The Antibody Repertoire of Early Human B Cells I. High Frequency of Autoreactivity and Polyreactivity

Abstract

Cord blood and fetal liver B cells were immortalized using Epstein-Barr virus, and IgM antibodies from the resulting lines and clones were examined for their binding to a variety of auto-antigens and micro-organisms by ELISA and fluorescence assays. Auto-antigens tested included Fc of IgG, ssDNA and dsDNA, cardiolipin, histones 1-4, collagens type I and II, thyroglobulin, cytoskeletal components, and a tissue section screen. Of 71 cell lines tested, all but 19 showed some autoreactivity. All 32 fetal liver lines reacted to some self-antigens. In cord blood clones, 16 out of 26 bound to auto-antigens. Many of the clones reacted with more than one auto-antigen and were 'polyreactive'. Some of the cord blood clones bound to extracts of micro-organisms, showing specificity for both endogenous and exogenous antigens. The high frequency of CD5+ B cells in the cord blood (greater than 50%) and fetal liver (greater than 70%) argues for many of these clones being derived from this subset. Therefore, our data support the concept that many 'early' B cells produce polyreactive IgM which can bind to a variety of different auto-antigens and micro-organisms. These IgM antibodies are similar to those described by others as 'natural antibodies'.

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

“…[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. 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).…”

Reconstitution of the B cell repertoire after bone marrow transplantation does not recapitulate human fetal development

“…In addition, the fetal immune system contains a high frequency of low-affinity self-reactive antibodies. 23,24 This may be associated with particular three-dimensional characteristics of fetal antigen receptors, 25 or the abundance of CD5 + B cells in fetal tissue (which are associated with formation of polyreactive autoantibodies). 26,27 The possibility that 'fetal-type' antigen receptors are common post BMT, in conjunction with an abundance of CD5 + B cells in the early post-transplant period, could explain self-reactive specificities occurring at this stage.…”

Doomsday Book, Vol. II

“…It takes between 2 and 5 years after birth to develop an adult repertoire of IgM memory B cells [18][19][20]. The less complex fetal and neonatal Ab repertoires are enriched for poly-reactive Abs of low affinity [21,22]. Neonatal Abs generally have longer CDR3 regions that present flatter areas composed more often of small, polar amino acids (tyrosine, threonine, serine and proline) that promote promiscuous binding of antigens [23][24][25].…”