Self-reactive antibodies (natural autoantibodies) in healthy individuals

Lacroix‐Desmazes, Sébastien; Kaveri, Srini V.; Mouthon, Luc; Ayouba, Ahidjo; Malanchère, Evelyne; Coutinho, António; Kazatchkine, Michel D.

doi:10.1016/s0022-1759(98)00074-x

Cited by 297 publications

(231 citation statements)

References 176 publications

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“…11 Many of the circulating IgM correspond to natural antibodies that exist prior to infection or immunization. [12][13][14] Natural IgM are polyreactive to evolutionary conserved structures 15 and bind efficiently to previously un-encountered antigen. 16 These antibodies compensate their low-antigen affinity with relatively high avidity and furthermore the effectiveness of the antigen-antibody interaction is enhanced by the high efficiency of IgM in engaging the complement pathway.…”

Section: Introductionmentioning

confidence: 99%

“…11,17 The preimmune Ig repertoire is thought to be composed by mature B cells either recirculating through follicles of secondary lymphoid organs (B2 cells), or joining compartments in specific locations as the marginal zone in the spleen (MZ B-cells) and the pleural or peritoneal cavities (B1 cells). 12 B2 and marginal zone B-cell development is initiated in the bone marrow and completed in the periphery 18,19 throughout life. B cells exported from the bone marrow maturate in the spleen 20 into subsets that differ in their surface phenotype, anatomic localization and immunologic function [21][22][23] and that ultimately are able to differentiate into antibody-producing plasma cells, upon antigenic stimulation.…”

Section: Introductionmentioning

confidence: 99%

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Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

et al. 2008

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Natural IgM are involved in numerous immunological functions but the genetic factors that control the homeostasis of its secretion and upholding remain unknown. Prompted by the finding that C57BL/6 mice had significantly lower serum levels of IgM when compared with BALB/c mice, we performed a genome-wide screen and found that the level of serum IgM was controlled by a QTL on chromosome 13 reaching the highest level of association at marker D13Mit266 (LOD score¼3.54). This locus was named IgMSC1 and covered a region encompassing the interferon-regulatory factor 4 gene (Irf4). The number of splenic mature B cells in C57BL/6 did not differ from BALB/c mice but we found that low serum levels of IgM in C57BL/6 mice correlated with lower frequency of IgM-secreting cells in the spleen and in the peritoneal cavity. These results suggested that C57BL/6 mice have lower efficiency in late B-cell maturation, a process that is highly impaired in Irf4 knockout mice. In fact, we also found reduced Irf4 gene expression in B cells of C57BL/6 mice. Thus, we propose Irf4 as a candidate for the IgMSC1 locus, which controls IgM homeostatic levels at the level of B-cell terminal differentiation

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

et al. 2008

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“…In AITP, highly specific anti-␣ IIb ␤ 3 Abs are frequently developed. The differences between natural Abs directed against self-components and autoantibodies developed in autoimmune diseases often rely on polyspecificity and idiotopes on their V region targeted by anti-idiotypic Abs (22). Defects in the idiotypic network that ensures homeostasis of autoreactivity could have thus contributed, in AITP disease, to the uncontrolled emergence and expansion of highly specific anti-␣ IIb ␤ 3 "pathogenic" autoantibodies presenting with a favorable VDJ rearrangement.…”

Section: Discussionmentioning

confidence: 99%

Human IgG Monoclonal Anti-αIIbβ3-Binding Fragments Derived from Immunized Donors Using Phage Display

