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PubMed1982

Autoantibodies and immunoglobulin allotypes in healthy North American Blacks of different age groups.

A population of 291 healthy North American Black subjects of different ages was studied for immunoglobulin (Ig) allotypes and the prevalence of autoantibodies, to determine possible associations between Ig allotypes and age, autoantibodies and age, and Ig allotypes and autoantibodies. Indirect immunofluorescence was used to detect anti-gastric parietal cell, anti-smooth muscle, anti-thyroid microsomal, anti-nuclear, and anti-mitochondrial antibodies. The sera were typed for the Ig allotypes Gm(1, 2, 3, 5, 6, 13, 14, 17, and 21) and Km(1) with a hemagglutination-inhibition assay. A significant association between advanced age and an increased prevalence of anti-nuclear antibodies was observed in females. There was no significant association between Ig allotypes and the autoantibodies tested. The results suggest that Ig allotypes are not involved in the development of autoantibodies in healthy Blacks.

Adolescent↗
PubMed1983

A bi-directional immune network mechanism: simultaneous induction of idiotype and anti-anti-idiotype in rabbits immunized with antibody to a common idiotypic specificity of anti-VHa2-allotype antibodies.

Recently, we identified a common idiotypic specificity (IdC) present on all of the allo and auto anti-VHa2-allotype antibodies tested. In this report, we immunized allotype-matched rabbits with anti-IdC Ab. When an a1a1 homozygote was immunized with anti-IdC Ab (also from an a1a1 rabbit), two distinct Ab populations were induced which were isolated through the use of immunoadsorbent column chromatography. One of these Ab populations, adsorbed to and eluted from an insolubilized a2 IgG column, was anti-VHa2-allotype Ab (Ab 1), which reacted with a2 Ig and inhibited the reaction between the a2 allotype and anti-VHa2-allotype Ab. The other Ab population, adsorbed to and eluted from an insolubilized immunogen anti-IdC column, was anti-anti-IdC Ab (Ab 3), which was specific for the immunogen anti-IdC Ab. In another experiment, when an a1a2 heterozygous rabbit was immunized with anti-IdC Ab, only the Ab 3 was induced, which appeared to be identical to the Ab 3 induced in the a1a1 rabbit. However, when the expression of the a2 allotype in an a1a2 heterozygous rabbit was suppressed and then this rabbit was immunized with anti-IdC Ab, both Ab 1 and Ab 3 were induced. These data indicate the occurrence of a bi-directional immune response within our immune network system. According to Jerne's network theory, Ab 3 appeared to be induced through a stimulation by the idiotope of the immunogen Ab 2, whereas Ab 1 appeared to be induced through a reverse stimulation by the paratope of the immunogen Ab 2. Furthermore, the production of Ab 1 in these rabbits exhibiting the bi-directional immune response was at least 3-5 times greater than that of Ab 3 production indicating that the response through the reverse stimulation appeared to be dominant. The importance of this bi-directional immune response is discussed in this paper.

Animals↗
PubMed1984

Tetraparental rabbits chimeric for their lymphoid system--I. Allotype expression.

We constructed tetraparental rabbits by immunosurgically prepared inner-cell-mass transplantation. The two constitutive parental strains were chosen so that they not only differed by their coat colour (brown and white rabbits) but also by the allotypic specificities of their immunoglobulins. It was thus possible to distinguish among the rabbits born from composite blastocysts those which were chimeric for their lymphoid system and to unambiguously quantitate the respective contribution of each parental strain to this chimerism. In this peculiar situation, the possible perturbation of the expression of immunoglobulin allotypic specificities could be tested. Thus further analysis of the tetraparental rabbit's immunoglobulins was performed to look at possible anomalies of their constitution. In only one out of the 20 tetraparental rabbits studied, we found IgG having heavy chains with the allotypic specificities of one parental strain and light chains with the allotypic specificities of the other parental strain. We did not observe, in any case, the expression of immunoglobulin allotypic specificities other than the expected ones. We always observed a marked decrease with time in the expression of the immunoglobulins produced by the lymphocytes of one parental strain accompanied by a concomitant increase in the expression of the immunoglobulins produced by the lymphocytes of the other parental strain. Two tetraparental rabbits were found to be germ-line chimeras. Analysis of the immunoglobulin allotypic specificities of the progeny of our tetraparental rabbits including these two did not reveal any perturbation in their hereditary transmission according to the usual Mendelian laws.

