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PubMed1991

Igh-1b-specific CD4+CD8- T cell clones of the Th1 subset selectively suppress the Igh-1b allotype in vivo.

The demonstration of major histocompatibility complex (MHC)-restricted T helper (Th) cells specific for peptides from the variable (V) regions of syngeneic immunoglobulin (Ig) (idiopeptides) opens the possibility that Th cells regulate B cell functions via idiopeptide-based cognate T-B interactions. As a model for such interactions we investigated the influence of Ig allotype-specific T cells on the differentiation of H-2-syngeneic B cells expressing that particular Ig allotype. We established a BALB/c (H-2d, Iga) CD4+CD8- T cell line and clones of the Th1 subset (interleukin 2+, interleukin 4-, interferon-gamma+, tumor necrosis factor-alpha+) that recognized Igh-1 (IgG2a) of the b allotype (Igh-1b) together with I-Ad. These T cells specifically suppressed surface Igh-1b+ B cells in vitro and in vivo. In 12 out of 15 6-week-old (BALB/c X B10.D2)F1 mice neonatally injected with Igh-1b-specific T cells, the serum Igh-1b concentrations were less than 5% of the levels in the controls. Thus, allotype suppression can be accomplished solely by adoptive transfer of Igh-1b-specific CD4+ T cells. The in vivo suppression was specific for Igh-1b+ B cells as the recipients' levels of Igh-1a and Igh-4b (IgG1b) were unaffected. The V beta 14-specific anti-T cell receptor (TcR) monoclonal antibody 14-2 inhibited activation of hybridomas derived from two of the clones. Collectively the data indicate that suppression resulted from cognate interactions between allopeptide-specific TcR alpha/beta+ T cells and normal unmanipulated B lymphocytes presenting their endogenous Igh-1b in association with MHC class II molecules. The data support the possibility that normal B cells can be suppressed by idiopeptide-specific T cells in vivo.

Animals↗
PubMed1985

The origin of the very variable haemolytic activities of the common human complement component C4 allotypes including C4-A6.

The human complement component C4 occurs in many different forms which show big differences in their haemolytic activities. This phenomenon seems likely to be of considerable importance both physiologically and pathologically. C4 is coded by duplicated genes between HLA-D and HLA-B loci in the major histocompatibility complex in man. Several fold differences in haemolytic activity between products of the two loci C4-A and C4-B have been correlated with changes of six amino acid residues in this large protein of 1722 residues and with differences of several fold in the covalent binding of C4 to antibody-antigen aggregates. Some allotypes of one locus also differ markedly, notably C4-A6 which has 1/10th the haemolytic activity of other C4-A allotypes. A monoclonal antibody affinity column has been prepared which is able to separate C4-A from C4-B proteins and, using serum from an individual expressing only the C4-A6 allele at the C4-A locus, C4-A6 protein has been prepared. Investigation has shown C4-A6 to have the same reactivity as other C4-A allotypes except in the formation of the complex protease, C5 convertase. This protease is formed from C4, C2 and C3 and if C4-A6 is used it has approximately 1/5th the catalytic activity compared with other C4-A allotype. Allelic differences in sequence identified in C4 proteins so far are few and it is probable that the big difference in catalytic activity of C5 convertase is caused by very small changes in structure.

Alleles↗
PubMed1991

Restricted utilization of germ-line VH genes in rabbits: implications for inheritance of VH allotypes and generation of antibody diversity.

The presence of inherited VH region allotypic specificities, a1, a2 or a3, on nearly all rabbit immunoglobulins has presented a paradox. We know the germline contains hundreds of VH genes, and if we assume that most of these are used in the generation of antibody diversity, then we must ask how have the a allotype-encoding regions been maintained over time? On the other hand, if we assume that only one (or a small number) of these VH gene(s) is (are) used in VDJ gene rearrangements, then, how is antibody diversity generated? To address these questions, we have cloned and determined the nucleotide sequence of the 3'-most germline VH genes from the a1, a2 and a3 chromosomes and shown in each case that the 3'-most H gene, VH1-a1, VH1-a2, or VH1-a3, encodes an a1, a2 or a3 VH region, respectively. Analysis of rearranged VDJ genes from leukemic B cells showed that VH1 was utilized in these rearrangements. Based on these data, we propose that the allelic inheritance of the VH allotypes is explained by the preferential usage of the VH1 gene in VDJ rearrangements. Support for this hypothesis was obtained from analysis of the mutant rabbit Alicia in which most serum Ig molecules do not have VHa allotypic specificities, but instead have so-called VHa-negative Ig molecules. In this rabbit, VH1 is not expressed as it has been deleted. Analysis of cDNA clones from spleen of Alicia rabbits suggests that the expressed VHa-negative molecules also are encoded by a single germline VH gene. Thus, we suggest that nearly all rabbit VH regions are encoded by one to two germline VH genes and that antibody diversity is generated primarily by somatic hypermutation and gene conversion.

