-cell receptors of the citrullinated antigen-binding B-cell response in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 1% of the world population. RA is associated with the presence of autoantibodies, of which anti-citrullinated protein antibodies (ACPA) are most prominent. ACPA are produced by citrullinated antigen-binding B cells that have presumably survived tolerance checkpoints.

Persistently activated, proliferative memory autoreactive B cells promote inflammation in rheumatoid arthritis.

Autoreactive B cells mediate autoimmune pathology, but exactly how remains unknown. A hallmark of rheumatoid arthritis (RA), a common autoimmune disease, is the presence of disease-specific anticitrullinated protein antibodies (ACPAs). Here, we showed that ACPA-positive B cells in patients with RA strongly expressed T cell-stimulating ligands, produced abundant proinflammatory cytokines, and were proliferative while escaping inhibitory signals.

Generation and Characterization of Anti-Citrullinated Protein Antibody-Producing B Cell Clones From Rheumatoid Arthritis Patients.

Objective: Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA). Aside from autoantibody production, the function of autoantigen-specific B cells remains poorly understood in the context of this disease. This study set out to elucidate autoantigen-specific B cell functions through the isolation and immortalization of unique citrullinated protein/peptide (CP)-reactive B cell clones from RA patients.

Synovial fluid mononuclear cells provide an environment for long-term survival of antibody-secreting cells and promote the spontaneous production of anti-citrullinated protein antibodies.

Objectives: In rheumatoid arthritis (RA), observations point to a crucial role for (autoreactive) B cells in disease pathogenesis. Here, we studied whether cells from the synovial environment impact on the longevity of autoreactive B cell responses against citrullinated antigens.

Methods: Synovial fluid mononuclear cells and peripheral blood mononuclear cells (SFMC/PBMC) were obtained from patients with established RA and assessed for the presence of B cell subpopulations.

Identification and characterisation of citrullinated antigen-specific B cells in peripheral blood of patients with rheumatoid arthritis.

Objectives: Immunity to citrullinated antigens is a hallmark of rheumatoid arthritis (RA). We set out to elucidate its biology by identifying and characterising citrullinated antigen-specific B cells in peripheral blood of patients with RA.

Methods: Differentially labelled streptavidin and extravidin tetramers were conjugated to biotinylated CCP2 or control antigens and used in flow cytometry to identify citrullinated antigen-specific B cells in peripheral blood.

Circulating plasmablasts/plasmacells as a source of anticitrullinated protein antibodies in patients with rheumatoid arthritis.

Objective: To study the characteristics and phenotype of anticitrullinated protein antibody (ACPA)-specific B cells in peripheral blood of patients with rheumatoid arthritis (RA).

Methods: Peripheral blood B cells from ACPA-positive patients with RA were cultured with or without stimulating factors. Following culture, supernatants were assessed for the presence of ACPA-IgG and non-specific total IgG by ELISA.

DX5(+)CD4(+) T cells modulate cytokine production by CD4(+) T cells towards IL-10 via the production of IL-4.

CD4(+) Th cells play a critical role in orchestrating the adaptive immune response. Uncontrolled Th1 responses are implicated in the pathogenesis of autoimmune diseases. T cells with immune-modulatory properties are beneficial for inhibiting such inflammatory responses.

The ACPA isotype profile reflects long-term radiographic progression in rheumatoid arthritis.

Background: The presence of anti-citrullinated protein antibodies (ACPA) is a powerful predictive factor for the development and progression of rheumatoid arthritis (RA). The ACPA response has been shown to consist of various isotypes, but the consequences of differences in isotype distribution have not been extensively investigated.

Objective: To investigate the relationship between ACPA isotypes, disease progression and radiological outcome.

Identification of citrullinated vimentin peptides as T cell epitopes in HLA-DR4-positive patients with rheumatoid arthritis.

Objective: Antibodies directed against citrullinated proteins (ACPAs) are highly specific for rheumatoid arthritis (RA). The production of ACPAs is most likely dependent on the presence of T cells, since ACPAs undergo isotype switching and are associated with the shared epitope (SE)-containing HLA-DRB1 alleles. Vimentin is a likely candidate protein for T cell recognition, since >90% of patients positive for ACPAs that are reactive with (peptides derived from) citrullinated vimentin carry SE-containing HLA-DRB1 alleles.

Immunomodulatory dendritic cells inhibit Th1 responses and arthritis via different mechanisms.

Dendritic cells (DCs) are professional APCs which have the unique ability to present both foreign and self-Ags to T cells and steer the outcome of immune responses. Because of these characteristics, DCs are attractive vehicles for the delivery of therapeutic vaccines. Fully matured DCs are relatively well-defined and even used in clinical trials in cancer.

