Germinal Centers Victora, Gabriel D; Nussenzweig, Michel C
Annual review of immunology,
04/2022, Letnik:
40, Številka:
1
Journal Article
Recenzirano
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Germinal centers (GCs) are microanatomical sites of B cell clonal expansion and antibody affinity maturation. Therein, B cells undergo the Darwinian process of somatic diversification and ...affinity-driven selection of immunoglobulins that produces the high-affinity antibodies essential for effective humoral immunity. Here, we review recent developments in the field of GC biology, primarily as it pertains to GCs induced by infection or immunization. First, we summarize the phenotype and function of the different cell types that compose the GC, focusing on GC B cells. Then, we review the cellular and molecular bases of affinity-dependent selection within the GC and the export of memory and plasma cells. Finally, we present an overview of the emerging field of GC clonal dynamics, focusing on how GC and post-GC selection shapes the diversity of antibodies secreted into serum.
Aberrant fusions between heterologous chromosomes are among the most prevalent cytogenetic abnormalities found in cancer cells. Oncogenic chromosomal translocations provide cells with a proliferative ...or survival advantage. They may either initiate transformation or be acquired secondarily as a result of genomic instability. Here, we highlight recent advances toward understanding the origin of chromosomal translocations in incipient lymphoid cancers and how tumor-suppressive pathways normally limit the frequency of these aberrant recombination events. Deciphering the mechanisms that mediate chromosomal fusions will open new avenues for developing therapeutic strategies aimed at eliminating lesions that lead to the initiation, maintenance, and progression of cancer.
Combination anti-retroviral therapy (ART) has revolutionized the treatment and prevention of HIV-1 infection. Taken daily, ART prevents and suppresses the infection. However, ART interruption almost ...invariably leads to rebound viremia in infected individuals due to a long-lived latent reservoir of integrated proviruses. Therefore, ART must be administered on a life-long basis. Here we review recent preclinical and clinical studies suggesting that immunotherapy may be an alternative or an adjuvant to ART because, in addition to preventing new infections, anti-HIV-1 antibodies clear the virus, directly kill infected cells and produce immune complexes that can enhance host immunity to the virus.
Germinal centers Victora, Gabriel D; Nussenzweig, Michel C
Annual review of immunology,
01/2012, Letnik:
30
Journal Article
Recenzirano
Germinal centers (GCs) were described more than 125 years ago as compartments within secondary lymphoid organs that contained mitotic cells. Since then, it has become clear that this structure is the ...site of B cell clonal expansion, somatic hypermutation, and affinity-based selection, the combination of which results in the production of high-affinity antibodies. Decades of anatomical and functional studies have led to an overall model of how the GC reaction and affinity-based selection operate. More recently, the introduction of intravital imaging into the GC field has opened the door to direct investigation of certain key dynamic features of this microanatomic structure, sparking renewed interest in the relationship between cell movement and affinity maturation. We review these and other recent advances in our understanding of GCs, focusing on cellular dynamics and on the mechanism of selection of high-affinity B cells.
Chromosomal rearrangements, including translocations, require formation and joining of DNA double strand breaks (DSBs). These events disrupt the integrity of the genome and are frequently involved in ...producing leukemias, lymphomas and sarcomas. Despite the importance of these events, current understanding of their genesis is limited. To examine the origins of chromosomal rearrangements we developed Translocation Capture Sequencing (TC-Seq), a method to document chromosomal rearrangements genome-wide, in primary cells. We examined over 180,000 rearrangements obtained from 400 million B lymphocytes, revealing that proximity between DSBs, transcriptional activity and chromosome territories are key determinants of genome rearrangement. Specifically, rearrangements tend to occur in
cis and to transcribed genes. Finally, we find that activation-induced cytidine deaminase (AID) induces the rearrangement of many genes found as translocation partners in mature B cell lymphoma.
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► A new genome-wide mapping method identifies translocations in primary cells ► Transcription favors chromosome rearrangement ► Rearrangements define chromosome territories in B cells ► AID-mediated translocations are found in many genes, including protooncogenes
Identification of chromosomal rearrangements on a genome-wide scale highlights the relative contributions of 3D-chromosomal organization, active transcription, and AID-activity to oncogenic translocations.
