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Abstract Objectives Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western populations, being rarer in Asian and African people. It has been suggested that patients with CLL from Africa might have a more aggressive disease compared with white patients. In this study, we aimed to identify genetic factors that may account for this difference. Methods We analyzed immunoglobulin heavy chain (IGH) genes’ mutational status by performing next-generation sequencing in 25 Senegalese and 50 Italian patients with CLL. Results We found that Senegalese patients more frequently had adverse prognostic factors and an unmutated profile. Furthermore, we documented that IGHV1 (IGHV1-69), IGHD3, and IGHJ6 were significantly more frequent in Senegalese patients, whereas IGHV3-30 was common and limited to the Italian cohort. Stereotyped receptors commonly detected in the white population were not recorded in our Senegalese series. Conclusions The different IGH repertoire we observed in the Senegalese cohort may reflect the diverse genetic and microenvironmental (ie, polymicrobial stimulation) background.

A major obstacle to a broadly neutralizing antibody (bnAb)-based HIV vaccine is the activation of appropriate cell precursors. Germline-targeting immunogens must be capable of priming rare bnAb precursors in the physiological setting. We tested the ability of the VRCOl-class bnAb germline-targeting immunogen eOD-GT8 60mer (60-subunit self-assembling nanoparticle) to activate appropriate precursors in mice transgenic for human immunoglobulin (Ig) loci. Despite an average frequency of, at most, about one VRC01-class precursor per mouse, we found that at least 29% of singly immunized mice produced a VRC01-class memory response, suggesting that priming generally succeeded when at least one precursor was present. The results demonstrate the feasibility of using germline targeting to prime specific and exceedingly rare bnAb-precursor B cells within a humanlike repertoire.

Heavy chain deposition disease (HCDD) is characterized by the deposition of truncated monoclonal immunoglobulin heavy chains along glomerular basement membranes. Truncated heavy chains are thought to be associated with plasma cell disease (PCD), but previous bone marrow cytology tests showed that only 30% of HCDD cases are related to PCDs. We report the first known use of immunoglobulin heavy chain (IGH) gene rearrangement to diagnose a patient with γ3-HCDD, although bone marrow morphology test identified no abnormalities. Our findings provide strong evidence for a correlation between PCDs and HCDD, which could help understand the genetic background underlying abnormal heavy chains and assess disease prognosis. Further, concordant with previous findings, bortezomib-based chemotherapy had a good therapeutic effect in our patient. We summarize the experience of diagnosing and treating a case of HCDD, and combine this with a literature review to further explore the correlation between PCDs and HCDD, which has important clinical value.

The MERS-CoV is an emerging virus, which already infected more than 1,300 humans with high (∼36%) mortality. Here, we show that m336, an exceptionally potent human anti-MERS-CoV antibody, is almost germline with only one somatic mutation in the heavy chain. The structure of Fab m336 in complex with the MERS-CoV receptor-binding domain reveals that its IGHV1-69-derived heavy chain provides more than 85% binding surface and that its epitope almost completely overlaps with the receptor-binding site. Analysis of antibodies from 69 healthy humans suggests an important role of the V(D)J recombination-generated junctional and allele-specific residues for achieving high affinity of binding at such low levels of somatic hypermutation. Our results also have important implications for development of vaccine immunogens based on the newly identified m336 epitope as well as for elucidation of mechanisms of neutralization by m336-like antibodies and their elicitation in vivo . m336 is an exceptionally potent germline-like antibody against the emerging MERS-CoV virus. Here, the authors solve the structure of m336 in complex with MERS-CoV receptor-binding domain and use it to reveal a role of junctional and allele-specific residues in the interaction and suggest implications for vaccine development.

We have previously demonstrated that C5-deficient A/J and recombinant congenic BcA17 mice suffer from cardiac dysfunction when infected with C. albicans blastospores intravenously. During these studies we had observed that, even in the control un-infected state, BcA17 hearts displayed alterations in gene expression that have been associated with pathological cardiac hypertrophy in comparison to parental C5-sufficient C57Bl/6J (B6) mice. Of note was an increase in the expression of Nppb, a member of the fetal gene program and a decrease in the expression of Rgs2, an inhibitor of the hypertrophic response. We now report that C5-deletion has also affected the expression of other elements of the fetal gene program. Moreover deleting the C5a receptor, C5aR, has essentially the same effect as deleting C5, indicating a key role for C5a-C5aR signaling in the phenotype. Having noted a pathological phenotype in the un-infected state, we investigated the role of C5 in the response to cardiac stress. In previous studies, comparison of the expression profiles of C. albicans-infected BcA17 and similarly infected B6 hearts had revealed a paucity of cardioprotective genes in the C5-deficient heart. To determine whether this was also directly linked to C5-deficiency, we tested the expression of 5 such genes in the C. albicans-infected C5aR -/- mice. We found again that deletion of C5aR recapitulated the alterations in stress response of BcA17. To determine whether our observations were relevant to other forms of cardiac injury, we tested the effect of C5-deficiency on the response to isoproterenol-induced hypertrophic stimulation. Consistent with our hypothesis, A/J, BcA17 and C5aR -/- mice responded with higher levels of Nppa expression than B6 and BALB/c mice. In conclusion, our results suggest that an absence of functional C5a renders the heart in a state of distress, conferring a predisposition to cardiac dysfunction in the face of additional injury. © 2011 Mullick et al.

