ISSN:0883-0185    

DOI:10.3109/08830189209055565

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

A hallmark of the immune system is the extraordinary diversity associated with antibodies. This is made possible by a series of genetic rearrangements involving variable region gene segments. Considerable detail is known about these genetic mechanisms except for the enzymatic machinery involved. An important question in studies of the generation of diversity is whether V genes are selected for rearrangement mainly in a random manner or selected by particular developmental rules. Past studies have indicated that the acquisition of fetal and neonatal specificity repertoires is a nonrandom process. In this report, we review our studies that directly compare the adult and fetal/neonatal V gene repertoires. The evidence suggests that the adult repertoire is more diverse with indications of a random use of VHgene families. However, whether V genes are indeed randomly used in the adult remains to be clarified at the VHgene member level. The fetal repertoire, on the other hand, appears nonrandom in V gene usage. In addition, the fetal repertoire is mostly germline encoded with little evidence of junctional diversity. Taken together, the results indicate different rules for generation of the adult and fetal repertoires, findings most likely explain by distinct B cell subsets and B cell progenitors at early stages in ontogeny.

ISSN:0883-0185    

DOI:10.3109/08830189209055566

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

Junctional diversity in immunoglobulin (Ig) from an adult mouse contributes significantly to the size of the final Ig repertoire. In adult pre-B cells, N region addition and deletion of nucleotides form coding regions produces very heterogenous CDR3 sequences. In contrast, Ig from fetal and newborn mice show very restricted junctional diversity. The reasons for this are: (a) the lack of N regions; and (b) the predominance of certain junctional sequences. These common junctional sequences all appear to occur by targeted rearrangement to short stretches of sequence homology near the ends of the segments to be joined. Targeted rearrangement may play a role in the over-expression of certain Vh genes early in ontogeny. These non-random junctional sequences in the neonate will reproducibly create certain Ig, for example, the dominant T15 anti-PC antibodies. Thus the immune system first creates a small repertoire of predictable Ig sequences. To the extent that these Ig are expressed in long-lived B cells, these early Ig sequences may persist in the adult. Superimposed upon this early repertoire is an enormously diverse adult Ig repertoire.

ISSN:0883-0185    

DOI:10.3109/08830189209055567

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

The most variable portion of immunoglobulin molecules is the third complementarity determining region (CDR3) of the heavy chain. This is simply because CDR3 encompasses the region of the rearranged gene where the three gene segments (VH-DH-JH) are joined. Since imprecisions exist in the recombinase reaction, significant differences can be generated at the sites of recombination. This results in the generation of antigen receptor molecules which can differ in their antigen specificity even though they derive from the same germline information. In sum, the significance of the inaccuracy in recombination is that antibodies which are reactive to different antigens can be derived from identical genetic information. This explains how the immune system (using only a limited amount of genetic information) can generate antibodies to virtually any antigen.Though the basic phenomenon of VH-DH-JHassembly has been appreciated for years, two recent findings demonstrate that the generation of CDR3 is more complex than originally believed. First, junctional modification is not a stochastic process as was initially presumed, but is in part developmentally regulated. Second, it has now been well documented that more complex recombinations (for example VH-DH-DH-JH, VH-DH-invDH-JH, etc.) are involved in generating the third hypervariable region of the heavy chain. Not only do these unusual rearrangements—which break the so-called“12/23”recombination rule—occur, but interestingly, certain predicted rearrangements (even some which do follow the“12/23”recombination rule) cannot be demonstrated and apparently do not occur. To date, there is no adequate explanation for the lack of these predicted recombinations. These results have important implications for both the generation of antibody diversity and the recombinase reaction itself.

ISSN:0883-0185    

DOI:10.3109/08830189209055568

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

In pre-B cells, theμchain is expressed at the cell surface in association with a“light chain surrogate”encoded by the V pre-B and theλ-like genes. Thisμ-ψ-L complex presumably triggers early steps of the B cell differentiation, possibly by controlling the Ig gene rearrangements. In the humans, theλ-like complex contains 3 genes, located in the 22q11.2-q12.3 band, telomeric to the IGCL locus, with which they share a similar organization, pointing to a common genetic origin. Only oneλ-like gene, 14.1, is functional and specifically expressed with V pre-B in pre-B cells. This expression starts in cells which still have the IGH locus in germline configuration (pro-B stage) and ceases as soon as the IGL loci rearrange. These pre-B specific transcripts provide useful markers of cells of the B lineage in both physiological and pathological situations.