Animals↗
PubMed1992

The heterogeneity of bovine IgG2--V. Differences in the primary structure of bovine IgG2 allotypes.

The partial amino acid sequences of the gamma chains of the bovine IgG2a(A1) and IgG2a(A2) allotypes were determined. Sequence differences were found in the CH1 domain, the hinge region, and the CH3 domain. The hinge regions displayed only 71.4% similarity and all of the differences were of a radical nature. The A2 hinge has isoleucine instead of serine at 229, histidine for asparagine at 235, proline for histidine at 238, and cysteine instead of proline in position 234; the latter has the potential for forming an additional interheavy chain disulphide bridge. The occurrence of such a bridge could explain the presence of a pepsin fragment consisting of the hinge region and the Fc. A corresponding fragment is not obtained with the A1 allotype. Both allotypes have a shortened hinge region and a truncated CH2 domain. This feature is characteristic of all reported sequences of IgG2 proteins but not IgG1 in cattle and the goat. This structural feature may be important in subclass-specific recognition by Fc gamma receptors in ruminants. A surprising discovery was the occurrence of five substitutions in the CH3 domain of the IgG2a(A2) in comparison with the A1, which are shared with the CH3 of IgG1. These permit the occurrence of isoallotypic determinants and can explain the difficulty encountered in preparing A2-specific antisera during which adsorption with IgG1 is a routine procedure. The primary sequence data we report confirm the presence of major structural differences between the A allotypes of cattle that was suggested by previous work. The sequence of the A1 allotype most closely agrees with the two IgG2 sequences deduced from their nucleotide sequences whereas the sequence differences in the hinge and C-terminal CH3 make IgG2a(A2) unique. The structural differences between allotypes could have major consequences for such biological activities as phagocytosis, transepithelial transport, lymphocyte and complement activation.

Amino Acid Sequence↗
PubMed1999

Differential complement activation by bovine IgG2 allotypes.

Immunoglobulin allotypes and complement (C) are known to be related to susceptibility to infection. Because bovine IgG2 is important in resistance to pyogenic infections and because its two allotypes, IgG2a and IgG2b, differ in sequence in the CH1, hinge, CH2, and CH3 regions, we tested the ability of these allotypes to initiate the bovine C cascade. Bovine IgG2a and IgG2b were standardized according to specific anti guinea pig red blood cell (GPRBC) ELISA activity using anti IgG2 reagents shown essentially unbiased for allotype. Complement activating activity of the allotypes was quantitated in a GPRBC lysis assay. With this system, IgG2b consistently had more than twice the activity in bovine C mediated lysis as compared with IgG2a. The fact that both EDTA and EGTA/Mg almost completely inhibited C mediated lysis of GPRBCs indicated that lysis was due to the classical pathway. Since antibody usually activates C by the classical pathway, this supports the supposition that activation was by the IgG2-GPRBC complexes. Flexibility analyses showed that IgG2b had a more rigid hinge than IgG2a, perhaps partially explaining the greater efficiency of IgG2b in C activation. Other mechanisms may include differences in glycosylation and in the amino acid at position 332. The difference in ability to activate C may mean that animals of the IgG2a allotype could be more susceptible to infection with extracellular pyogenic pathogens which are killed by C or by phagocytes after opsonization with IgG2 and C.

Animals↗
PubMed1979

B-cell influences on the induction of allotype suppressor T cells.

Allotype suppressor T-cell (Ts) populations that persist for the life of the animal arise in (BALB/c x SJL)F(1) hybrids exposed perinatally to antibody to the paternal (Ig-1b) allotype on IgG(2a)-isotype immunoglobulin H chains. These Ts suppress Ig-lb production by depleting the supply of allotype- specific helper T cells (Th) required, in addition to carrier-specific Th, for the latter stages of Ig-1b memory B-cell differentiation. In this publication, we show that specific Ig-1 allotype Ts are induced by perinatal exposure to antisera which interfere with normal B-cell maturation, i.e., by antibodies reactive with surface IgM on immature precursors of IgG(2a), memory cells. Antibodies to IgM (Ig-6) allotypes carried on precursors induce specific suppression for the IgG2, allotype produced by progeny of the target precursor. Anti-Ig-6a and anti-Ig-6b induce Ts that specifically suppress Ig-1a and Ig-1b, respectively. Heterologous (goat) anti-IgM induces suppression for both IgG(2a) immunoglobulins (Ig-1a and Ig-1b). Ts activity in these antiprecursor-Ig-suppressed mice is expressed in adoptive transfer assays and, as with anti-Ig-1b-induced Ts, is rendered ineffective by cotransfer of adequate numbers of T cells but not B cells from nonsuppressed mice. The Ts induction, in contrast with Ts expression, is reversed by the introduction of appropriate adult B-cell populations from nonsuppressed donors. Taken together, these data suggest that the development of mature B cells plays a central role in the early establishment of the balance between helper cells and suppressor cells that determines whether Ts or Th will dominate in regulating Ig-1b production in adult animals.

Age Factors↗
PubMed1984

Rheumatoid factors in 129XB recombinant inbred strains. Igh-1-linked control of allotypic and isotypic specificities.

To examine the role of autologous IgG in the induction of murine rheumatoid factors (RF) we have analyzed the allotypic specificity of anti-IgG2a RF in recombinant inbred strains derived from 129/Sv (Igh-1a) and C57BL/6 (Igh-1b) mice. In five of six Igh-1a strains, anti-IgG2a RF reacted with IgG2aa but failed to react with IgG2ab. In contrast, isotype-specific RF, which reacted equally well with a and b allotypes of IgG2a, represented the major RF species in one Igh-1a and all five Igh-1b strains tested. An additional form of RF specific for IgG2ab and not reactive with IgG2aa was detected in one Igh-1b strain. RF specific for a give allotype was thus only found in the presence of that allotype, which strongly suggests the involvement of autologous IgG in the induction of mouse RF synthesis. The specificity of RF was apparently further controlled by genes linked to but different from the Igh-C locus, as indicated by the absence of IgG2aa-specific RF in one of the 6 Igh-1a strains tested. Because this strain, 129XBG, has been shown to express idiotypic markers characteristic of Igh-1b mice, it is likely that the genes, which in the presence of a given allotype induce the production of isotype rather than allotype-specific RF, are identical to those that control the expression of idiotypes. Evidence was also obtained to indicate that Igh-1-linked genes influence the isotypic specificity and the isotype of RF itself: IgA anti-IgG2a predominated in Igh-1a strains and IgM anti-IgG1 in Igh-1b strains. Interestingly enough, total IgA and IgG2a levels also were higher in Igh-1a than in Igh-1b strains.

Animals↗
PubMed1991

A mouse monoclonal antibody specific for an allotypic determinant of the Igha allele of murine IgM: genetic and functional analysis of Igh-6a epitopes using anti-IgM monoclonal antibodies.

An IgG1 mouse monoclonal antibody (MAb) specific for a mouse IgM allotypic determinant in the a, c, f, g, h, and j haplotypes was derived from a fusion of SP2/O-Ag14 mouse myeloma cells with C57BL/6 mouse spleen cells (Igh-Cb) immune to TC31, a MAb of the IgMa allotype. MAb from one hybridoma derived from this fusion (designated DS1) was demonstrated to bind in an ELISA to immunoglobulin bearing the IgMa allotype (TC31, MOPC104E), but not to immunoglobulin bearing the IgMb allotype (C.BPC112). Fluorescein-conjugated DS1 was shown to bind to the surface of BALB/cByJ splenic B cells, but was shown to have negligible binding on C57BL/6J cells. Similarly, DS1-conjugated Sepharose beads were able to stimulate in vitro proliferation of BALB/c, but not C57BL/6 splenic B cells. DS1 was unable to bind to spleen cells from BALB/c allotype congenic strains, BAB/14 (Igh-Cb) and C.AL-20 (Igh-Co), demonstrating that DS1 recognizes a determinant under the control of a gene linked to the Igh-C gene complex. Using sera from recombinant inbred lines, the determinant defined by DS1 was shown to be linked to the Igh-1 locus. Furthermore, the determinant was localized to the CH1 domain of the mu heavy chain. Sera from BALB/cByJ, NMRI, CBA/J, SEA/GnJ, RIIIs/J, and CE/J mouse strains were shown to bind to DS1 in an ELISA, while sera from A/J, SJL/J, NZB/B1NJ, AKR/J, C57BL/6J, and C57BL/10SnJ mouse strains did not bind to DS1. From these data we propose that DS1 is reactive with specificity Igh-6.1, which was originally defined by an allotypic antiserum developed by Black et al. (Immunogenetics 7:213, 1978).

