摘要:

Elucidation of the cellular and molecular mechanisms which determine the expressed antibody repertoire remains a major challenge in immunology. Knowledge of V gene diversity, organization, and expression is important to an understanding of the formation of the antibody repertoire in normal as well as diseased states. In the last few years, great advances have been made in our understanding of the human heavy chain variable region (VH) gene locus. In this review we present the current knowledge of VHgene diversity, organization, and utilization in normal individuals followed by a discussion of the possible relevance of these findings to autoimmunity.

ISSN:0883-0185    

DOI:10.3109/08830189009056729

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

摘要:

Developing fetal B cells preferentially rearrange a restricted subset of the encoded antibody gene segments. There are striking structural similarities between elements expressed early in man and in mouse, most evident on comparison of murine VHelements from the VH7183 family to human VHelements of the VH3 family. The similarity is pronounced in two framework regions which together encode a possible binding site that is distinct from the classical antigen-combining site. By comparing all known human and murine VHgene sequences, we have demonstrated that these regions have been conserved in a family-specific manner throughout the mammalian radiation. The“non-conserved”spacer of the recombinase recognition signal is also highly conserved in a family-specific manner, suggesting a mechanism by which the expression of family-dependent features may be regulated. The evidence that such features contribute to the high incidence of self-and poly-specificity in the fetal antibody repertoire is reviewed.

ISSN:0883-0185    

DOI:10.3109/08830189009056730

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

ISSN:0883-0185    

DOI:10.3109/08830189009056731

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

ISSN:0883-0185    

DOI:10.3109/08830189009056732

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

摘要:

Important questions about pathogenic autoantibodies are whether they arise from germline V genes that contribute to the immunoglobulin repertoire in normal persons, whether they stem from“abnormal”V genes that are peculiar to patients with autoimmune diseases, and whether they are encoded by unmodified or somatically mutated immunoglobulin genes. These issues influence the way we think about three aspects of autoimmunity: genetic susceptibility to autoimmunization, the origins of lesion-producing autoantibodies, and the prevention and medical management of autoimmune disorders.

ISSN:0883-0185    

DOI:10.3109/08830189009056733

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

摘要:

The potential for autoreactivity that has been well documented in normal individuals implies that natural autoimmune responses must serve some physiologic function. To investigate the genetic mechanisms involved in the emergence of such responses, we have determined the sequences of heavy (VH) and light (VL) chain variable region genes for several human monoclonal autoantibodies and compared these with corresponding sequences reported for other antibodies and autoantibodies. Our data reveal that natural autoantibodies can be encoded by nonmutated germline VHand VLgenes which are essentially identical to V genes expressed in early B cell ontogeny as well as in some B-Iineage tumors. Taken together with other structural data on human autoantibodies, these findings suggest that natural autoimmune responses originate early in ontogeny and that such antibodies may play a regulatory role in development of the normal immune repertoire and possibly in suppressing pathogenic autoimmune or malignant responses.

ISSN:0883-0185    

DOI:10.3109/08830189009056734

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

摘要:

Approximately thirty common DNA antibody idiotypes have been described on hybridoma derived or affinity purified DNA-binding antibodies. There are associations between some idiotypes and the clinical manifestations of systemic lupus erythematosus although none are sufficiently firm to be clinically useful in identifying subsets of SLE or in assessing disease activity in individual patients. The expression of these idiotypes is not confined to DNA antibodies in SLE. They may be found in the serum from patients with a range of autoimmune rheumatic disorders, infectious diseases and blood dyscrasias. In most cases the antigen binding specificity of the antibody bearing the idiotype is unknown. The precise relationship between the various idiotypes is becoming better understood with increasing availability of genetic and structural data. DNA antibody idiotype manipulation may provide a potential new therapeutic modality in SLE.

ISSN:0883-0185    

DOI:10.3109/08830189009056735

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

摘要:

We have adopted an idiotypic approach to study the double stranded DNA (dsDNA) binding antibodies of systemic lupus erythematosus (SLE). Three anti-idiotypic reagents, 8.12, 31, and F4, identify cross reactive idiotypes that are each expressed on anti-dsDNA antibodies in the sera of many patients with SLE. These idiotypic antibodies are implicated in the pathogenesis of SLE as they are present in immune complex deposits in the kidneys of patients with SLE glomerulonephritis. The autoantibody associated idiotypes are also expressed on antibodies that do not bind DNA. We are investigating the origin of the pathogenic anti-dsDNA antibodies of SLE by comparing the autoantibodies, the antibodies to foreign antigens, and the myeloma proteins that express each SLE associated idiotype. In conjunction with serological analysis of these idiotypic systems, molecular genetic studies indicate that both the 8.12 and the 31 autoantibody associated idiotypes may be germline encoded, while the F4 idiotype is generated by somatic mutation. The data further suggest that the antigenic specificity of the pathogenic anti-DNA antibodies of SLE is acquired through somatic mutation of germline immunoglobulin genes. By studying the regulation of genes capable of encoding pathogenic autoantibodies, in both SLE patients and non-autoimmune individuals, we may be able to elucidate the pathogenesis of autoimmune disease and begin to design more effective therapeutic interventions.

ISSN:0883-0185    

DOI:10.3109/08830189009056736

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

ISSN:0883-0185    

DOI:10.3109/08830189009056728

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor