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Fabienne Mackay

Publications and source records attributed to Fabienne Mackay.

30 records · Page 2Linked to original sources
PubMed2004

TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma.

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.

Animals↗
PubMed2004

The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF.

The TNF family ligand B cell-activating factor (BAFF, BLyS, TALL-1) is an essential factor for B cell development. BAFF binds to three receptors, BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA), but only BAFF-R is required for successful survival and maturation of splenic B cells. To test whether the effect of BAFF is due to the up-regulation of anti-apoptotic factors, TACI-Ig-transgenic mice, in which BAFF function is inhibited, were crossed with transgenic mice expressing FLICE-inhibitory protein (FLIP) or Bcl-2 in the B cell compartment. FLIP expression did not rescue B cells, while enforced Bcl-2 expression restored peripheral B cells and the ability to mount T-dependent antibody responses. However, many B cells retained immaturity markers and failed to express normal amounts of CD21. Marginal zone B cells were not restored and the T-independent IgG3, but not IgM, response was impaired in the TACI-IgxBcl-2 mice. These results suggest that BAFF is required not only to inhibit apoptosis of maturating B cells, but also to promote differentiation events, in particular those leading to the generation of marginal zone B cells.

Animals↗
PubMed2004

The role of the BAFF/APRIL system in B cell homeostasis and lymphoid cancers.

Signaling through the B cell antigen receptor promotes activation and survival of mature B cells. B cell-activating factor belonging to the tumor necrosis factor family (BAFF) is another critical survival factor for B cells, and is also necessary for B cell maturation. Abnormal production of BAFF disturbs immune tolerance by allowing the survival of autoreactive B cells, thus triggering autoimmune disorders. BAFF can also have an important impact on B cell malignancies. In contrast to normal B cells, malignant B cells show uncontrolled cell proliferation. BAFF levels are elevated in the serum of patients with systemic autoimmune diseases, and, importantly, in patients with B-lymphoid malignancies. Furthermore, BAFF is produced by malignant B cells and acts as an essential autocrine survival factor. The strong dependence of certain lymphoid cancer cells on BAFF might be a point of vulnerability, which offers exciting new therapeutic possibilities.

Antibodies, Monoclonal↗
PubMed2004

Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches.

The role of BAFF in B cell self tolerance was examined by tracking the fate of anti-HEL self-reactive B cells in BAFF transgenic mice using four different models of self-reactive B cell deletion. BAFF overexpression did not affect the development of self-reactive B cells normally deleted in the bone marrow or during the early stages of peripheral development. By contrast, self-reactive B cells normally deleted around the late T2 stage of peripheral development were rescued from deletion, matured, and colonized the splenic follicle. Furthermore, self-reactive B cells normally selectively deleted from the marginal zone repopulated this compartment when excess BAFF was present. Self-reactive B cells rescued by excess BAFF were not anergic. BAFF overexpression therefore rescued only self-reactive B cells normally deleted with relatively low stringency and facilitated their migration into otherwise forbidden microenvironments. This partial subversion of B cell self tolerance is likely to underlie the autoimmunity associated with BAFF overexpression.

Animals↗
PubMed2003

BAFF selectively enhances the survival of plasmablasts generated from human memory B cells.

The generation of Ig-secreting cells (ISCs) from memory B cells requires interactions between antigen-specific (Ag-specific) B cells, T cells, and dendritic cells. This process must be strictly regulated to ensure sufficient humoral immunity while avoiding production of pathogenic autoantibodies. BAFF, a member of the TNF family, is a key regulator of B cell homeostasis. BAFF exerts its effect by binding to three receptors - transmembrane activator of and CAML interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). To elucidate the contribution of BAFF to the differentiation of B cells into ISCs, we tracked the fate of human memory B cells stimulated with BAFF or CD40L. BAFF and CD40L significantly increased the overall number of surviving B cells. This was achieved via distinct mechanisms. CD40L induced proliferation of nondifferentiated blasts, while BAFF prevented apoptosis of ISCs without enhancing proliferation. The altered responsiveness of activated memory B cells to CD40L and BAFF correlated with changes in surface phenotype such that expression of CD40 and BAFF-R were reduced on ISCs while BCMA was induced. These results suggest BAFF may enhance humoral immunity in vivo by promoting survival of ISCs via a BCMA-dependent mechanism. These findings have wide-ranging implications for the treatment of human immunodeficiencies as well as autoimmune diseases.

