BLyS in humoral immunity
- Chaim Putterman1
© Current Science Ltd 2000
Published: 29 August 2000
The identification and biological actions of a newly described TNF homologue alternatively known as BLyS, BAFF and zTNF4 has generated much interest among immunologists. In previous paper reports, I discussed recent articles describing autoimmune features in BAFF-transgenic mice. A possible role for this molecule in autoimmunity could also be inferred by the presence of high levels of this mediator in murine models of lupus, and a moderate therapeutic effect of the soluble BAFF receptor TACI (transmembrane activator and CAML-interactor) in murine lupus. To study the molecular effects of the molecule and define a role for BLyS in humoral immunity.
In agreement with previous reports, Yan et al found that the receptor for BLyS was TACI, a previously identified orphan member of the TNF receptor family. Labeled human BLyS bound to cells transfected with a TACI-expression plasmid, and a TACI-Fc fusion protein bound to cells transfected with transmembrane human BLyS. Binding of BLyS to TACI was also confirmed by co-immunoprecipitation experiments. As TNF receptor family members can signal via NF-?B, activation of this transcription factor by BLyS-TACI interaction was studied. Tranfection of TACI alone into cells resulted in little change, while addition of purified BLyS or BLyS co-transfection resulted in significant NF-?B activation. To determine if BLyS-TACI interaction in vivo is important in humoral immune responses, mice were immunized with NP-CGG and treated with TACI-Fc. TACI-Fc significantly inhibited NP-specific IgM and the total and high affinity IgG1 anti-NP antibody responses. No antibody forming cell foci were seen in the splenic periarteriolar lymphoid sheath (PALS) area in treated mice. Furthermore, no germinal centers were present in spleens of TACI-Fc treated mice 14 days after immunization, while splenic follicular architecture was preserved.
Interactions between members of the tumor necrosis factor (TNF) ligand superfamily and their receptors play critical roles in T and B cell responses. BLyS is a newly described member of this family; several recent studies have suggested an important role for this molecule in autoimmunity. Furthermore, inhibiting BLyS might also have a therapeutic role in downregulating autoimmune disease. This paper expands on the role of BLyS interacting with its receptor (TACI) in a normal humoral response. Using a fusion molecule of TACI with Fc to inhibit BLyS-TACI interaction facilitated the study of the normal effects of TACI-BLyS engagement. In vitro, BLyS was found to signal via NF-?B activation and increase IgM production in B cells. In a primary immunization model using hapten carrier, BLyS blockade inhibited IgM and IgG anti-hapten antibody responses and germinal center formation. Interesting homologies between the BLyS-TACI and CD40-CD40L systems will no doubt lead to further investigation into possible relationships between these TNF-TNF receptor-like ligand-receptor pairs. The results confirm a critical role for BLyS-TACI interaction in the normal humoral immune response. Interfering with BLyS-TACI interaction using TACI-Fc or a different agent in autoimmune conditions may have therapeutic potential; however, this modality will need to be fine tuned so as to not inhibit the normal protective aspects of the humoral immune response against infection and other foreign antigens.
The BLyS receptor was cloned and identified by staining with labeled BLyS cells transfected with cDNAs from a BLyS responsive B cell line. Activation of the transcription factor NF-?B was determined after transfection of the receptor, and stimulation with BLyS. The effects of BLyS-receptor interaction in humoral immunity were tested by treating mice immunized with nitrophenyl-conjugated chicken gamma globulin (CGG) with the receptor-Fc fusion protein, and following the serum antibody response and splenic histology.