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Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
Although most cases of CVID represent sporadic forms of presentation, pedigrees consistent with autosomal dominant or autosomal recessive inheritance have also been described (Figure 33.2). Association with the human leukocyte antigen (HLA) region has been reported; however, the underlying gene defect has not been identified in most subjects with these disorders. Mutations of the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) have been identified in approximately 10% of patients, most often in heterozygosity. TACI is expressed by B lymphocytes and interacts with the B-cell activating factor (BAFF) and with a proliferation inducing ligand (APRIL). In particular, APRIL and TACI interaction promotes B-cell activation and immunoglobulin class-switch recombination. Disruption of TACI in mice leads to lymphoid proliferation, resembling lymphoid hyperplasia that is often seen in humans with CVID. However, the significance of TACI mutations in CVID pathogenesis remains unclear; with few exceptions, it seems that they may represent susceptibility, rather than disease-causing mutations. A similar significance of CVID-predisposing factors has also been attributed to mutations of BAFF receptor (BAFF-R) and CD20, reported in a few patients with CVID. In contrast, a clear causal role has been demonstrated for mutations of ICOS, CD19, and CD81. ICOS is a costimulatory molecule, expressed by T cells, that interacts with ICOS-ligand (ICOS-L) expressed by B lymphocytes. CD19 and CD81 form a cell-surface protein complex that participates in BCR-mediated signaling. Patients with CVID are highly prone to a variety of gastrointestinal manifestations (Table 33.2), including infections, autoimmunity, inflammation, and tumors. In addition, abnormalities of liver function have been reported.
CD40- and CD95-specific antibody single chain-Baff fusion proteins display BaffR-, TACI- and BCMA-restricted agonism
Published in mAbs, 2020
Johannes Nelke, Juliane Medler, Daniela Weisenberger, Andreas Beilhack, Harald Wajant
IgG antibody-mediated activation of CD95 or CD40 typically requires IgG cross-linking or antibody binding to FcγRs.12,17-21 In accordance with the idea that it is the sheer cell surface anchoring that confers agonistic activity to FcγR-bound αCD40 and αCD95 antibodies, we recently demonstrated that αCD40 and αCD95 fusion proteins harboring a CD20-specific scFv domain at the C-terminus of the heavy chain acquire strong agonism upon binding to CD20-expressing cells.12 Therefore, we wondered whether αCD40 and αCD95 fusion proteins with an MM-specific anchoring domain allow in a similar fashion FcγR-independent MM cell-mediated activation of CD40 and CD95. To investigate this question, we genetically fused a single-chain encoded trimer of soluble Baff protomers (scBaff) to the C-terminus of the heavy chain of IgG1N297A and Fab2 variants of the αCD40 antibody G28.5 and the αCD95 antibody E0922,23 resulting in the antibody fusion proteins αCD40N297A-scBaff, αCD95N297A-scBaff, αCD40Fab2-scBaff and αCD95Fab2-scBaff (Figure 1). Baff is a ligand of the TNFSF and interacts with three receptors of the TNFRSF: TACI, BCMA and Baff receptor (BaffR).24 Expression of all three Baff-interacting receptors is restricted to cells of the B-cell compartment, and especially BCMA is highly expressed on plasma cells and myeloma cells.24,25 Indeed, BCMA was successfully targeted in clinical trials with ADCs, CAR-T cells and bispecific T-cell engagers.25
B cell depletion in the treatment of multiple sclerosis
Published in Expert Opinion on Biological Therapy, 2019
Kjell-Morten Myhr, Øivind Torkildsen, Andreas Lossius, Lars Bø, Trygve Holmøy
Notably, all MS therapies have a pronounced effect on memory B cells [73]. Novel drugs that specifically target B cells include inebilizumab (MEDI-551), a therapeutic monoclonal antibody targeting CD19, which showed an acceptable safety profile in a phase 1 MS trial [74] and is also currently included in a trial of NMOSD [75]. A greater impact on the immunoglobulin synthesis is expected from anti-CD19 therapy, but the clinical significance is not known. A phase 2 study of atacicept, a recombinant fusion protein that binds and inactivates BAFF and APRIL, surprisingly increased clinical disease activity [76]. Phase 2 studies on monoclonal antibodies targeting BAFF (tabalumab) and BAFF receptor (VAY736) have been completed, but the results are so far not published [69]. Data from the primary analysis of a phase 2 trial on a Bruton’s tyrosine kinase inhibitor was recently presented, showing a significant reduction in MRI disease activity [69,77]
Emerging targets for the treatment of lupus erythematosus: There is no royal road to treating lupus
Published in Modern Rheumatology, 2019
BAFF [alternatively called B-lymphocyte stimulator (BLyS) or tumor necrosis factor ligand superfamily, member 13B (TNFSF13B)] and a proliferation-inducing ligand or TNFSF13 (APRIL) are B-cell survival factors. BAFF is overexpressed in the plasma of patients with SLE, and its levels correlate with disease activity [21]. BAFF binds to BAFF receptor, transmembrane activator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen (BCMA), whereas APRIL binds only to TACI and BCMA. BAFF receptor is widely expressed on the surface of immature B cells, mature B cells, activated B cells, and memory B cells but not on bone marrow plasma cells. In contrast, TACI and BCMA are expressed from memory B cells to plasma cells and on plasma cells, respectively. Thus, belimumab (BEL), an anti-BAFF antibody, blocks BAFF-mediated signaling, whereas atacicept (TACI-Ig) inhibits both BAFF- and APRIL-mediated signaling in broader subpopulations of B cells.