Virus-induced preferential antibody gene-usage and its importance in humoral autoimmunity

Cappelletti, Francesca; Clementi, Nicola; Mancini, Nicasio; Clementi, Massimo; Burioni, Roberto

doi:10.1016/j.smim.2015.03.008

Cited by 13 publications

(11 citation statements)

References 94 publications

(116 reference statements)

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“…The results expand the concept of germline-restricted usage of antibodies suggested mostly for viral pathogens505152 and extend this to a bacterial pathogenic protein. In addition, our work also illustrates for the first time how germline V-gene encoded residues can be so dominant in driving antibody binding that resulting antibodies from different individuals exhibit nearly identical binding mechanism.…”

Section: Discussionsupporting

confidence: 71%

Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire

et al. 2016

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Staphylococcus aureus is both an important pathogen and a human commensal. To explore this ambivalent relationship between host and microbe, we analysed the memory humoral response against IsdB, a protein involved in iron acquisition, in four healthy donors. Here we show that in all donors a heavily biased use of two immunoglobulin heavy chain germlines generated high affinity (pM) antibodies that neutralize the two IsdB NEAT domains, IGHV4-39 for NEAT1 and IGHV1-69 for NEAT2. In contrast to the typical antibody/antigen interactions, the binding is primarily driven by the germline-encoded hydrophobic CDRH-2 motifs of IGHV1-69 and IGHV4-39, with a binding mechanism nearly identical for each antibody derived from different donors. Our results suggest that IGHV1-69 and IGHV4-39, while part of the adaptive immune system, may have evolved under selection pressure to encode a binding motif innately capable of recognizing and neutralizing a structurally conserved protein domain involved in pathogen iron acquisition.

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Section: Discussionsupporting

confidence: 71%

Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire

et al. 2016

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“…On the other hand, this peculiar characteristic can promote autoreactivity phenomena triggered by the cross-recognition of host cellular components, i.e. cellular membranes, leading to a self-antigen recognition [ 50 , 51 ].…”

Section: Influenza Vaccines Under-developmentmentioning

confidence: 99%

Towards a universal influenza vaccine: different approaches for one goal

Sautto

Kirchenbaum

Ross

2018

Virol J

173

140

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Influenza virus infection is an ongoing health and economic burden causing epidemics with pandemic potential, affecting 5–30% of the global population annually, and is responsible for millions of hospitalizations and thousands of deaths each year. Annual influenza vaccination is the primary prophylactic countermeasure aimed at limiting influenza burden. However, the effectiveness of current influenza vaccines are limited because they only confer protective immunity when there is antigenic similarity between the selected vaccine strains and circulating influenza isolates. The major targets of the antibody response against influenza virus are the surface glycoprotein antigens hemagglutinin (HA) and neuraminidase (NA). Hypervariability of the amino acid sequences encoding HA and NA is largely responsible for epidemic and pandemic influenza outbreaks, and are the consequence of antigenic drift or shift, respectively. For this reason, if an antigenic mismatch exists between the current vaccine and circulating influenza isolates, vaccinated people may not be afforded complete protection. There is currently an unmet need to develop an effective “broadly-reactive” or “universal” influenza vaccine capable of conferring protection against both seasonal and newly emerging pre-pandemic strains. A number of novel influenza vaccine approaches are currently under evaluation. One approach is the elicitation of an immune response against the “Achille’s heel” of the virus, i.e. conserved viral proteins or protein regions shared amongst seasonal and pre-pandemic strains. Alternatively, other approaches aim toward eliciting a broader immune response capable of conferring protection against the diversity of currently circulating seasonal influenza strains.In this review, the most promising under-development universal vaccine approaches are discussed with an emphasis on those targeting the HA glycoprotein. In particular, their strengths and potential short-comings are discussed. Ultimately, the upcoming clinical evaluation of these universal vaccine approaches will be fundamental to determine their effectiveness against preventing influenza virus infection and/or reducing transmission and disease severity.