Amino Acid Sequence↗
PubMed1984

A strong association between the antinuclear antibody anti-La (SS-B) and the kappa chain allotype Km(1).

The distribution of immunoglobulin allotypes of the Gm and Km systems was examined in 51 patients with antinuclear antibodies (ANA), which reacted with two saline-extractable non-DNA nuclear antigens, anti-La (SS-B) and anti-RNP, which characterize certain multisystem autoimmune diseases. Forty-six percent of the 26 patients with anti-La were positive for the Km(1) allotype compared with 14% of the 35 with anti-RNP and 16% of 1204 of healthy subjects (corrected P value less than 0.005). The high frequencies of the Km(1) allotype (46%), female sex (100%), and the HLA-B8, DR3 phenotype (greater than 90%) in patients with anti-La are indicative of a substantial inherited predisposition to the development or expression of this autoantibody. The strong association between the Km(1) allotype and the anti-La response may be due to linkage disequilibrium between genes coding for the constant region of immunoglobulin kappa light chains and genes coding for the variable regions of kappa light chains which confer antibody specificity for the special configuration of the ribonucleoprotein known as La.

Antibodies, Antinuclear↗
PubMed1986

The purification and properties of some less common allotypes of the fourth component of human complement.

Human complement component C4 is coded by two genes situated between HLA-D and HLA-B. Both genes are highly polymorphic; C4-A gene products normally carry the blood group antigen Rodgers and C4-B proteins usually carry the Chido antigen. Using a monoclonal antibody which binds Rodgers-positive and Chido-positive proteins with different affinities, we have purified a number of less common C4 allotypes and compared their properties. All C4-B allotypes tested have similar specific hemolytic activities and binding efficiencies to small molecules. All C4-A proteins tested had similar binding to small molecules and hemolytic activities except for the C4-A6 proteins from two individuals with different extended haplotypes, both of which had identical hemolytic activities and much lower ones than other C4-A allotypes. Two allotypes, C4-A1, Rodgers-negative but Chido-positive, and C4-B5, Chido-negative but probably Rodgers-positive, were found to behave as typical C4-A and C4-B proteins, respectively, apart from the switch in their antigenic properties.

Antibodies, Monoclonal↗
PubMed1989

Donor Igh-linked genetic control of allotype-specific antibody response.

Immunogenicity of allogeneic immunoglobulins in mice were studied, measuring the allotype-specific antibody activity by agglutination of allogeneic antibody-coated red blood cells. It was found that the serum from C.B-20 mice (Ighb, BALB/c-congenic) was uniquely immunogenic in BALB/c mice for allotype antibody response. Whereas the C57BL/6 (Ighb) serum was immunogenic only when heat aggregated and/or combined with adjuvant, the ultracentrifugation-deaggregated C.B-20 serum was definitely immunogenic when administered in a moderate dose (100 microliters/mouse). Even more surprising was the fast that very low doses (0.01-0.1 microliter) of soluble C.B-20 serum, but not C57BL/6 serum, down regulated the allotype-specific response effectively. Genetic analysis on congenic mice suggested that the immunogenicity is controlled by donor Igh or Igh-V (Id-C.B) inasmuch as the serum from BALB/c-congenic C.B-20 (Igh-VbCb), but not BALB/c-congenic BAB/14 (Igh-VaCb), mice was active in BALB/c mice in soluble form. Further studies showed that the Id-C.B was dominantly expressed on the immunoglobulins of (BALB/c x C.B-20)F1 and (C56BL/6 X C.B-20)F1 strains, and was originally derived from the C57BL/Ka strain. The major determinant for the antibody production was encoded in Igh-C, but not in Igh-V. It is suggested that Id-C.B controls the allotype-specific antibody response in an unusual manner, possibly acting as a unique determinant activating helper T cells.

Animals↗
PubMed1984

Imbalance in recruitment of IgG (Gm) allotype-producing B-cell subsets from blood to brain in multiple sclerosis.