A novel role of complement factor C1q in augmenting the presentation of antigen captured in immune complexes to CD8+ T lymphocytes.

Ag-IgG immune complexes (IC) are efficiently taken up, and Ag-derived peptides are subsequently processed and presented by APC. In vitro experiments indicate that IgG Fc Receptors (FcgammaR) facilitate the efficient uptake of IC by dendritic cells. Previous experiments showed that the cross-presentation of Ag-derived peptides after s.

Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells.

Foxp3 plays a key role in CD4+ CD25+ T(reg) cell function in mice and represents a specific marker for these cells. Despite the strong association between FOXP3 expression and regulatory function in fresh human T cells, little is known about the dynamics of endogenous FOXP3 expression and its relation to the suppressive function in activated human T cells. Here, we addressed the dynamics of FOXP3 expression during human CD4+ T cell activation by plate-bound anti-CD3 Ab as well as the relationship between its expression and regulatory function at the single-cell level.

Dendritic cells, but not macrophages or B cells, activate major histocompatibility complex class II-restricted CD4+ T cells upon immune-complex uptake in vivo.

Professional antigen-presenting cells (APC) are able to process and present exogenous antigen leading to the activation of T cells. Antigen-immunoglobulin (Ig)G complexes (IC) are much more efficiently processed and presented than soluble antigen. Dendritic cells (DC) are known for their ability to take up and process immune complex (IC) via FcgammaR, and they have been shown to play a crucial role in IC-processing onto major histocompatibility complex (MHC) class I as they contain a specialized cross-presenting transport system required for MHC class I antigen-processing.

Murine Fc receptors for IgG are redundant in facilitating presentation of immune complex derived antigen to CD8+ T cells in vivo.

Antigen(Ag)-immunoglobulin (Ig)G complexes (IC) are more efficiently processed and presented than soluble Ag. IC can bind to various cell types via different types of Fc-Receptors or, upon binding to complement factors, by complement receptors. Murine professional antigen-presenting cells (APC) express four types of FcgammaReceptors (FcgammaR) via which they are able to capture IC; three activating receptors (FcgammaRI, III and IV) and one inhibitory receptor (FcgammaRII).

Control of systemic B cell-mediated autoimmune disease by nonmyeloablative conditioning and major histocompatibility complex-mismatched allogeneic bone marrow transplantation.

Systemic autoimmune disease (AID) can be controlled with conventional therapies in most patients. However, relapses are common, leading to progressive disability and premature death. Nonmyeloablative conditioning and allogeneic bone marrow transplantation (BMT) could be an effective treatment for severe AID, because of mild toxicity of the conditioning and the potential benefits of donor chimerism.

Functional regulatory immune responses against human cartilage glycoprotein-39 in health vs. proinflammatory responses in rheumatoid arthritis.

The class of immune response against autoantigens could profoundly influence the onset and/or outcome of autoimmune diseases. Until now, there is only limited information on the antigen-specific balance between proinflammatory and regulatory responses in humans. Here we analyzed the natural immune response against a candidate autoantigen in rheumatoid arthritis, human cartilage glycoprotein-39 (HC gp-39).

Activation of dendritic cells that cross-present tumor-derived antigen licenses CD8+ CTL to cause tumor eradication.

The fate of naive CD8(+) T cells is determined by the environment in which they encounter MHC class I presented peptide Ags. The manner in which tumor Ags are presented is a longstanding matter of debate. Ag presentation might be mediated by tumor cells in tumor draining lymph nodes or via cross-presentation by professional APC.

Antigen-specific immunomodulation of collagen-induced arthritis with tumor necrosis factor-stimulated dendritic cells.

Objective: Dendritic cells (DCs) are crucial for the initiation of T cell immunity and therefore play an important role in the initiation and regulation of immune responses in arthritis. Full mobilization of effector T cells depends on the proper maturation of DCs. Current evidence indicates that the type of T cell response induced is crucially dependent on the activation status of the DCs.

CD40 stimulation leads to effective therapy of CD40(-) tumors through induction of strong systemic cytotoxic T lymphocyte immunity.

Adequate spontaneous activation of tumor-specific T lymphocytes in tumor-bearing hosts is rare, despite the expression of tumor antigens that are potentially highly immunogenic. For example, failure of the immune system to raise competent responses against established tumors expressing the human adenovirus E1A-antigen allows this tumor to grow in immunocompetent mice. We show that systemic in vivo administration of agonistic anti-CD40 antibodies into tumor-bearing mice results in tumor eradication mediated by CD8(+) T cells.