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“…Both viruses cloak almost the entire surface of their viral glycoprotein with N-linked self-glycans, making it extremely difficult and slow for the immune system to produce virusneutralizing antibodies. [77][78][79][80][81][82] A specific example of this idea has been articulated by Lerner 88 Lerner proposed that in situations where humans were infected with a strain of influenza to which they have no previous antigenic experience these IGHV1-69 antibodies could form part of an emergency "SOS response" to neutralize the virus until more specific antibodies can develop ( Figure 2). 76 Given the conundrum of generating holes in the immune repertoire, retaining weakly self-reactive antibodies on anergic B cells F I G U R E 1 Rationale for immune system being based on a nascent repertoire of polyspecific B cells capable of clonal redemption.…”

Section: Anerg I C Cell S a S Provider S Of Protec Tive P Olyre Ac mentioning

confidence: 99%

“…antibodies account for many of the broadly neutralizing antibodies to the conserved hydrophobic hemagglutinin stalk on phylogenetically divergent influenza A viruses, yet their serum titers fall rapidly and are displaced by antibodies against strain-specific epitopes on the hemagglutinin globular head. [85][86][87][88] In healthy people, B cells with IGHV1-69 surface IgM and IgD bearing this hydrophobic CDR2 epitope (recognized by anti-idiotype monoclonal antibody G6) account for approximately 5% of the naive B cell repertoire but are much less frequent in the memory repertoire. 89 IGHV1-69 antibodies show significant autoreactivity, which can only be partially abrogated by somatic hypermutation and have been linked to autoimmune disease.…”

Section: Anerg I C Cell S a S Provider S Of Protec Tive P Olyre Ac mentioning

confidence: 99%

“…89 IGHV1-69 antibodies show significant autoreactivity, which can only be partially abrogated by somatic hypermutation and have been linked to autoimmune disease. 88 Lerner proposed that in situations where humans were infected with a strain of influenza to which they have no previous antigenic experience these IGHV1-69 antibodies could form part of an emergency "SOS response" to neutralize the virus until more specific antibodies can develop ( Figure 2). 83 As such, this would suggest that in emergency situations the body would preferentially prioritize infection control even at the expense of some autoreactivity.…”

Section: Anerg I C Cell S a S Provider S Of Protec Tive P Olyre Ac mentioning

confidence: 99%

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Clonal redemption and clonal anergy as mechanisms to balance B cell tolerance and immunity

Burnett

Reed

Christ

et al. 2019

Immunological Reviews

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The adaptive immune system is tasked with producing antibodies that recognize a wide scope of potential pathogens, including those never before encountered, and concurrently avoiding formation of antibodies binding host tissues. The diverse repertoire of antibodies produced by V(D)J recombination inevitably includes autoantibodies that bind to self‐antigens, estimated to be as much as 70% of nascent antibodies on immature B cells. Early theoretical models of tolerance hypothesized that such self‐reactive clones could not possibly be allowed to survive and mature. However from the first direct view of the fate of nascent B cells carrying a self‐binding antibody it was clear that many “forbidden clones” circulate to secondary lymphoid tissues, where they adopt an IgMlow IgD+ cell surface phenotype and are prevented from secreting autoantibodies by a series of tolerance checkpoints referred to as “clonal anergy.” Since anergic B cells can be reactivated to secrete pathogenic autoantibodies in certain settings, the advantage of controlling self‐reactive antibodies by clonal anergy has until recently remained enigmatic. Here we review this topic and recent advances showing that anergic B cells are recruited into the germinal center to mutate away from self‐reactivity, undergoing “clonal redemption” into cells making antibodies with exquisite specificity for foreign immunogens.

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Virus-induced preferential antibody gene-usage and its importance in humoral autoimmunity

Cited by 13 publications

References 94 publications

Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire

Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire

Towards a universal influenza vaccine: different approaches for one goal

Clonal redemption and clonal anergy as mechanisms to balance B cell tolerance and immunity

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