Jacobin

Laroche‐Traineau

Little

et al. 2002

The Journal of Immunology

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Previous studies of the immune response in polytransfused Glanzmann thrombasthenia (GT) patients and in autoimmune thrombocytopenic purpura (AITP) have relied on serum analysis and have shown the frequent development of Abs directed against the αIIbβ3 integrin. However, little is known about the molecular diversity of the humoral immune response to αIIbβ3 due to the paucity of mAbs issuing from these pathologies. We have isolated human IgG anti-αIIbβ3 binding fragments using combinatorial libraries of single-chain IgG created from the B cells of a GT and an AITP patient, both with serum Abs. Ab screening was performed using activated platelets or activated αIIbβ3-expressing Chinese hamster ovary cells. Sequencing of selected phage Abs showed that a broad selection of genes from virtually all V gene families had been used, indicating the diversity of the immune response. About one-half of the VH and VL segments of our IgG anti-αIIbβ3 fragments displayed extensive hypermutations in the complementarity-determining region, supporting the idea that an Ag-driven immune response was occurring in both patients. The H chain complementarity-determining region 3 analysis of phage Abs revealed motifs other than the well-known RGD and KQAGDV integrin-binding sequences. To our knowledge, our study is the first to illustrate multiple human IgG anti-αIIbβ3 reactivities and structural variations linked to the anti-platelet human immune response. Human αIIbβ3 Abs preferentially directed against the activated form of the integrin were further characterized because platelet αIIbβ3 inhibitors are potential therapeutic reagents for treating acute coronary syndromes. Currently available αIIbβ3 antagonists do not specifically recognize the activated form of the integrin.

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“…Antigenic selection also has been suggested for the development and maintenance of natural autoantibodies (13,14,20,23). This is supported by studies showing that such polyreactive Ig are encoded by a limited and conserved set of Ig V H genes (24).…”

Section: T He Elimination Of B Cells Expressing Ig With Self-reactivitymentioning

confidence: 96%

“…Polyreactive autoantibodies are naturally occurring Ig, primarily of the IgM isotype, that bind with low affinity to two or more distinct self-or nonself-Ags, such as hIgG, ssDNA, dsDNA, histones, cardiolipin, actin, and/or cytoskeletal components (13,14). The autoreactive B cells that produce these Ig are not rendered anergic, because the autoantibodies they produce constitute a large fraction of total serum Ig.…”

Section: T He Elimination Of B Cells Expressing Ig With Self-reactivitymentioning

confidence: 99%

Transgenic Expression of a Human Polyreactive Ig Expressed in Chronic Lymphocytic Leukemia Generates Memory-Type B Cells That Respond to Nonspecific Immune Activation

Widhopf

Brinson

Kipps

et al. 2004

The Journal of Immunology

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We generated transgenic mice, designated SMI, expressing unmutated H and L chain Ig genes encoding a low-affinity, polyreactive human (h)IgM/κ rheumatoid factor. These animals were compared with control AB29 transgenic mice expressing a hIgM/κ rheumatoid factor specific for human IgG, with no detectable reactivity with mouse proteins. SMI B cells expressed significantly lower levels of surface hIgM/κ than did the B cells of AB29 mice, but still could be induced to proliferate by surface Ig cross-linking in vitro and could be deleted with anti-Id mAb in vivo. Transgene-expressing B cells of AB29 mice had a B-2 phenotype and were located in the primary follicle. In contrast, a relatively high proportion of hIgM-expressing B cells of SMI mice had the phenotype of B-1 B cells in the peritoneum or marginal zone B cells in the spleen, where they were located in the periarteriolar sheath, marginal zone, and interfollicular areas that typically are populated by memory-type B cells. Although the relative proportions of transgene-expressing B cells in both types of transgenic mice declined with aging, SMI mice experienced progressive increases in the serum levels of IgM transgene protein over time. Finally, SMI transgene-expressing B cells, but not AB29 transgene-expressing B cells, were induced to secrete Ab when cultured with alloreactive T cells. These results indicate that expression of polyreactive autoantibodies can allow for development of B cells that are neither deleted nor rendered anergic, but instead have a phenotype of memory-type or Ag-experienced B cells that respond to nonspecific immune activation.

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Self-reactive antibodies (natural autoantibodies) in healthy individuals

Cited by 297 publications

References 176 publications

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

Human IgG Monoclonal Anti-αIIbβ3-Binding Fragments Derived from Immunized Donors Using Phage Display

Transgenic Expression of a Human Polyreactive Ig Expressed in Chronic Lymphocytic Leukemia Generates Memory-Type B Cells That Respond to Nonspecific Immune Activation

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