Predominant Autoantibody Production by Early Human B Cell Precursors

  title={Predominant Autoantibody Production by Early Human B Cell Precursors},
  author={Hedda Wardemann and Sergey Yurasov and Anne Schaefer and James W. Young and Eric Meffre and Michel C. Nussenzweig},
  pages={1374 - 1377}
During B lymphocyte development, antibodies are assembled by random gene segment reassortment to produce a vast number of specificities. A potential disadvantage of this process is that some of the antibodies produced are self-reactive. We determined the prevalence of self-reactive antibody formation and its regulation in human B cells. A majority (55 to 75%) of all antibodies expressed by early immature B cells displayed self-reactivity, including polyreactive and anti-nuclear specificities… 

B-cell tolerance checkpoints in health and autoimmunity.

Regulation of B-cell development by antibody specificity.

Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance.

B-cell tolerance.

How knowledge of checkpoints involving receptor editing, deletion, anergy and competition for growth factors may be used to gain a better understanding of transplant tolerance and the generation of alloantibodies is considered.

Autoantibody selection and production in early human life.

This issue of the JCI presents a molecular basis for the limited and common repertoire of antibodies produced by fetal B cells, which may be distinct from the abnormalities in B cell development described in patients with autoimmune diseases.

The double life of a B-1 cell: self-reactivity selects for protective effector functions

An overview of the developmental processes that shape the B-1 cell pool in mice is provided, the functions of B- 1 cells in both the steady state and during host defence are outlined, and possible functional B-2 cell homologues that exist in humans are discussed.

B-cell self-tolerance in humans.

Antibodies: Eliminating the bad guys

  • E. Bell
  • Biology, Medicine
    Nature Reviews Immunology
  • 2003
The extent of autoantibody production is established and indicates two stages at which self reactivity is modified, showing that self-reactive antibodies are eliminated at two distinct stages of development.



Receptor editing in self-reactive bone marrow B cells

In mice transgenic for anti-H-2Kk,b antibody genes, in which a homogeneous clone of developing B cells can be analyzed for the outcome of autoantigen encounter, surface immunoglobulin M+/idiotype+ immature B cells binding to self-antigens in the bone marrow are induced to alter the specificity of their antigen receptors.

Contribution of Receptor Editing to the Antibody Repertoire

It is found that B cells are targeted for editing during a 2-hour delay in development at the pre-BII cell stage, and that about 25% of all antibody molecules are produced by gene replacement.

Polyspecific natural antibodies and autoantibodies secreted by human lymphocytes immortalized with Epstein-Barr virus.

The results indicate that immunoglobulins secreted by human monoclonal lymphoid cell lines can have polyspecific autoantibody functions, similar to those found in normal human polyclonal antibodies, in human monOClonal paraproteins and in natural monoklonal antibodies synthesized by murine or rat clones obtained from physiologically normal animals.

Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice

Findings indicate that self tolerance may result from mechanisms other than clonal deletion, and are consistent with the hypothesis that IgD may have a unique role in B-cell tolerance.

Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes

B-cell tolerance in transgenic mice using genes for IgM anti-H–2k MHC class I antibody is studied and it is suggested that very large numbers of autospecific B cells can be controlled by clonal deletion.

B‐cell subsets and the mature ­preimmune repertoire. Marginal zone and B1 B cells as part of a “natural immune memory”

Findings indicate a functional heterogeneity within the mature B‐lymphocyte population, in contrast to FO B cells, that has the unique capacity to generate effector cells in early stages of the immune response against (particulate) antigens that are scavenged efficiently in these specialized anatomical sites.

Receptor Editing Occurs Frequently during Normal B Cell Development

It is suggested that receptor editing occurs at a surprisingly high frequency in normal B cells, as it is shown that RS recombination is frequently induced by, and inactivates, functionally rearranged κ loci.

Atypical VH-D-JH rearrangements in newborn autoimmune MRL mice.

B cells from the autoimmune-prone MRL mice have significantly increased numbers of atypical VH-D-JH rearrangements (D-D fusions and D inversions), which could confer an increased propensity to produce unusual VH and JH rearranged early in ontogeny.

Continued RAG expression in late stages of B cell development and no apparent re-induction after immunizion

Endogenous RAG messenger RNA is expressed in immature B cells in bone marrow and spleen and decreases by two orders of magnitude as they acquire higher levels of surface immunoglobulin M (IgM).

Immature surface Ig+ B cells can continue to rearrange kappa and lambda L chain gene loci

It is shown that early during the differentiation of pre-B cells, upregulation of R AG-1 and RAG-2 expression go hand in hand with rearrangements of the Ig gene loci, and deposition of a complete Ig molecule on the surface of a B cell does not automatically stop the Ig-rearrangement machinery.