Development and Function of the Early B Cell Repertoire

Abstract

The early B cell repertoire is characterized by extensive interconnectivity, autoreactivity and multispecificity. Our preliminary sequence analysis of some of the idiotype specific antibodies is beginning to provide molecular clues to explain the observed multireactivity and the expression of shared idiotypic determinants on immunoglobulins of early B cells. The VH gene rearrangements analyzed are typical of the early pre-B cell and CD5 B cell repertoire. Some of these include shared or identical CDR3 regions resulting from the use of germline VH, D and JH gene segments in the absence of N region addition. As previously described, the most D proximal VH genes are also used most frequently. Collectively these genetic restrictions, together with the lack of somatic mutation, suggest that the characteristic self reactivity of the early B cell repertoire is related to the expression of germline gene segments and limited use of diversification mechanisms. It has also been possible for the first time to isolate hybridomas secreting functional IgM molecules which use the most D proximal VH gene, VH81X. These antibodies and another example from the VH7183 family have a broad multireactivity pattern possibly because of the presence of an unusually high number of charged amino acid groups present in the VH region. These findings are preliminary and more extensive studies are needed to establish if these groups are responsible for the highly cross-reactive nature of these antibodies. Nevertheless, these unusual characteristics signify a unique role for antibodies expressing this VH gene during B cell development. It is also clear that the observed anti-lymphocyte reactivity, another feature of the newborn repertoire, is the result of the prevalence of B cells using similar if not identical VHDJH genes and DJH joins. The development of these B cells appears to occur consistently in early ontogeny and, again, are not found in conventional splenic B cells obtained from the normal adult. Understanding the functional significance of the early appearance of these antibodies may help to clarify and understand their role during development as well as in autoimmunity. We propose that the unique self reactive nature of the early repertoire provides a pattern within which self-assertiveness develops and results in the establishment of the adult repertoire. In doing so, dominant clones are established which may or may not be within, but whose selection and differentiation is directed by the CD5 B cell subset.(ABSTRACT TRUNCATED AT 400 WORDS)

Isolation of germinal centerlike events from human spleen RNA. Somatic hypermutation of a clonally related VH6DJH rearrangement expressed with IgM, IgG, and IgA.

“…In addition, we have isolated numerous VH6 rearrangements from spleens ofsubjects with neither malignancy nor autoimmune disease (unpublished data). The findings also argue against restriction ofVH6 expression in the postnatal period as may occur in the J-proximal murine VH gene VH 81 X which is preferentially expressed early in murine ontogeny and does not appear to encode antibodies in the adult mouse (29). Indeed, in this experiment from RNA from this one spleen fragment, we have isolated 31 unique clones representing 18 unique rearrangement events, and, in addition, we have isolated in other experiments 22 other clones representing another 10 rearrangements from RNA from the same spleen (unpublished data).…”

Antibody Repertoire Development in Fetal and Neonatal Piglets: XIX. Undiversified B Cells with Hydrophobic HCDR3s Preferentially Proliferate in the Porcine Reproductive and Respiratory Syndrome

“…This hypergammaglobulinemia is often associated with autoimmunity (7, 12, 13) perhaps because of nonspecific proliferation of B cells expressing a preimmune-like repertoire that is known to be polyreactive and to recognize autoantigens (67)(68)(69)(70). Although previous spectratypic analyses show that B cell HCDR3s from PRRSVinfected piglets were a signature for polyclonal activation, certain HCDR3 lengths were pronounced (12).…”

Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires.

“…The competitive basis for culling at this stage may explain the retention of a larger fraction of newly formed B cells (20), lack of V-region skewing (25,32), and greater prevalence of autoantibody-forming cells (33)(34)(35) when the peripheral B-cell pool is lymphopenic. A similar process may eliminate B cells that recognize IgG (36), singlestranded DNA (37), T-cell-specific surface antigens (38), or the range of autoantigens bound by the VH81X element (39)(40)(41).…”