Self-reactive VH4-34–expressing IgG B cells recognize commensal bacteria

Schickel, Jean-Nicolas; Glauzy, Salomé; Ng, Yen Shing; Chamberlain, Nicolas; Massad, Christopher; Isnardi, Isabelle; Katz, Nathan; Uzel, Gülbû; Holland, Steven M.; Pïcard, Capucine; Puel, Anne; Casanova, Jean‐Laurent; Meffre, Eric

doi:10.1084/jem.20160201

Cited by 68 publications

(88 citation statements)

References 55 publications

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“…[24][25][26] May unmutated NMDAR autoantibodies have been similarly selected because of evolutionary importance (eg, for neutralization of released NMDAR protein), thereby preventing dysfunctional immune stimulation? 28 Future studies should examine antibody effects beyond receptor internalization 29 and clarify under which conditions NR1 (and potentially further) autoantibodyproducing cells escape negative selection and expand to cause encephalitis. 27 Also, there are examples of other germline antibodies that are reactive to commensal bacteria at mucosal barriers, but at the expense of pathogenic reactivity to self-proteins.…”

Section: Discussionmentioning

confidence: 99%

N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit

Wenke

Kreye

Andrzejak

et al. 2019

Annals of Neurology

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Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody‐mediated synaptic dysfunction. Cerebrospinal fluid–derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline‐configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose‐ and time‐dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771–776

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Section: Discussionmentioning

confidence: 99%

N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit

Wenke

Kreye

Andrzejak

et al. 2019

Annals of Neurology

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“…In contrast to what is observed under homeostatic conditions, circulating V H 4‐34 Abs are relatively easy to detect in some particular clinical conditions such autoimmune disorders including SLE and also different infectious diseases like mononucleosis, AIDS, or hepatitis C infection . In the context of self‐reactivity, it is known that these Abs recognize a conserved carbohydrate epitope, constituted by a linear chain of poly‐ N ‐acetyl‐lactosamine or i‐antigen present on human erythrocytes and B lymphocytes …”

Section: Innate‐like Vh4‐34‐expressing B Cellsmentioning

confidence: 97%

Innate-like B cell subsets during immune responses: Beyond antibody production

Romero‐Ramírez

Navarro-Hernandez

Cervantes‐Díaz

et al. 2018

Journal of Leukocyte Biology

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B lymphocytes are recognized for their crucial role in the adaptive immunity since they represent the only leukocyte lineage capable of differentiating into Ab‐secreting cells. However, it has been demonstrated that these lymphocytes can exert several Ab‐independent functions, including engulfing and processing Ags for presentation to T cells, secreting soluble mediators, providing co‐stimulatory signals, and even participating in lymphoid tissues development. Beyond that, several reports claiming the existence of multiple B cell subsets contributing directly to innate immune responses have appeared. These “innate‐like” B lymphocytes, whose phenotype, development pathways, tissue distribution, and functions are in most cases notoriously different from those of conventional B cells, are crucial to early protective responses against pathogens by exerting “crossover” defensive strategies that blur the established boundaries of innate and adaptive branches of immunity. Examples of these mechanisms include the rapid secretion of the polyspecific natural Abs, increased susceptibility to innate receptors‐mediated activation, cytokine secretion, downstream priming of other innate cells, usage of specific variable immunoglobulin gene‐segments, and other features. As these new insights emerge, it is becoming preponderant to redefine the functionality of B cells beyond their classical adaptive‐immune tasks.

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“…VH4‐34 antibodies are also associated with other conditions, such as infectious mononucleosis, cold agglutinin disease and AIDS . However, there seems to be a beneficial role for VH4‐34 encoded antibodies as they preferentially bind to commensal bacteria antigens and have the ability to neutralize viral infection in vitro . This indicates that in order to prevent autoimmunity, cells harbouring VH4‐34 gene segments must be tightly regulated, possibly by mutating away from self‐reactivity .…”

Section: Discussion Clinical Applications and Future Studymentioning

confidence: 99%

B‐cell receptor repertoire sequencing in patients with primary immunodeficiency: a review

et al. 2017

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SummaryThe advent of next-generation sequencing (NGS) now allows a detailed assessment of the adaptive immune system in health and disease. In particular, high-throughput B-cell receptor (BCR) repertoire sequencing provides detailed information about the functionality and abnormalities of the B-cell system. However, it is mostly unknown how the BCR repertoire is altered in the context of primary immunodeficiencies (PID) and whether findings are consistent throughout phenotypes and genotypes. We have performed an extensive literature search of the published work on BCR repertoire sequencing in PID patients, including several forms of predominantly antibody disorders and combined immunodeficiencies. It is somewhat surprising that BCR repertoires, even from severe clinical phenotypes, often show only mild abnormalities and that diversity or immunoglobulin gene segment usage is generally preserved to some extent. Despite the great variety of wet laboratory and analytical methods that were used in the different studies, several findings are common to most investigated PIDs, such as the increased usage of gene segments that are associated with self-reactivity. These findings suggest that BCR repertoire characteristics may be used to assess the functionality of the B-cell compartment irrespective of the underlying defect. With the use of NGS approaches, there is now the opportunity to apply BCR repertoire sequencing to multiple patients and explore the PID BCR repertoire in more detail. Ultimately, using BCR repertoire sequencing in translational research could aid the management of PID patients by improving diagnosis, estimating functionality of the immune system and improving assessment of prognosis.

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Self-reactive VH4-34–expressing IgG B cells recognize commensal bacteria

Cited by 68 publications

References 55 publications

N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit

N‐methyl‐D‐aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit

Innate-like B cell subsets during immune responses: Beyond antibody production

B‐cell receptor repertoire sequencing in patients with primary immunodeficiency: a review

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