Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies. However, the underlying cause of disease appears to relate to defects in T cell tolerance or T cell help to B cells. Transgenic (Tg) mice overexpressing the cytokine B cell–activating factor of the tumor necrosis factor family (BAFF) develop an autoimmune disorder similar to SLE and show impaired B cell tolerance and altered T cell differentiation. We generated BAFF Tg mice that were completely deficient in T cells, and, surprisingly, these mice developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did, however, require B cell–intrinsic signals through the Toll-like receptor (TLR)–associated signaling adaptor MyD88, which controlled the production of proinflammatory autoantibody isotypes. TLR7/9 activation strongly up-regulated expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which is a receptor for BAFF involved in B cell responses to T cell–independent antigens. Moreover, BAFF enhanced TLR7/9 expression on B cells and TLR-mediated production of autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, but requires TLR signaling and is independent of T cell help. It is possible that SLE patients with elevated levels of BAFF show a similar basis for disease.

TNF is well characterized as a mediator of inflammatory responses. TNF also facilitates organization of secondary lymphoid organs, particularly B cell follicles and germinal centers, a hallmark of T-dependent Ab responses. TNF also mediates defense against tumors. We examined the role of TNF in the development of inflammatory autoimmune disorders resembling systemic lupus erythematosus and Sjögren’s syndrome induced by excess B cell-activating factor belonging to the TNF family (BAFF), by generating BAFF-transgenic (Tg) mice lacking TNF. TNF−/− BAFF-Tg mice resembled TNF−/− mice, in that they lacked B cell follicles, follicular dendritic cells, and germinal centers, and have impaired responses to T-dependent Ags. Nevertheless, TNF−/− BAFF-Tg mice developed autoimmune disorders similar to that of BAFF-Tg mice. Disease in TNF−/− BAFF-Tg mice correlates with the expansion of transitional type 2 and marginal zone B cell populations and enhanced T-independent immune responses. TNF deficiency in BAFF-Tg mice also led to a surprisingly high incidence of B cell lymphomas (>35%), which most likely resulted from the combined effects of BAFF promotion of neoplastic B cell survival, coupled with lack of protective antitumor defense by TNF. Thus, TNF appears to be dispensable for BAFF-mediated autoimmune disorders and may, in fact, counter any proneoplastic effects of high levels of BAFF in diseases such as Sjögren’s syndrome, systemic lupus erythematosus, and rheumatoid arthritis.

B cell-activating factor belonging to the TNF family (BAFF; BLyS) is a critical regulator of B cell maturation and survival, and its overexpression in BAFF transgenic (Tg) mice results in the development of autoimmune disorders. BAFF also affects T cell function through binding to one of the BAFF receptors, BAFF-R. Using BAFF Tg mice, we examined a typical Th1-mediated response, the cutaneous delayed-type hypersensitivity reaction, and found a much greater degree of paw swelling and inflammation than in control mice. Importantly, delayed-type hypersensitivity scores correlated directly with BAFF levels in serum. Conversely, in a Th2-mediated model of allergic airway inflammation, BAFF Tg mice were largely protected and showed markedly reduced Ag-specific T cell proliferation and eosinophil infiltration associated with the airways. Thus, local and/or systemically distributed BAFF affects Th1 and Th2 responses and impacts on the course of some T cell-mediated inflammatory reactions. Our results are consistent with the idea that BAFF augments T cell as well as B cell responses, particularly Th1-type responses. Results in BAFF Tg mice may reflect the situation in certain autoimmune patients or virally infected individuals, because BAFF levels in blood are comparable.

B cell-activating factor belonging to the TNF family (BAFF) is a B cell survival factor required for B cell maturation. BAFF transgenic (Tg) mice develop autoimmune disorders characterized by autoantibody production, which leads to nephritis and salivary gland destruction (sialadenitis), features reminiscent of systemic lupus erythematosus and Sjögren's syndrome (SS), respectively. Disease in BAFF Tg mice correlates with the expansion of the marginal zone (MZ) B cell compartment and the abnormal presence of MZ-like B cells in the blood, LN and inflamed salivary glands, suggesting a role for these cells in BAFF-induced autoimmunity. Lymphotoxin-b (LTb)-deficient mice show disrupted splenic architecture, lack MZ B cells and some peripheral LN, and are unable to mount T cell-dependent immune responses. BAFF Tg mice lacking LTb (LTb~-BTg) retained these defects, yet still developed nephritis associated with the presence of B-1 B cells in the kidneys. However, in contrast to old BAFF Tg mice, aging LTb~-BTg mice no longer developed sialadenitis. Thus, autoimmune disorders in BAFF Tg mice are possibly events coordinated by MZ and B-1 B cells at separate anatomical sites.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/36270_s.pdf Introduction B cell-activating factor belonging to the TNF family (BAFF, also termed BLyS, TALL-1, zTNF-4, THANK, and TNFSF13b) has emerged as a cytokine critical for peripheral B cell survival and maturation (reviewed in [1][2][3][4]). BAFF supports the survival of both splenic immature transitional and mature B cells, and maturation beyond the immature transitional type 1 (T1) stage is impaired in BAFF-deficient mice (BAFF -/-) [5][6][7]. In addition, BAFF supports T-independent isotype switching from IgM to IgA [8,9]. Mice overexpressing BAFF (BAFF Tg mice) develop autoimmune disorders similar The splenic MZ B cell compartment contains both non-circulating naïve B cells and some memory B cells, which are particularly responsive to blood-borne Ag in a T cell-independent manner (reviewed in [15,16]). MZ B cells have been shown to be potentially poly-reactive (dual receptor) and/or self-reactive [17,18] and their expansion is often associated with autoimmune disorders in mice [19,20]. In BAFF Tg mice, numbers of splenic MZ B cells are increased, and MZ-like B cells reside outside of the spleen, in the blood, LN and in inflamed salivary glands of BAFF Tg mice [6,11]. The abnormal presence of MZ-like B cells outside the spleen may be important, as sequestration of MZ B cells in the MZ appears to be essential to preserve immune tolerance [17]. However, a direct connection between MZ B cell activation and kidney damage has never been made. This issue prompted us to study a model in which MZ B cells are absent.Lymphotoxin-a/b (LTa/b) is a TNF-like ligand essential for peripheral LN (PLN) development, lymphoid organ architecture and T-dependent immune responses (reviewed in [21,22]). Mice lacking LTa/b lack MZ B cells [23]. LTa/b, expressed on a...

B‐cell‐activating factor of the TNF family (BAFF)/BLyS contributes to B‐cell homeostasis and function in the periphery. BAFF is expressed as a membrane‐bound protein or released by proteolytic cleavage, but the functional importance of this processing event is poorly understood. Mice expressing BAFF with a mutated furin consensus cleavage site, i.e. furin‐mutant BAFF (fmBAFF), were not different from BAFF‐deficient mice with regard to their B‐cell populations and responses to immunization. It is however noteworthy that an alternative processing event releases some soluble BAFF in fmBAFF mice. Mild overexpression (∼5‐fold) of fmBAFF alone generated intermediate levels of B cells without improving humoral responses to immunization. Processed BAFF was however important for B‐cell homeostasis, as peripheral B‐cell populations and antibody responses were readily restored by administration of soluble BAFF trimers in BAFF‐deficient mice. However, the rescue of CD23 expression in B cells of BAFF‐deficient mice required both soluble BAFF trimers and fmBAFF, or a polymeric form of soluble BAFF (BAFF 60‐mer). These results point to a predominant role of processed BAFF for B‐cell homeostasis and function, and indicate possible accessory roles for membrane‐bound BAFF.