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Background The B-cell receptor transmembrane activator and calcium modulator ligand interactor (TACI) is important for T-independent antibody responses. One in 200 blood donors are heterozygous for the TACI A181E mutation. Objective We sought to investigate the effect on B-cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice. Methods Nuclear factor κB (NF-κB) activation was measured by using the luciferase assay in 293T cells cotransfected with wild-type and mutant TACI. TACI-driven proliferation, isotype switching, and antibody responses were measured in B cells from heterozygous TACI A144E knock-in mice. Mouse mortality was monitored after intranasal pneumococcal challenge. Results Levels of natural antibodies to the pneumococcal polysaccharide component phosphocholine were significantly lower in A181E-heterozygous than TACI-sufficient Swedish blood donors never immunized with pneumococcal antigens. Although overexpressed hTACI A181E and mTACI A144E acted as dominant-negative mutations in transfectants, homozygosity for A144E in mice resulted in absent TACI expression in B cells, indicating that the mutant protein is unstable when naturally expressed. A144E heterozygous mice, such as TACI +/− mice, expressed half the normal level of TACI on their B cells and exhibited similar defects in a proliferation-inducing ligand–driven B-cell activation, antibody responses to TNP-Ficoll, production of natural antibodies to phosphocholine, and survival after intranasal pneumococcal challenge. Conclusion These results suggest that TACI A181E heterozygosity results in TACI haploinsufficiency with increased susceptibility to pneumococcal infection. This has important implications for asymptomatic TACI A181E carriers. [ABSTRACT FROM AUTHOR]

Abstract: Immunoglobulin D (IgD) was recently suggested to be an ancient Ig class, as old as IgM, arising approximately 500 million years ago. Its encoding gene has now been identified in nearly all classes of jawed vertebrates (except birds). Variance in the number of CH encoding exons and alternative RNA splicing confers this Ig class a marked structural plasticity, which differs substantially from IgM. Expression of the δ gene can be achieved through co-transcription with the μ gene or by class switching. Although a recent study has suggested that IgD functions as an immunomodulator in immunity and inflammation in humans, its functions are still far from clear. Further studies at the protein levels in additional species may help answer this question. [Copyright &y& Elsevier]

Background Genetic variation at human leukocyte antigen (HLA) alleles influences many phenotypes and mediate susceptibility to a wide range of human diseases include Immunoglobulin A Deficiency (IgAD). The high resolution SNP genotyping has enabled large cohort studies in this complex region. Aim To Investigate the HLA association of IgAD using high resolution SNP data and to identify the combinations of biologically relevant amino acid (AA) residues directly involved in disease. Methods HLA imputation was performed in 1046 samples including 758 IgAD individual and 288 ethnically matched controls. The imputation results were further confirmed by high resolution typing. Subsequently, multiple tools include SKDM HLA tools, SNP2HLA and Plink were used to investigate the amino acid binding pocket association in IgAD cohorts. Finally, 3D visualization of the predicted HLA amino acid sequence was performed using RaptorX. Results Strong IgAD association were observed in HLA-B*0801 ( p = 5.364 ∗ 10 −14 ), HLA-B*1402 ( p = 0.0016), HLA-DRB1*0301 ( p = 3.276 ∗ 10 −12 ), HLA-DRB1*0102 ( p = 0.001 ∗ 10 −12 ), HLA-DRB1*1201 ( p = 1.684 ∗ 10 −4 ), HLA-DQB1*0201 ( p = 1.835 ∗ 10 −12 ). Conversely, HLA-B*1501 ( p = 1.358 ∗ 10 −5 ), HLA-B*0702 ( p = 5.662 ∗ 10 −7 ), HLA-DRB1*1501 ( p = 6.34 ∗ 10 −23 ), HLA-DQB1*0402 ( p = 0.004) and HLA-DQB1*0602 ( p = 9.396 ∗ 10 −23 ) showed strong protection against IgAD. In addition, most significant AA residues in different HLA region associated with IgAD are: HLA-B ((AA 9, Asp, pockets 2 and 3, p = 8.047 ∗ 10 −14 ); (AA 156, Asp, pockets 4 and 5, p = 4.396 ∗ 10 −13 )); HLA-DRB1 ((AA 26, Tyr, pocket 4, p = 8.249 ∗ 10 −10 ); (AA 67, Leu, pocket 7, p = 5.236 ∗ 10 −8 )); HLA-DQB1 ((AA 38, Val, pocket 9, p = 4.894 ∗ 10 −10 ); (AA 37, Ile, pocket 9, p = 8.216 ∗ 10 −9 ), (AA 28 Ser and AA 47 Phe, pocket 7, p = 8.216 ∗ 10 −9 ); (AA 30, Ser, pocket 6, p = 8.216 ∗ 10 −9 ); (AA 71, Lys, pockets 4 and 7, p = 8.216 ∗ 10 −9 )). Conclusion The results suggested that certain peptide-binding residues of the HLA class I and class II molecule is associated with susceptibility to IgAD. [ABSTRACT FROM AUTHOR]

Abstract: Based on presently available genome data, we characterized the genomic organization of all three light chain gene (ρ, σ and type III) loci in Xenopus tropicalis. The ρ gene locus in X. tropicalis, structurally similar to the κ gene loci in mammals, was shown to contain a single C ρ gene and nine J ρ segments. The σ locus also contains a single C gene, although two distinct C σ genes have previously been found in Xenopus laevis (most likely due to chromosome polyploidy). Four J σ gene segments were identified upstream of the C σ . The type III light chain gene locus, spanning approximately 170kb DNA, structurally resembles the topology of mammalian λ gene loci, containing three C genes (CIII1–3). CIII2 and CIII3 are both preceded by single, unique, J genes, whereas CIII1 contains three J gene segments. Furthermore, two additional J gene segments, termed JIIIx1 and JIIIx2, were found in the intron separating VIII2 and pVIII1 (a pseudogene). Based on BLAST searches against the X. tropicalis EST database, all the C genes identified in this study were shown to be functional. On the basis of similarity of protein sequences, genomic organization and chromosomal location of the light chain genes among frogs and mammals, our data strongly support the previous suggestions that the ρ genes belong to the κ gene lineage, whereas the type III genes share a common origin with the λ genes. [Copyright &y& Elsevier]