In Gm3/Gm3 homozygous multiple sclerosis (MS) patients, in vitro production of the G1m(3) allotype of IgG1 induced by the T-independent polyclonal B-cell activator Salmonella paratyphi B (SPB) was lower than that of normal individuals of the same Gm phenotype. In contrast, lymphocytes from Gm1/Gm3 heterozygous MS patients responded to the same stimulus with a significantly increased G1m(3) allotype synthesis not observed in normal individuals of the same phenotype. The high level of intrathecal IgG1 production observed in MS patients might be achieved by a selection at the blood-brain barrier of some peripheral T-independent B-cell clones which in Gm3/Gm3 homozygous would bear the G1m(3) allotype, hence a peripheral depletion of this subset, whereas in Gm1/Gm3 heterozygous a preferential admission of the G1m(1)-producing B-cells would lead to a preferential synthesis of this allotype in the central nervous system and to a relative increase of G1m(3) production by the remaining peripheral B cells.

B-Lymphocytes↗
PubMed1982

The use of cellulose carbonate-based immunoadsorbents in the isolation of minor allotypic components of rabbit immunoglobulin populations.

Cellulose trans-2,3-carbonate has been used as a new insoluble matrix for the simple coupling of a1- and b4-positive rabbit immunoglobulin to make immunoadsorbents capable of purifying from serum, with great efficiency, alloantibodies to these allotypic determinants. The antibodies have themselves been conjugated to prepare specific antibody immunoadsorbents of high binding activity for their allotypic target molecules. With these anti-allotypic solid-phase reagents it has been possible to affinity purify a1- and b4-positive immunoglobulin molecules and to deplete serum immunoglobulin of these molecules to leave in the eluates only the allotypically uncontaminated minor immunoglobulin components which are a-negative or b-negative (lambda chain-bearing) molecules. lambda chain molecules were also purified in very small quantities by affinity chromatography on a sheep anti-rabbit lambda chain column. This method of purifying minor populations of rabbit immunoglobulin from normal serum by special immunoadsorbent applications offers new opportunities to study the products of rarely expressed immunoglobulin genes in normal rabbits.

Animals↗
PubMed1986

Allotype-specific probes. A molecular approach to the study of serologically defined determinants.

A new approach to the study of serologically defined immunoglobulin determinants is described. We designed DNA probes which distinguished between the rabbit kappa light chain allotypic sequences in Northern analyses of mRNAs and Southern analyses of genomic DNAs. S1 nuclease protection experiments are described which detect allotype-specific sequences in as little as 100 pg of total RNA. The use of molecular biological techniques overcomes many of the problems inherent in using serological reagents and techniques. In addition, the sensitivity of the assays described here allows the detection of low level expression of the allotypic genes. This work was extended to include the discrimination of the VHa allotypes.

Animals↗
PubMed1985

IgG (Gm) allotypes and multiple sclerosis in a French population: phenotype distribution and quantitative abnormalities in CSF with respect to sex, disease severity, and presence of intrathecal antibodies.

The association of a given Gm allotype or phenotype with MS susceptibility, as previously described in some Caucasian populations, was not observed in a large French MS group, whether or not considering the possible influence of sex or disease severity. This result could be related to variations in geographical distribution of Gm alleles and MS susceptibility gene(s) or suggests the simultaneous involvement of Gm and other genetic system(s). In contrast, the corresponding CSFs exhibited already known MS-associated abnormalities of IgG1 (G1m) allotype contents, which therefore did not merely result from a Gm-associated MS susceptibility. These quantitative abnormalities were not sex dependent, but may fluctuate with MS severity. The G1m allotype levels in each CSF were not correlated with titers of various intrathecal antibodies but with the number of antibody specificities detected, a picture arguing for a polyclonal, non-antigen-specific activation of G1m allotype-producing B cells present in MS brain.

Antibodies↗
PubMed1984

The molecular basis of T helper cell function--I. Allotype- and MHC-linked determinants on antigen-specific, H-2-restricted T cell lines, hybridomas and lymphomas.

A T-cell hybridoma clone, which produces antigen-specific helper factors and a T-cell lymphoma clone which produces non-specific helper factors was used to study the expression of T-cell allotypes and Ia antigens. Use was made of rabbit antisera against isolated T-cell receptor material and of monoclonal mouse antibodies against isolated rat Ia antigen. The rabbit antisera detected endogenously produced determinants both on the membrane and on intracellular polypeptides of these cells. The monoclonal mouse anti-rat-Ia antibodies detected polymorphic determinants on mouse Ia antigens and reacted with endogenously produced molecules on the membrane and on intracellular molecules of the hybridoma and lymphoma cells. The molecules carrying Tcr allotypes were single-chain polypeptides with mol. wts of 60,000-70,000 and the molecules carrying Ia-like antigenic determinants were single-chain polypeptides with mol. wts of 40,000-50,000. Thus T-cell allotypes and Ia antigens were found on separate polypeptide chains. The role and genetic localization of allotype-like and Ia-like molecules in T-cell products is discussed.

Animals↗
PubMed1985

Broad phylogenetic expression of heavy-chain determinants detected by rabbit antisera to VHa allotypes.

Immunoglobulin molecules from diverse vertebrate species were examined, using an enzyme-linked immunosorbent assay (ELISA), for the expression of determinants detectable by rabbit antisera to VHa allotypes. The data indicate that immunoglobulins of elasmobranchs, teleosts, amphibians and birds express determinants cross-reactive with those specified by the a1, a2 and a3 alleles in the domestic rabbit. We localize VHa cross-reactive specificity to the denatured heavy chain of a primitive vertebrate, the Galapagos shark (Carcharhinus galapagensis). Furthermore, the N-terminal amino acid sequence of the shark heavy chain shows significant homology with rabbit heavy chains of known VHa type at positions where allotype-correlated differences have been implicated. VHa-related determinants are shared by immunoglobulins of a wide range of vertebrates from sharks to man and thus seem to be epitopes which have been conserved during vertebrate evolution. The determinants detected on immunoglobulins of lower vertebrates by rabbit anti-VHa allotype sera most probably are VH-subgroup rather than allotypic markers. Their distribution demonstrates a strong phylogenetic conservation of VH-regions.

Amino Acid Sequence↗
PubMed1986

Analysis of the hepatobiliary transport of IgA with monoclonal anti-idiotype and anti-allotype antibodies.

The processing and fate of mixed immune complexes is influenced by the antibody isotypes present. The hepatobiliary transport of mixed immune complexes containing the mouse IgA myeloma protein J558 and corresponding monoclonal IgG or IgM anti-J558 idiotype or monoclonal IgG anti-mouse IgA allotype antibodies has been studied. The anti-idiotype or anti-allotype antibodies were radiolabeled and injected into mice with or without mouse polymeric IgA (J558). IgG anti-idiotype antibodies to J558 IgA were selectively transported into bile by J558 IgA. This process occurred with a radiolabeled Fab preparation of the IgG anti-idiotype and was inhibitable with IgA of an irrelevant antigenic specificity. Thus, polymeric IgA influenced the fate of IgA-IgG idiotype-anti-idiotype serum immune complexes. A monoclonal anti-idiotype antibody of the IgM isotype (D8-3) was not selectively transported into bile by itself or as an IgA-IgM complex. A monoclonal IgG antibody (CB5-6) to a mouse allotype determinant in the Fc portion of IgA was not selectively transported into bile. This anti-allotype monoclonal antibody inhibited the hepatobiliary transport of 125I-polymeric J558 IgA and therefore appeared to directly or indirectly block the site in the Fc region of IgA recognized by the hepatic receptor.

Animals↗
PubMed1987

Escape from b locus allotype suppression in the rabbit is mediated by IgM molecules bearing an allotope-restricted variant of kappa light chain.

Rabbits homozygous for b6 at the kappa light chain b locus were suppressed for the expression of the b6 allotype and then induced to produce auto anti-b6 antibody. Rabbits which subsequently escaped suppression produced auto antibody with restricted allotype specificity. Escape from allotype suppression was mediated by IgM bearing a kappa chain variant with a restricted number of b6 allotopes and having a diminished interaction with auto anti-b6 antibodies from the same and other rabbits escaping b6 suppression. This suggested that there were allelic variants or subpopulations of the b6 light chain which were under independent regulation of expression, clearly influenced by the specificity of auto anti-allotype antibody. Since escape from suppression was mediated by IgM it is proposed that a normal pathway of B cell differentiation occurs during recovery from suppression.

Animals↗
PubMed1987

A "new allotype" of the a series in rabbit immunoglobulins (a107).

An allotype (a107) which strongly cross-reacts with a1 specificity has been detected in the wild rabbit population of Zembra Island, Tunisia. It is different from the a1 allotype since an anti-a1 monoclonal antibody recognizes a1 but not a107 specificity. Genetic data and localization on the Fd fragment are in agreement to designate this allotype to the a series. The a107 allotype has been found in wild rabbit populations of Spain and Portugal but not in France.

Animals↗
PubMed1985

Demonstration of the clonality and specificity of an auto-antibody response to a suppressed immunoglobulin allotype of the rabbit kappa chain b locus.

A regulatory idiotypic network is proposed to control allotype expression in normal rabbits. We have used suppression of the kappa chain b6 allotype in an attempt to restrict the number of regulatory idiotypes involved in an induced auto anti-allotype response. These auto anti-b6 antibodies were examined by an agarose imprint immuno-fixation IEF technique using iodinated allotype-bearing IgG. All totally b6-suppressed rabbits produced a clonally complex response which was generally spectrotypically unique - thus contradicting previous claims of a dominant common idiotypic pattern. The compensating light chains thus have available as many regulatory V genes as does the kappa 1 light chain. However, the b6/b6 homozygotes breaking b6 suppression produce an auto anti-b6 antibody which does not interact with their "escaping" molecules and which is clonally restricted. We propose a regulatory mechanism limiting the V genes utilised to produce the autoantibody, the latter then allowing only molecules bearing non-interactive allotopes to "escape" suppression.

Animals↗
PubMed2005

Identification of novel VH1/J558 immunoglobulin germline genes of C57BL/6 (Igh b) allotype.

Although a rich database of Igh a allotype mouse immunoglobulin germline genes exists, current information on Igh b allotype immunoglobulin germline genes is limited. Among the immunoglobulin VH genes, single-cell amplified from six Igh b (C57BL/6 background) spleens in this study, 602 clonally independent immunoglobulin VH sequences belonging to the VH1/J558 family were identified. Whereas 335 of these sequences could be traced to have originated from 29 different VH1/J558 germline genes deposited in the NCBI Igblast database, the remaining 267 sequences appeared to have originated from 21 novel germline genes. Of the 50 VH1/J558 germline genes utilized in the peripheral repertoire of these Igh b allotype mice, the most frequently used genes included 45.21.2, V165.1, J558.6, J558.18A, and V23. Whereas the majority of the novel genes uncovered represented allelic counterparts of previously described Balb/c (Igh a allotype) genes, some appeared to represent truly novel germline genes. Collectively, the VH1/J558 germline genes exhibited high amino acid residue usage variability at the CDR1 positions, H31, H33, and H35, and the CDR2 positions, H50, H52, H53, H54, H56, and H58. The 50 VH1/J558 germline genes expressed in the peripheral Igh b repertoire also varied widely in the net charge of their CDR regions, raising the possibility that they may be differentially utilized to encode anti-nuclear autoantibodies.

Animals↗
PubMed2003

Rabbit immune repertoires as sources for therapeutic monoclonal antibodies: the impact of kappa allotype-correlated variation in cysteine content on antibody libraries selected by phage display.

The rabbit immune repertoire has long been a rich source of diagnostic polyclonal antibodies. Now it also holds great promise as a source of therapeutic monoclonal antibodies. On the basis of phage display technology, we recently reported the first humanization of a rabbit monoclonal antibody. The allotypic diversity of rabbit immunoglobulins prompted us to compare different rabbit immune repertoires for the generation and humanization of monoclonal antibodies that bind with strong affinity to antigens involved in tumor angiogenesis. In particular, we evaluated the diversity of unselected and selected chimeric rabbit/human Fab libraries that were derived from different kappa light chain allotypes. Most rabbit light chains have an extra disulfide bridge that links the variable and constant domains in addition to the two intrachain disulfide bridges shared with mouse and human kappa light chains. Here we evaluate the impact of this increased disulfide bridge complexity on the generation and selection of chimeric rabbit/human Fab libraries. We demonstrate that rabbits with mutant bas and wild-type parental b9 allotypes are excellent sources for therapeutic monoclonal antibodies. Featured among the selected clones with b9 allotype is a rabbit/human Fab that binds with a dissociation constant of 1nM to both human and mouse Tie-2, which will facilitate its evaluation in mouse models of human cancer. Examination of 228 new rabbit antibody sequences allowed for a comprehensive comparison of the LCDR3 and HCDR3 length diversity in rabbits. This study revealed that rabbits exhibit an HCDR3 length distribution more closely related to human antibodies than mouse antibodies.

Animals↗