Synthetic Autoantigens of Immunoglobulins and T-Cell Receptors: Their Recognition in Aging, Infection, and Autoimmunity

Abstract

Immunoglobulins and their close relatives, the antigen-specific T-cell receptors, are recognition proteins that express structures which readily serve as self-immunogens. Healthy humans can produce antibodies against variable region-defined recognition structures termed idiotypes, as well as against constant region structures, and the levels of these can increase markedly in autoimmune disease; e.g., rheumatoid factors are autoantibodies directed against a conformational determinant of the gamma heavy chain. More recent analyses employing synthetic peptide technologies and construction of recombinant T-cell receptors document that autoantibodies directed against both variable and constant region markers of the alpha/beta T-cell receptor occur in healthy individuals. Alterations in levels of antibody, usage of IgM or IgG isotypes, and specificity for particular peptide-defined regions vary with natural physiological processes (aging, pregnancy), with artificial allografting, with retroviral infection, and with the inception and progression of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus). Two of the major autoimmunogeneic regions of the Tcr alpha/beta are "constitutive" markers inasmuch as all individuals tested produce antibodies against these regions. The most frequently observed autoantibodies are against Tcr V beta CDR1 and Fr3 markers. It is hypothesized that these are normally involved in immunoregulation. Autoantibodies usually are not detected against CDR2 region determinants, or the "private idiotypes" defined by the CDR3 region, or the highly conserved FR4 segment specified by the joining gene segment. However, autoantibodies against the CDR2 of the Tcr alpha chain occur in some SLE patients, and healthy pregnant women produce antibodies against the common peptide determinant expressed by the joining gene and the beginning of the C alpha or C beta domain. Although the precise role of the naturally occurring autoantibodies in immunoregulation remains to be determined, modification of the course of autoimmune diseases in experimental rodent models (experimental allergic encephalomyelitis) has been successfully carried out by immunization with synthetic peptides corresponding to the CDR2 and Fr3/CDR3 segments, and immunization of humans with synthetic V beta CDR2 segments may prove helpful in multiple sclerosis. Moreover, infusion of intravenous immunoglobulins has been successful in the treatment of many autoimmune diseases, including examples where levels of T cells bearing particular V beta gene subsets were elevated. The recent knowledge gained from T-cell receptor structural analysis and antigenic modeling holds promise for determining the roles of particular variable domain structures in antigen recognition MHC-restriction and immunoregulation, and in the development of synthetic and recombinant reagents for modulation of autoimmune and infectious diseases.

Retrovirally Induced Mouse Anti‐TCR Monoclonals can Synergize the In Vitro Proliferative T Cell Response to Bacterial Superantigens

“…Fields et al [49] showed that Vb CDR1 and HV4, as well as CDR2, bound in a cleft between the two domains of the SAgs and that the CDR3 did not have direct contacts. There is thus considerable overlap between the SAg-binding sites of MHCrestricted TCR which supports our hypothesis that the Vb CDR1 is a regulatory idiotope [4] susceptible to modulation by binding of autoantibodies. In the amplification of the SAg response, it is likely that the monoclonal autoantibodies can contribute by binding to CDR1 when SAg contact might be optimal.…”

“…The detection of autoantibodies directed against peptide defined epitopes of the T-cell receptor (TCR) b chain in normal sera and various physiological and disease states has been established in our laboratory using synthetic overlapping peptides and subsequent synthetic peptide epitope homologue analysis [1][2][3][4]. Initially, 22 nested synthetic 16-mer peptides were synthesized with five residue overlaps in order to mimic the covalent structure of the TCR b chain for epitope mapping studies of the Bence-Jones protein Mcg (l light chain: see [5]) and the YT35 TCR b gene product (TCR Vb8.1 human: see Refs 1,4 and 6).…”

T‐cell‐receptor dose and the time of treatment during murine retrovirus infection for maintenance of immune function

“…A set of overlapping 16-mer peptides that duplicate covalent structure of the VbDbJbCb protein 10,16 predicted from a human TCR-b gene sequence 17 has been produced. TCR Vb CDR1 has a sequence, C K P I S G H N S L F W Y R Q T, that corresponds to the completed CDR1 and N-terminal five residues of Fr2 10,18 of the human Vb8.1 gene product.…”

Are anti-ribosomal P protein antibodies a type of anti-lymphocyte antibody?

“…Activated T cells, which exhibit a higher density of many surface membrane antigens than do resting cells and also express neoantigens, were found to be special targets of such autoantibodies [8]. Considerable information also has accrued concerning IgM ALAB target antigens: IL-2 receptor [9]; b 2 -microglobulin [10,11]; HLA class I heavy chains [12]; a DR framework epitope [13]; IgD, which functions as an antigen receptor on B cells [14]; B and T cell membrane glycosphingolipids [15]; CD45 [16][17][18]; and synthetic T cell receptor (TCR) peptides [19]. Almost certainly, there are additional specificities that have not yet been characterized.…”