Objective. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with unknown etiology and only partially defined pathogenesis. The aim of this study was to establish a murine model of chronic arthritis in which the development of tertiary lymphoid tissue, a hallmark of human RA, is locally induced, and to characterize the roles of the homeostatic chemokine receptors CXCR5 and CCR7 in this process.Methods. We developed a modified model of chronic antigen-induced arthritis (AIA) in mice with a strong bias toward inflammation. Disease pathology was assessed up to 9 months in wild-type, CXCR5-deficient, and CCR7-deficient mice by determination of knee joint swelling and cellular and humoral immune responses, as well as by histologic analysis of arthritic knee joints.Results. In this novel model of AIA, mice developed organized ectopic lymphoid follicles with topologically segregated B cell and T cell areas, high endothelial venules, and germinal center formation within the chronically inflamed synovial tissue. Analysis of the initiation and progression of AIA in wild-type, CXCR5 ؊/؊ , and CCR7 ؊/؊ mice revealed a reduction of acute inflammatory parameters in both knockout strains as well as significantly reduced joint destruction in CXCR5 ؊/؊ mice. Most importantly, the development and organization of tertiary lymphoid tissue were significantly impaired in CXCR5-deficient and CCR7-deficient mice.Conclusion. Our results suggest that an inflammatory microenvironment efficiently triggers lymphoid neogenesis in autoimmune diseases such as RA. Moreover, the generation of autoreactive tertiary lymphoid tissues, which is entirely dependent on homeostatic chemokines, may in turn maintain local aberrant chronic immune responses.

Immunity to Mycobacterium tuberculosis infection is critically dependent on the timely priming of T effector lymphocytes and their efficient recruitment to the site of mycobacterial implantation in the lung. E-, P-, and L-selectin counterreceptors control lymphocyte homing to lymph nodes and leukocyte trafficking to peripheral sites of acute inflammation, their adhesive function depending on fucosylation by fucosyltransferases (FucT) IV and VII. To address the relative importance of differentially glycosylated selectin counterreceptors for priming of T cell effector functions in a model of mycobacteria-induced granulomatous pulmonary inflammation, we used aerosol-borne M. tuberculosis to infect FucT-IV−/−, FucT-VII−/−, FucT-IV−/−/FucT-VII−/−, or wild-type control mice. In lymph nodes, infected FucT-IV−/−/FucT-VII−/− and, to a lesser extent, FucT-VII−/− mice had severely reduced numbers of T cells and reduced Ag-specific effector responses. By contrast, recruitment of activated T cells into the lungs was similar in all four groups of mice during infection and expression of T cell, and macrophage effector functions were only delayed in lungs of FucT-IV−/−/FucT-VII−/− mice. Importantly, lungs from all groups expressed CXCL13, CCL21, and CCL19 and displayed organized follicular neolymphoid structures after infection with M. tuberculosis, which suggests that the lung served as a selectin ligand-independent priming site for immune responses to mycobacterial infection. All FucT-deficient strains were fully capable of restricting M. tuberculosis growth in infected organs until at least 150 days postinfection. Our observations indicate that leukocyte recruitment functions dictated by FucT-IV and FucT-VII-dependent selectin ligand activities are not critical for inducing or maintaining T cell effector responses at levels necessary to control pulmonary tuberculosis.

Current animal models of arthritis only partially reflect the complexity of rheumatoid arthritis and typically lack either chronicity or autoantibody formation. Here we describe a model that combines features of antigen-induced arthritis and collagen-induced arthritis, which can be efficiently induced in BALB/c and C57BL/6 mice. However, BALB/c mice generate significantly higher titres of anticollagen and anticitrullinated peptide antibodies, show a stronger progressive joint destruction, and in the chronic phase the disease spreads between joints. Concomitant to the observation of a more severe pathology, we discovered a previously undescribed small periarticular lymph node in close proximity to the knee joint of BALB/c mice, which acts as the primary draining lymph node for the synovial cavity. Our model more closely reflects the pathology of rheumatoid arthritis than classical models of arthritis and is hence particularly suitable for further studies of disease pathogenesis.