Alleles↗
PubMed1986

Serum allotypes in ovarian follicular fluids of pigs.

Sera and ovarian follicular fluids of 158 sows were tested with 27 allotype reagents. Immunodiffusion in agar gel (microtest) and haemagglutination inhibition were used as detection methods. Out of eight 'individual' (Lpb 1,-2,-3,-4,-5,-6,-7,-9) and four 'common' (Lpb 12,-13,-14,-16) specificities of serum beta-lipoproteins (LDL), 11 were present in sera, but none in follicular fluids. On the other hand, Lpr 1 and Lpr (x) allotypes of the VHDL + VLDL beta-lipoprotein system were detected both in sera and in follicular fluids. Of four antigens of the Gp system (Gp A,-a, -B,-b), only the 'dominant' characters, Gp A and Gp B, occurred in the follicular fluid. The typing of polymorphic IgG immunoglobulins (IgG-a or IgG-b system) showed that B1 or A2, B2 or A1 and B3 or A(x) allotypes could be detected both in serum and follicular fluid. Among allotypes that were not yet genetically classified, only the P3 specificity was not found in the population tested. The G1 allotype (preliminarily described as an alpha-globulin) was present in sera only, and the remaining allotypes, G9, P1, P16 and P23 (alpha- or beta-globulins) were present both in sera and follicular fluids. The mechanism of the transmission of serum proteins into ovarian follicles and their possible importance is discussed.

Animals↗
PubMed1998

Serum IgG2 level, Gm(23) allotype and FcgammaRIIa and FcgammaRIIIb receptors in refractory periodontal disease.

The purpose of this investigation was to compare the levels of serum IgG2, the frequency of detection of Gm(23)-negative allotype and frequency of detection of FcgammaRIIa and FcgammaRIIIb receptor haplotypes in 32 refractory, 54 successfully treated and 27 periodontally healthy individuals. Refractory subjects showed mean full mouth attachment loss and/or >3 sites with attachment loss >2.5 mm within 1 year after both scaling and root planing, and surgery plus systemically administered tetracycline. Successfully treated subjects showed mean attachment level gain and no sites with attachment loss >2.5 mm 1 year post-therapy. Periodontally healthy subjects exhibited no pocket depth or attachment level >3 mm, and no evidence of progressing disease during 1 year of monitoring. Blood was obtained from each subject at baseline. Serum IgG2 and Gm(23) allotype were determined using radial immunodiffusion. DNA was extracted from whole blood and the FcgammaR genotypes determined using PCR and allele specific oligonucleotide probes. Significance of differences among clinical groups were sought using the Kruskal-Wallis or chi-square tests. Associations between 2 or more variables were tested using regression analysis. Refractory subjects exhibited higher mean attachment loss and pocket depth than successfully treated or periodontally healthy subjects. Smoking status did not differ significantly among groups. No significant differences in serum IgG2 levels and frequency of detection of Gm(23)-negative allotype were observed among the clinical groups. Serum IgG2 level was positively associated with the number of serum antibody responses to subgingival species (r=0.51, p<0.001). Subjects with the Gm(23)-negative allotype exhibited lower mean levels of serum IgG2 (3.06+/-0.3 versus 3.9+/-0.2, p<0.01) and mean number of serum antibodies to subgingival species (17.7+/-1.7 versus 23.3+/-1.4, p<0.05) than allotype positive individuals. No significant differences in FcgammaR haplotype distribution were observed among the 3 clinical groups. Associations of serum IgG2 level, Gm(23) allotype, FcgammaRIIa and FcgammaRIIIb receptor haplotypes and smoking status were weakly related or not related to clinical status. This lack of relationship may have been due to a reality of no relationship, or the inadvertent pooling of subjects where these factors were of primary importance with subjects in whom these factors played a less important role.

Adult↗
PubMed1985

Correlation between G2m(n) immunoglobulin allotype and human antibody response and susceptibility to polysaccharide encapsulated bacteria.