ISSN:0883-0185    

DOI:10.3109/08830189209055569

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

During the development of the immune system, a restricted set of VHgene segments provides the bulk of the immunoglobulin heavy chain repertoire. Most of these VHgenes have been found later in life encoding autospecificities either in normals or in patients with autoimmune diseases. Additionally, there is considerable evidence that the fetal/neonatal B-cell repertoire is autoreactive and idiotypically connected. In the course of sequencing the heavy chain of a panel of human autoantibodies mainly derived from patients with autoimmune diseases, we found that one of the VHfamilies, and more specifically one single VHgene contributes to a large extent to the adult autoimmune repertoire in restricted as well as unrestricted responses. This VHgene segment is not particularly overexpressed in the fetus. Since the only common element to these autoreactive responses is the region encoded by the VHgene itself, these observations may provide an important insight into B-cell regulation.

ISSN:0883-0185    

DOI:10.3109/08830189209055570

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

The B cell repertoire consists of three tiers of clonotype diversity. One tier, which is the product of H chain V region rearrangements in the absence of N additions, is of limited diversity (<108clonotypes) so that clonotypes of this tier would be expected to recur within and among B cells of individuals of an inbred strain. These clonotypes, therefore, could be subjected to, and conserved by, evolutionary selective pressures such as those imposed by ubiquitous bacterial pathogens. The second tier of clonotypes is created by H chain V region rearrangements that include N additions, and is, therefore, exceedingly diverse. Clonotypes of this tier would be unlikely to recur; however, by providing maximal diversity they would ensure protection against a wide spectrum of pathogens. The third tier of diversity is that which is generated by the superimposition of somatic mutations on clonotypes of the other two tiers. This tier of clonotypes is reflective of the refinement of specificities that are destined for expression in memory B cells.B cells exist as three distinct subpopulations, Ly-1 B cells, conventional primary B cells and memory B cells. These subpopulations differ functionally, developmentally, and by the extent to which they are impacted by immunoregulatory processes. Furthermore, B cells of these subpopulations differentially express the three tiers of clonotype diversity.

ISSN:0883-0185    

DOI:10.3109/08830189209055571

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

ISSN:0883-0185    

DOI:10.3109/08830189209055572

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

Ly-1 B cells in mouse show numerous phenotypic and functional features that distinguish them from the bulk of IgDhigh/Ly-1−B cells. Their association with autoantibody production and the presence of Ly-1 on a group of murine B lymphomas that also exhibit certain specificities enriched in the normal population has stimulated continuing interest in this population. We have taken two approaches in our investigations of these cells: 1) defining the origins of Ly-1 B cells (the“lineage question”); and 2) studying the expression of particular specificities and associated immunoglobulin V genes enriched in this population. In this review we present the experimental background that supports our current understanding of Ly-1 B cells as the remnant of a fetal B cell differentiation pathway and suggest that the selection of cells from this fetal/neonatal population into the adult long-lived pool results in the over-expression of certain germline-encoded autoreactivities, such as antibody to bromelain-treated mouse red blood cells and intact thymocytes.

ISSN:0883-0185    

DOI:10.3109/08830189209055573

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

The data presented focus on three topics: 1) Self-reactivity of early B cells as a constitutive feature of the immune system; 2) Self-reactive V regions and their possible involvement in immune regulation; and 3) Autoantibodies directed at T cell surface molecules as a new form of direct regulation of the B cell repertoire on the T cell compartment. Evidence is provided for lack of substantial difference in the reactivity of neonatal hybridomas from normal and autoimmune mice, and the proposal is made that the immune systems of normal and autoimmune neonatal mice start with similar characteristics implying that avoidance of autoimmune disease is matter of active regulation through a process learned in ontogeny. Two general possibilities for immune regulation are discussed. One is based on the V regions of self-reactive antibodies and their antigenic determinants. The other is through natural autoantibodies able to interfere with the state of activation of T cells. It is concluded that the role of highly conserved structures like self antigens is to maintain immunoglobulin genes and favor their expression in the incipient immune system so that simple patterns of regulation can be set in motion and made available.

ISSN:0883-0185    

DOI:10.3109/08830189209055574

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor