IgG antibodies to phosphorylcholine exhibit more diversity than their IgM counterparts

Gearhart, Patricia J.; Johnson, Nelson D.; Douglas, R.; Hood, Leroy

doi:10.1038/291029a0

Cited by 499 publications

(300 citation statements)

References 61 publications

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“…Polyreactivity was ob- served in ∼26% of our human anti-PC mAbs (Supplemental Table II), which is in the same range of what has been reported for other specificities (26). Using surface plasmon resonance, we determined the affinity of ten mAbs to free monomeric PC-hapten, and the results were compared with the previously reported affinity of mouse T-15 (27) (Table III). Several of the tested human mAbs had affinities similar to T-15.…”

Section: Expressed Human Anti-pc Mabs Bind To Pcmentioning

confidence: 82%

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Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

Fiskesund

Stéen

Amara

et al. 2014

The Journal of Immunology

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Phosphorylcholine (PC) is a classic T-independent Ag that is exposed on apoptotic cells, oxidized phospholipids, and bacterial polysaccharides. Experimental as well as epidemiological studies have over the past decade implicated Abs against PC (anti-PC) as anti-inflammatory and a strong protective factor in cardiovascular disease. Although clinically important, little is known about the development of anti-PC in humans. This study was conceived to dissect the human anti-PC repertoire and generate human mAbs. We designed a PC-specific probe to identify, isolate, and characterize PC-reactive B cells from 10 healthy individuals. The donors had all mounted somatically mutated Abs toward PC using a broad variety of Ig genes. PC-reactive B cells were primarily found in the IgM+ memory subset, although significant numbers also were detected among naive, IgG+, and CD27+CD43+ B cells. Abs from these subsets were clonally related, suggesting a common origin. mAbs derived from the same donors exhibited equivalent or higher affinity for PC than the well-characterized murine T-15 clone. These results provide novel insights into the cellular and molecular ontogeny of atheroprotective PC Abs, thereby offering new opportunities for Ab-based therapeutic interventions.

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Section: Expressed Human Anti-pc Mabs Bind To Pcmentioning

confidence: 82%

“…Once considered a model epitope, PC was an intensively researched topic that helped to lay the foundation of modern immunology (27)(28)(29). Although the study of PC went out of fashion during the late 1980s, in recent years, the field has undergone a renaissance.…”

Section: Discussionmentioning

confidence: 99%

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

Fiskesund

Stéen

Amara

et al. 2014

The Journal of Immunology

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“…It was not until decades later that mutations were actually observed, first in the immunoglobulin protein 32 and then at the DNA level [33][34][35][36] , providing proof that a process of adaptive mutation targeted to a single locus, not observed in any other living organism, was co-opted by the immune system.…”

Section: Somatic Hypermutation and Dna Polymerasesmentioning

confidence: 99%

DNA polymerases in adaptive immunity

Weill

Reynaud

2008

Nat Rev Immunol

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PrefaceTo cope with an unpredictable variety of potential pathogenic insults, the immune system must generate an enormous diversity of recognition structures, and it does so by making stepwise modifications of key genetic loci in each lymphoid cell. This proceeds through the action of lymphoid-specific proteins acting together with the general DNA-repair machinery of the cell. Strikingly, these general mechanisms are usually diverted from their normal functions, being used in rather atypical ways in order to privilege diversity over accuracy. In this Review, we focus on the contribution of a set of DNA polymerases discovered in the last decade to these unique DNA transactions.

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“…While it is likely that antigenic stimulation and subsequent environmental selection may alter or increase repertoire diversity and permit the expression and selection of mutations within variable region gene segments (37,38), the primary B cell repertoire itself emerges from the generative cell pool within the bone marrow of adult individuals as an already highly diverse population of clonotypes (15). Additionally, clonotype distributions (such as the expression of high frequency predominant specificities) that characterize the mature primary B cell repertoire also characterize the prereceptor B cell repertoire.…”

Section: Response To Pc Of Cells Derived From Mice That Were Neonatalmentioning

confidence: 99%

Role of variable region gene expression and environmental selection in determining the antiphosphorylcholine B cell repertoire.

Stone¹

1983

The Journal of Experimental Medicine

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To evaluate the role of environmental selective processes, as opposed to variable region gene expression, in the determination of B cell repertoire expression, we have assessed the phosphorylcholine (PC)-specific repertoire of precursor cells that remain in bone marrow cell populations after the removal of surface immunoglobulin (sIg)-bearing cells. Such cells are assumed to represent a stage in B cell maturation before the expression of sIg, and thus at a time when they have not as yet interfaced with environmental influences that operate through sIg receptors such as antigenic stimulation, tolerance, or antiidiotypic regulation. The repertoire as expressed in these cells, therefore, should reflect the readout of immunoglobulin variable region genes as they are expressed in progenitors to B cells. The results of these studies indicate that, as in mature primary B cell pools of BALB/c mice, the majority of PC-responsive sIg- bone marrow cells are of the T15 clonotype. Thus, environmental selective mechanisms would not appear to be required for the high frequency of B cells of the T15 idiotype in the primary B cell repertoire of BALB/c mice. Analysis of the sIg- bone marrow cells in (CBA/N X BALB/c)F1 male mice demonstrated that the deficit of PC-responsive mature B cells, which is a characteristic of this murine strain, must occur after receptor expression, since a normal frequency of PC-responsive and T15-expressing cells is present in their sIg- bone marrow population. Finally, these same mice were used to obtain bone marrow cell preparations from individual leg bones, so as to permit an analysis of the occurrence of T15+ and T15- clonotypes within individual bone marrow populations. The findings from these studies indicate that T15+ B cells occur as a high frequency event within bone marrow generative cell pools. Furthermore, bone marrow populations that are positive for PC-responsive precursor cells often display multiple copies of such precursor cells that are exclusively either T15+ or T15-. This finding indicates that clonal expansion of cells within the B cell lineage apparently occurs before immunoglobulin receptor acquisition.

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IgG antibodies to phosphorylcholine exhibit more diversity than their IgM counterparts

Cited by 499 publications

References 61 publications

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

DNA polymerases in adaptive immunity

Role of variable region gene expression and environmental selection in determining the antiphosphorylcholine B cell repertoire.

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