To determine whether genetic factors influence the human antibody response to polysaccharides, we correlated Ig allotypes with the concentrations of antibody to 14 bacterial capsular antigens in 130 actively immunized Caucasian adults. The 88 individuals possessing G2m(n), an allotype antigen of IgG2 subclass heavy chains, had significantly higher postimmunization antibody levels to Haemophilus influenzae type b (Hib) and 8 of 11 pneumococcal types (P less than 0.05) than the 42 lacking this antigen. For Hib, pneumococcus type 14, and meningococcus group C, an increased response was observed in IgG class but not in IgM or IgA classes of antibody. The G2m(n) positive individuals also had higher preimmunization antibody levels to most polysaccharide antigens. Total IgG2 concentrations were correlated with the mean postimmunization antibody concentrations to pneumococci (P = 0.005), but this correlation was independent of G2m(n) by multiple regression analysis. To determine if the lack of G2m(n) was associated with increased susceptibility to infection, we compared the frequencies of various Ig allotypes in 98 children infected with Hib and 98 matched controls. Caucasian children with Hib infections other than epiglottitis were significantly more likely to lack the G2m(n) allotype than controls (P less than 0.05). G2m(n) negative Caucasian children less than or equal to 18 mo old have a 5.1-fold higher risk of nonepiglottitic Hib infections than G2m(n) positive children (P less than 0.01). We conclude that allotypic variants of the gamma-2 heavy chain genes, or genes in linkage equilibrium with them, exert a regulatory influence on the caucasian antibody response to a variety of immunologically distinct bacterial polysaccharide antigens. Young Caucasian children of the low responder phenotype, i.e., those lacking the G2m(n) allotype, are genetically predisposed to Hib and perhaps other bacterial infections.

Adult↗
PubMed1976

Effect on synthetic capacity of antibodies directed against receptors of allotype-bearing rabbit cells.

Rabbit immunoglobulin molecules possess antigenically distinct allotypic markers. Immunoglobulin molecules possessing such markers which are attached to the surfaces of lymphocyte precursors of antibody-forming cells are believed to serve as antigen receptors. Interactions between allotypic determinants and antibodies directed against them can provide useful models for the study of immunoregulatory phenomena. Exposure of a fetal or neonatal rabbit to antibodies against one of its immunoglobulin allotypes results in a persistent defect in expression of that type (allotype suppression). Some evidence indicates that this phenomenon involves specific active suppression by lymphoid cells. By examining the effects of anti-allotype antibodies on allotype-bearing lymphocytes in vitro, certain specific events surrounding the processes of lymphocyte ontogeny, and the differentiation and maturation of antibody-forming cells are being analyzed.

Aging↗
PubMedDate not supplied

Serological and chemical studies of latent allotypes in the rabbit.

Genetic data has shown that antigenic variants or allotypes of variable and constant regions of the heavy and light chains of immunoglobulins represent products of allelic structural genes. New findings in several animal systems have demonstrated the non-allelic behavior of immunoglobulin allotypes. In the present study we report the results of our efforts to confirm the presence of latent allotypes in rabbit sera. Varying amounts of latent allotypes for groups a and b markers were detected in 95% of all normal and immune sera tested. Several rabbits expressed high levels of latent a and b allotypes (in excess of 200 micrograms/ml of serum). By gel diffusion and radioimmune inhibition analysis, the latent b4 marker from one b6b6 rabbit, B240, was identical to the nominal b4 allotype. Also, the L chains bearing the latent b4 marker were isolated from B240 IgG and analyzed chemically by taking advantage of an acid-labile aspartic acid-proline bond at positions 109 and 110, which is unique for b4 and b9 kappa L chains.

Alleles↗
PubMedDate not supplied

Recovery from allotype suppression in rabbits and release from this suppression in specific immune response.

The recovery of allotypic expression in allotype suppressed rabbits was followed up in specific antibodies and in bulk immunoglobulins. The primary antigenic stimulation with BSA and/or MS2 phage was given at 4 weeks of age. In the early recovery group, where the recovery from suppression began at 11-13 weeks of age, specific antibodies bearing the suppressed allotype were found to be synthesized by the primary stimulation or with successive allotype was scarely expressed in specific antibodies despite its recovered expression in bulk immunoglobulins. The X-ray irradiation followed by the immunization procedures promoted the recovery of the suppressed allotype expression in anti-BSA antibody and in bulk immunoglobulins but not in anti-MS2 phage antibody. The results are discussed in terms of regulatory mecahnisms of immune response in allotype suppressed animals.

