Control systems and decision making for antibody production

Goodnow, Christopher C.; Vinuesa, Carola G.; Randall, Katrina L.; Mackay, Fabienne; Brink, Robert

doi:10.1038/ni.1900

Cited by 378 publications

(398 citation statements)

References 127 publications

Supporting

Mentioning

385

Contrasting

Unclassified

Order By: Relevance

“…2G). The bias toward GC differentiation in self-reactive B cells may result from decreased BCR signaling to NF-κB and consequent poor induction of Ebi2 and Irf4 in anergic B cells (37), because induction of these genes favors plasma cell differentiation and disfavors GC differentiation (38)(39)(40).…”

Section: Resultsmentioning

confidence: 99%

Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity

Sabouri

Schofield

Horikawa

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

214

256

View full text Add to dashboard Cite

The best-understood mechanisms for achieving antibody self/nonself discrimination discard self-reactive antibodies before they can be tested for binding microbial antigens, potentially creating holes in the repertoire. Here we provide evidence for a complementary mechanism: retaining autoantibodies in the repertoire displayed as low levels of IgM and high IgD on anergic B cells, masking a varying proportion of autoantibody-binding sites with carbohydrates, and removing their self-reactivity by somatic hypermutation and selection in germinal centers (GCs). Analysis of human antibody sequences by deep sequencing of isotype-switched memory B cells or in IgG antibodies elicited against allogeneic RhD+ erythrocytes, vaccinia virus, rotavirus, or tetanus toxoid provides evidence for reactivation of anergic IgM low IgD+ IGHV4-34+ B cells and removal of cold agglutinin self-reactivity by hypermutation, often accompanied by mutations that inactivated an N-linked glycosylation sequon in complementarity-determining region 2 (CDR2). In a Hy10 antibody transgenic model where anergic B cells respond to a biophysically defined lysozyme epitope displayed on both foreign and self-antigens, cell transfers revealed that anergic IgM low IgD+ B cells form twice as many GC progeny as naïve IgM hi IgD+ counterparts. Their GC progeny were rapidly selected for CDR2 mutations that blocked 72% of antigen-binding sites with N-linked glycan, decreased affinity 100-fold, and then cleared the binding sites of blocking glycan. These results provide evidence for a mechanism to acquire self/non-self discrimination by somatic mutation away from self-reactivity, and reveal how varying the efficiency of N-glycosylation provides a mechanism to modulate antibody avidity.self-tolerance | affinity maturation | clonal selection | autoimmunity

show abstract

Section: Resultsmentioning

confidence: 99%

Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity

Sabouri

Schofield

Horikawa

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

214

256

View full text Add to dashboard Cite

show abstract

“…Alternatively and not mutually exclusive, selftolerance of bone marrow plasma cells may be ensured by negative selection of autoreactive antigen-experienced B cells, for example, during their differentiation in the germinal center or before homing to the bone marrow and occupying niches that promote long-term plasma cell survival. Activation of the inhibitory IgG Fc receptor IIb (FcγRIIb) by autoantigen-containing immune complexes may provide a mechanism to regulate specifically autoreactive germinal center B cells and memory B cells in mice and humans (25,26). FcγRIIb also regulates plasma cell survival in both species (27,28).…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of self-reactivity discriminates between IgG⁺human circulating memory B cells and bone marrow plasma cells

Scheid

Mouquet

Köfer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Long-term humoral immunity is maintained by the formation of high-affinity class-switched memory B cells and long-lived antibody-secreting plasma cells. In healthy humans, a substantial fraction of IgG-positive memory B cells express self-reactive and polyreactive IgG antibodies that frequently develop by somatic mutations. Whether self-and polyreactive IgG-secreting B cells are also tolerated in the long-lived plasma cell pool is not known. To address this question, we cloned and expressed the Ig genes from 177 IgG-producing bone marrow plasma cells of four healthy donors. All antibodies were highly mutated but the frequency of self-and polyreactive IgG antibodies was significantly lower than that found in circulating memory B cells. The data suggest that in contrast to the development of memory B cells, entry into the bone marrow plasma cell compartment requires previously unappreciated selective regulation by mechanisms that limit the production of self-and polyreactive serum IgG antibodies. N ewly developing self-reactive B cells are efficiently counterselected at two tolerance checkpoints before becoming circulating naive B cells (1, 2). Antigen-mediated activation of naive B cells in the presence of T-cell help induces germinal centers and the development of memory B cells and long-lived bone marrow plasma cells that express high affinity, isotype class-switched antibodies (3, 4). Surprisingly, compared with naive B cells, circulating IgG-positive memory B cells are significantly enriched for self-reactive and polyreactive antibodies (5). These antibodies develop in the germinal center from nonself-reactive or polyreactive precursors by somatic mutations and appear in the serum of healthy humans in low amounts (6). Whether cells producing self-reactive and polyreactive IgG can enter the bone marrow plasma cell compartment has not been determined.To address this question, we produced recombinant monoclonal antibodies from isolated IgG-secreting plasma cells from bone marrow of four healthy donors (HDs) and compared the Ig gene features and antibody reactivity profiles to historic data obtained from IgG-positive memory B cells (5, 7). Ig gene sequence analysis showed that bone marrow plasma cells carry significantly higher numbers of somatic mutations than circulating memory B cells and that the two compartments differ in their Ig light (IgL) chain variable (V) gene use and IgG isotype subclass distribution. Further, the frequency of polyreactive and self-reactive IgG-positive antibodies was significantly lower in bone marrow plasma cells than in the memory B-cell compartment. In summary, the data suggest that entry into the bone marrow plasma cell compartment is selective for B cells producing highly mutated antibodies that are not self-or polyreactive.

show abstract

“…In the case of classical immune induction, production of anti-therapeutic protein responses is the end result of a sequence of events that lead to B cell activation, and can be divided into T cell-independent (Ti) or T cell-dependent (Td) antibody production [3,4]. Ti activation of B cells occurs when particular structural patterns, such as polymeric repeats, are able to directly induce stimulation and activation of a B cell subset.…”

Section: Basis Of Therapeutic Protein Immunogenicitymentioning

confidence: 99%

Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience

Jawa

Cousens

Groot

2013

Fusion Protein Technologies for Biopharmaceuticals

View full text Add to dashboard Cite

Control systems and decision making for antibody production

Cited by 378 publications

References 127 publications

Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity

Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity

Differential regulation of self-reactivity discriminates between IgG⁺human circulating memory B cells and bone marrow plasma cells

Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience

Contact Info

Product

Resources

About

Control systems and decision making for antibody production

Cited by 378 publications

References 127 publications

Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity

Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity

Differential regulation of self-reactivity discriminates between IgG+human circulating memory B cells and bone marrow plasma cells

Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience

Contact Info

Product

Resources

About

Differential regulation of self-reactivity discriminates between IgG⁺human circulating memory B cells and bone marrow plasma cells