Polyreactive igm antibodies in the circulation are masked by antigen binding

Sigounas, George; Kolaitis, Nick; Monell-Torrens, E.; Notkins, Abner Louis

doi:10.1007/bf01546322

Cited by 38 publications

(30 citation statements)

References 27 publications

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“…3C). The level of serum Abs in ppc1-5H mice may be an underestimate because these polyreactive Abs may be masked by self-Ag binding (50) and cleared rapidly (51). These results demonstrate that the ppc1-5H/ 1 NAA is "naturally" produced in vivo.…”

Section: Analysis Of Abs Of Ppc1-5h Sd-tg Micementioning

confidence: 83%

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

Tian¹,

Beardall²,

Xu³

et al. 2006

The Journal of Immunology

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Despite stringent regulation of disease-associated autoantibodies, a substantial proportion of circulating Abs in sera of healthy individuals exhibit self-reactivity. These Abs are referred to as naturally occurring or natural autoantibodies (NAAs). To understand the origin and function of NAAs, we have generated a new site-directed transgenic mouse model in which a prerearranged VDJ gene coding for the H chain of a typical polyreactive NAA, ppc1-5, is inserted into the IgH locus. This H chain, when combined with its original L chain, the λ1 L chain, yields a NAA that characteristically binds a variety of self and non-self Ags including ssDNA, actin, ubiquitin, and nitrophenyl phosphocholine. Despite their autoreactivity, B cells expressing ppc1-5H/λ1 NAA are not negatively selected, but rather are overrepresented in the transgenic mice. The shift toward λ1 expression mainly occurs during the transition of immature to mature B cells in the spleen, suggesting a BCR selection process. The ppc1-5H/λ1 B cells exhibit a phenotype that is different from those of the known mature B cell populations, and they are located predominantly in the lymphoid follicles of the spleen and the lymph nodes. These B cells are functionally active, producing high levels of Abs in vivo and responding well to BCR stimulation in vitro. The findings indicate that the ppc1-5/λ1 natural autoantibodies originate from a distinct B cell subset that may be positively selected by virtue of its poly/autoreactivity.

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Section: Analysis Of Abs Of Ppc1-5h Sd-tg Micementioning

confidence: 83%

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

Tian¹,

Beardall²,

Xu³

et al. 2006

The Journal of Immunology

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“…Very recent studies revealed that the amount of free unbound polyreactive Ab in the peripheral circulation is low due to the fact that it is bound to and masked by endogenous Ag. However, when these IgM Ab molecules in the circulation are affinity purified so as to dissociate bound endogenous Ag , the resulting IgM molecules are highly polyreactive [21].…”

Section: [I 157361mentioning

confidence: 99%

Polyreactive antigen‐binding B cells in the peripheral circulation are IgD⁺ and B7⁻

et al. 1996

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Polyreactive antibodies are naturally occurring antibodies, primarily of the IgM isotype, that are capable of reacting with a wide variety of different self and non-self antigens. Previously, we reported that a B cell capable of making polyreactive antibody has Ig receptors on its surface that can bind different antigens. The present investigation was initiated to characterize these polyreactive antigen-binding B cells further. A panel of fluorescein isothiocyanate-labeled antigens (insulin, IgG Fc fragment or beta-galactosidase) served as probes to select polyreactive antigen-binding B cells by cell sorting. Our experiment revealed that these polyreactive antigen-binding B cells were mainly of the IgD isotype. They expressed high levels of CD40 and major histocompatibility complex class II molecules, but little or no B7-1, B7-2, or Fas. In contrast to the binding of antigens to monoreactive receptors (usually high affinity), the binding of antigens to polyreactive receptors (usually moderate or low affinity) did not up-regulate the expression of B7-1 or B7-2. Antigens that bound to polyreactive receptors, however, were internalized and degraded, although not as efficiently as antigens that bound to monoreactive receptors. Despite the ability of these B7- cells to process antigens, they were not able to activate T cells in a mixed leukocyte reaction. It is concluded that polyreactive antigen-binding B cells have properties that are consistent with the ability to induce immunological tolerance.

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“…The specific antibodies reacted with a single protein, whereas polyreactive antibodies crossreacted with a series of unrelated proteins including autoantigens (8).…”

mentioning

confidence: 99%

The epitopes for natural polyreactive antibodies are rich in proline

Tchernychev

Cabilly

Wilchek

1997

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

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ABSTRACT''Natural'' polyreactive antibodies, which bind in a nonspecific manner to a range of biological molecules both of self-and nonself-origin, are normal constituents of serum and are a significant part of the immune repertoire in many species, including humans. Autoantibodies to sTNF-R (the 55-kDa extracellular domain of the human receptor to tumor necrosis factor ␣) were affinity purified from normal human sera using immobilized sTNF-R. The isolated antisTNF-R IgG bound both native and denatured forms of the receptor with low affinity. These antibodies also bound to different proteins and therefore are considered to be polyreactive. We used the anti-sTNF-R antibodies and purified polyreactive antibodies to mannose-specific lectin from garlic (Allium sativum) for screening a peptide library displayed on filamentous M13 phage. After the biopanning procedure, we failed to find epitopes with a consensus sequence; however, we found that proline is the most frequent amino acid in the selected phagotopes. Proline is commonly present at solventexposed sites in proteins, such as loops, turns, N-terminal first turn of helix, and random coils. Thus, structures containing proline can serve as conformation-dependent common ''public'' epitopes for polyreactive natural antibodies. Our findings may be important for understanding polyreactivity in general and for the significance of polyreactive natural antibodies in immunological homeostasis.

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Polyreactive igm antibodies in the circulation are masked by antigen binding

Cited by 38 publications

References 27 publications

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

Polyreactive antigen‐binding B cells in the peripheral circulation are IgD⁺ and B7⁻

The epitopes for natural polyreactive antibodies are rich in proline

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Polyreactive igm antibodies in the circulation are masked by antigen binding

Cited by 38 publications

References 27 publications

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

Polyreactive antigen‐binding B cells in the peripheral circulation are IgD+ and B7−

The epitopes for natural polyreactive antibodies are rich in proline

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Polyreactive antigen‐binding B cells in the peripheral circulation are IgD⁺ and B7⁻