53BP1 is a DNA damage protein that forms phosphorylated H2AX (γ-H2AX) dependent foci in a 1 Mb region surrounding DNA double-strand breaks (DSBs). In addition, 53BP1 promotes genomic stability by ...regulating the metabolism of DNA ends. We have compared the joining rates of paired DSBs separated by 1.2 kb to 27 Mb on chromosome 12 in the presence or absence of 53BP1. 53BP1 facilitates joining of intrachromosomal DSBs but only at distances corresponding to γ-H2AX spreading. In contrast, DNA end protection by 53BP1 is distance independent. Furthermore, analysis of 53BP1 mutants shows that chromatin association, oligomerization, and N-terminal ATM phosphorylation are all required for DNA end protection and joining as measured by immunoglobulin class switch recombination. These data elucidate the molecular events that are required for 53BP1 to maintain genomic stability and point to a model wherein 53BP1 and H2AX cooperate to repress resection of DSBs.
► 53BP1 facilitates the joining of DSBs depending on the distance between breaks ► 53BP1 prevents DNA end resection independent of the distance between breaks ► In the absence of H2AX, 53BP1 is chromatin associated but does not block resection ► Multiple functions of 53BP1 are needed for end protection and Ig class switching
The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination ...(HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP18A, comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP18A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP18A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.
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•The mechanisms by which 53BP1 promotes NHEJ and inhibits HR are distinct•PTIP and RIF1 separate 53BP1 functions in productive and mutagenic DNA repair•PTIP promotes genome instability in BRCA1-deficient cells by inhibiting DSB resection•PTIP is required for NHEJ of dysfunctional telomeres
The DNA repair protein 53BP1 relies on two different cofactors to mediate its productive function in B cell class switching and its mutagenic function in BRCA1-deficient cells, raising the possibility of targeting one without disrupting the other.
Broadly neutralizing antibodies (bNAbs) against HIV-1 provide both effective pre-exposure prophylaxis and treatment of HIV-1 infection in murine and nonhuman primate models, suggesting their ...potential use in humans. Although much is known about the role of variable domains in the neutralization breadth and potency of these bNAbs, the contribution of Fc domains to their activities is, by contrast, poorly characterized. Assessment of the in vivo activity of several bNAbs revealed that FcγR-mediated effector function contributes substantially to their capacity to block viral entry, suppress viremia, and confer therapeutic activity. Enhanced in vivo potency of anti-HIV-1 bNAbs was associated with preferential engagement of activating, but not inhibitory FcγRs, and Fc domain-engineered bNAb variants with selective binding capacity for activating FcγRs displayed augmented protective activity. These findings reveal key roles for Fc effector function in the in vivo activity of anti-HIV-1 bNAbs and provide strategies for generating bNAbs with improved efficacy.
Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent infection and are therefore of great importance for HIV-1 vaccine design. Notably, bNAbs are highly somatically mutated and generated by a ...fraction of HIV-1-infected individuals several years after infection. Antibodies typically accumulate mutations in the complementarity determining region (CDR) loops, which usually contact the antigen. The CDR loops are scaffolded by canonical framework regions (FWRs) that are both resistant to and less tolerant of mutations. Here, we report that in contrast to most antibodies, including those with limited HIV-1 neutralizing activity, most bNAbs require somatic mutations in their FWRs. Structural and functional analyses reveal that somatic mutations in FWR residues enhance breadth and potency by providing increased flexibility and/or direct antigen contact. Thus, in bNAbs, FWRs play an essential role beyond scaffolding the CDR loops and their unusual contribution to potency and breadth should be considered in HIV-1 vaccine design.
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► Framework mutations play a crucial role in broadly neutralizing HIV-1 antibodies ► Mutations in the antibody framework are critical for HIV-1 neutralization ► Increased antibody flexibility can enhance HIV-1 neutralization activity ► FWR mutations can extend direct antigen contact resulting in improved activity
Framework regions play an essential role in the potency of broadly neutralizing antibodies beyond scaffolding and thus should be considered in HIV-1 vaccine design.
Plasma Neutralization of the SARS-CoV-2 Omicron Variant Schmidt, Fabian; Muecksch, Frauke; Weisblum, Yiska ...
New England journal of medicine/The New England journal of medicine,
02/2022, Letnik:
386, Številka:
6
Journal Article
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