ADP-ribosyl Cyclase↗
PubMed2002

TNF ligands and receptors in autoimmunity: an update.

Over two decades of research have increased the interest in factors from the tumor necrosis factor family. The vast majority of these factors are powerful modulators of critical immune functions and participate in pathogenic mechanisms leading to autoimmune disease. This field constantly evolves with the addition of new family members and the discovery of their function. During the past few years several additional factors from this family, such as BAFF, RANKL, TRAIL and GITRL, have emerged with novel functions that regulate both T and B cell immune tolerance and participate in tissue destruction in autoimmunity. These new findings revealed exciting innovative strategies for the treatment of autoimmune diseases.

Animals↗
PubMed2002

BAFF: a fundamental survival factor for B cells.

B-cell-activating factor of the tumour-necrosis-factor family (BAFF) enhances B-cell survival--a function that is indispensable for B-cell maturation--and has a role in enhancing immune responses. Moreover, the overexpression of BAFF results in severe autoimmune disorders in mice, and elevated serum levels of BAFF occur in some patients who have autoimmune diseases. The elucidation of the role of BAFF has set the stage for a new approach to the treatment of autoimmune disease.

Animals↗
PubMed2002

Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome.

BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sjögren's syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. In humans, SS also correlates with elevated levels of circulating BAFF, as well as a dramatic upregulation of BAFF expression in inflamed salivary glands. A likely explanation for disease in BAFF Tg mice is excessive survival signals to autoreactive B cells, possibly as they pass through a critical tolerance checkpoint while maturing in the spleen. The marginal zone (MZ) B cell compartment, one of the enlarged B cell subsets in the spleen of BAFF Tg mice, is a potential reservoir of autoreactive B cells. Interestingly, B cells with an MZ-like phenotype infiltrate the salivary glands of BAFF Tg mice, suggesting that cells of this compartment potentially participate in tissue damage in SS and possibly other autoimmune diseases. We conclude that altered B cell differentiation and tolerance induced by excess BAFF may be central to SS pathogenesis.

Age Factors↗
PubMed2002

Manipulation of lymphoid microenvironments in nonhuman primates by an inhibitor of the lymphotoxin pathway.

Reticular networks in lymphoid organs play critical roles in the organization of local microenvironments. A number of these elements are maintained by continual signaling through the lymphotoxin system. Evaluation of the lymphotoxin (LT) pathway in primates using a fusion protein decoy provides a unique opportunity to assess modulation of splenic microenvironments in a species with considerably greater background immunological activity compared with rodents. Within the germinal center microenvironment, treatment resulted in a collapse of follicular dendritic cell (FDC) networks and in the disappearance of a ringlike network of immune complex-carrying cells, although some other attributes of the germinal center appeared to be unaltered. Treatment also resulted in changes in the splenic marginal zone, a microenvironment where the architecture is notably different from that of the rodent. Cessation of treatment and recovery allowed us to monitor reemergence of these cell types and revealed that FDCs rely on LT-dependent signals to recompact into appropriately positioned tight networks. Despite the loss of FDC networks, the primary Ab response to keyhole limpet hemocyanin was unaltered over a 20-day period. Manipulation of these microenvironments may represent a novel approach to modulating immune function in human disease.

Animals↗
PubMed2001

BAFF AND APRIL: a tutorial on B cell survival.

BAFF, a member of the TNF family, is a fundamental survival factor for transitional and mature B cells. BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients. APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role. The BAFF system provides not only potential insight into the development of autoreactive B cells but a relatively simple paradigm to begin considering the balancing act between survival, growth, and death that affects all cells.

Animals↗
PubMedDate not supplied

The TNF family members BAFF and APRIL: the growing complexity.

B cell activating factor belonging to the TNF family (BAFF) and apoptosis-inducing ligand (APRIL) are two related members of the TNF ligand superfamily. Although they share two receptors, TACI and BCMA, transgenic and knockout mice in this system reveal that their functions are not redundant. BAFF is a critical survival/maturation factor for peripheral B cells and this activity is mediated through a BAFF-specific receptor, BAFF-R. Overexpression of BAFF has been linked to autoimmune disease and aspects of B cell neoplasia. APRIL appears to play a role in T-independent type II antigen responses and T cell survival, but can also induce proliferation/survival of non-lymphoid cells. Elevated expression of APRIL has been found in some tumor cell lines and in tumor tissue libraries. Therapies designed to inhibit the BAFF and APRIL pathways holds great promise for the future.

Animals↗