Most cases of swallowing‐induced atrial tachycardia require radiofrequency catheter ablation for a permanent cure; however, the arrhythmia subsided after temporary prescription of verapamil in a patient with genotyped hypertrophic cardiomyopathy. Most cases of swallowing‐induced atrial tachycardia require radiofrequency catheter ablation for a permanent cure; however, the arrhythmia subsided after temporary prescription of verapamil in a patient with genotyped hypertrophic cardiomyopathy.

B-cell lymphomas with MYC/8q24 rearrangement and IGH@BCL2/t(14;18)(q32;q21), also known as double-hit or MYC/BCL2 B-cell lymphomas, are uncommon neoplasms. We report our experience with 60 cases: 52 MYC/BCL2 B-cell lymphomas and 8 tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals/copies. There were 38 men and 22 women with a median age of 55 years. In all, 10 patients had antecedent/concurrent follicular lymphoma. Using the 2008 World Health Organization classification, there were 33 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (henceforth referred to as unclassifiable, aggressive B-cell lymphoma), 23 diffuse large B-cell lymphoma, 1 follicular lymphoma grade 3B, 1 follicular lymphoma plus diffuse large B-cell lymphoma, 1 B-lymphoblastic lymphoma, and 1 composite diffuse large B-cell lymphoma with B-lymphoblastic lymphoma. Using older classification systems, the 33 unclassifiable, aggressive B-cell lymphomas most closely resembled Burkitt-like lymphoma (n=24) or atypical Burkitt lymphoma with BCL2 expression (n=9). Of 48 cases assessed, 47 (98%) had a germinal center B-cell immunophenotype. Patients were treated with standard (n=23) or more aggressive chemotherapy regimens (n=34). Adequate follow-up was available for 57 patients: 26 died and 31 were alive. For the 52 patients with MYC/BCL2 lymphoma, the median overall survival was 18.6 months. Patients with antecedent/concurrent follicular lymphoma had median overall survival of 7.8 months. Elevated serum lactate dehydrogenase level, ≥2 extranodal sites, bone marrow or central nervous system involvement, and International Prognostic Index >2 were associated with worse overall survival (P<0.05). Morphological features did not correlate with prognosis. Patients with neoplasms characterized by extra MYC signals plus IGH@BCL2 (n=6) or MYC rearrangement with extra BCL2 signals (n=2) had overall survival ranging from 1.7 to 49 months, similar to patients with MYC/BCL2 lymphomas. We conclude that MYC/BCL2 lymphomas are clinically aggressive, irrespective of their morphological appearance, with a germinal center B-cell immunophenotype. Tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals, respectively, appear to behave as poorly as MYC/BCL2 lymphomas, possibly expanding the disease spectrum.

We have mapped and annotated the variable region of the immunoglobulin heavy (IGH) gene locus of the Brown Norway (BN) rat (assembly V3.4; Rat Genomic Sequence Consortium). In addition to known variable region genes, we found 12 novel previously unidentified functional IGHV genes and 1 novel functional IGHD gene. In total, the variable region of the rat IGH locus is composed of at least 353 unique IGHV genes, 21 IGHD genes, and 5 IGHJ genes, of which 131, 14, and 4 are potentially functional genes, respectively. Of all species studied so far, the rat seems to have the highest number of functional IGHV genes in the genome. Rat IGHV genes can be classified into 13 IGHV families based on nucleotide sequence identity. The variable region of the BN rat spans a total length of approximately 4.9 Mb and is organized in a typical translocon organization. Like the mouse, members of the various IGHV gene families are more or less grouped together on the genome, albeit some members of IGHV gene families are found intermingled with each other. In the rat, the largest IGHV gene families are IGHV1, IGHV2, and IGHV5. The overall conclusion is that the genomic organization of the variable region of the rat IGH locus is strikingly similar to that of the mouse, illustrating the close evolutionary relationship between these two species.

We performed an immunogenetic analysis of 345 IGHV–IGHD–IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele * 04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2 * 04 peaked at 31%. The IGHV1-2 * 04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2 * 04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97–99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2 * 04 allele.

Multiple myeloma (MM) is a heterogeneous disease, the full understanding of whose pathogenesis remains elusive. While B-cell receptors are known to play a pivotal role in myeloma pathogenesis, the characterization of immunoglobulin heavy-chain ( IGH ) gene repertoire and their clinical significance in Chinese patients has not been fully explored. In this study, we analyzed the profiling of clonal IGH gene rearrangements via NGS assay, and its cytogenetic abnormalities by FISH in a cohort of 301 Chinese patients with newly diagnosed MM. We identified a particular subgroup, which was characterized by a marked overrepresentation of IGHV4-39 . Additionally, IGHV4-39 was correlated with a higher somatic hypermutation rate and shorter HCDR3 length. Notably, IGHV4-39 was significantly more prevalent in patients with high-risk cytogenetic abnormalities, particularly the recurrent IGH translocations involving t(4;14). Our findings, represented the largest IGH data in MM series from Asia, and investigated the association between specific IGHV and cytogenetic alterations in Chinese MM patients for the first time.