Animals↗
PubMed1976

Preferential expression of anti-azobenzenearsonate antibodies of heterozygous a1a3 rabbits in the a1 allotype.

The preferential expression of anti-As antibodies in the allotype a1 of heterozygous a1a3 rabbits immunized with As-TMA-BSA has been investigated by means of quantitative methods. The average content of the anti-As antibodies in a1 and a3 allotypes was 84 and 11%, respectively; the analogous values for anti-TMA antibodies were 41 and 56%, and for anti-BSA antibodies they were 54 and 41%. The molar anti-As/anti-TMA ratios in the heterozygous a1a1 rabbits sensitized with As-TMA-BSA. The very low yields of anti-As-antibodies of allotype a3 cannot be caused by a lack of genes for the production of anti-As antibodies of allotype a3 because a3a3 homozygotes produce considerable amounts of anti-As antibody of allotpye a3. Competition between lymphoid cells having anti-As receptors of different allotype and different affinity for the antigenic p-azobenzenearsonate determinant is discussed as a possible cause for the preferential expression in the a1 allotype.

Animals↗
PubMed1992

Regulation of C gamma 3 expression. Role of switch in the allotype-associated variation of human serum IgG3 levels.

Serum IgG3 levels are associated with G3m allotypes in humans. However, the molecular basis of this association has not been understood. In this study we have analyzed the biologic half-life, the secretion, the cell surface expression, the cytoplasmic content, and the mRNA expression of different allotypes. The biologic properties of the allotypes did not differ. However, the frequency of cells with membrane IgG3, cytoplasmic IgG3, and C gamma 3 mRNA was decreased in donors with a low serum IgG3, whereas the level of C gamma 3 mRNA expression in individual cells did not differ among cells of the different allotypes. As these findings indicated a pretranscriptional control of C gamma 3 expression, genomic DNA from donors with different allotypes were also studied. Despite the absence of gross, allotype-related differences in the I gamma 3 regions, we favor an upstream cis-element influencing C gamma 3 switching as the most likely explanation for variations in IgG3 serum levels.

Animals↗
PubMed1991

IgG allotypes of the domestic mink: genetics, expression and evolution.

A brief review summarized the results we obtained with the identification, analysis of population distribution, genetics, expression, and evolution of 12 IgG allotypes in the American mink and several closely related mustelids. The American mink is a unique species with respect to expressed allotypic polymorphism of Ig lambda chains. In contrast to the rabbit, human, mouse and rat, the phenotypic expression of IgC gamma allotypes shows unusual variations which mask their true genetic relationships (linkage of C gamma genes; C gamma = constant region of IgG chains). The allotypic IgG polymorphism in the American mink during mustelid phylogenesis underwent saltatory change. A parallelism between the data on changes in IgG allotype frequencies in man and mink in disease is emphasized. In mink, these changes are provided by allotype-specific activation of the expression of the 2 CH genes (CH = constant region of the Ig heavy chains). The results make apparent the need of including more taxa in investigations of Ig genetics. In addition, the Aleutian disease of the mink is presented as a model of human disease.

Animals↗
PubMed1988

Comparison of latent and nominal rabbit Ig VHa1 allotype cDNA sequences.

The genetic basis for the expression of a latent VH allotype in the rabbit was investigated. VH region cDNA libraries were produced from spleen mRNA derived from a homozygous a2a2 rabbit expressing an induced latent VHa1 allotype and, for comparison, from a normal homozygus a1a1 rabbit expressing nominal VHa1 allotype. The deduced amino acid sequences of the nominal VHa1 cDNA were concordant with previously published VHa1 protein sequences. A comparison of two complete VH-DH-JH and six partial VHa1 sequences reveals highly conserved sequence within VH framework regions (FR) and considerable diversity in complementarity-determining regions and D region sequences. Two functional JH genes or alleles are evident. Amino acid sequencing of the N-terminal 15 residues of pooled affinity-purified latent VHa1 H chain showed complete sequence identity with the nominal VHa1 sequences. Possible latent VHa1-encoding cDNA clones, derived from the a2a2 rabbit, were selected by hybridization with oligonucleotide probes corresponding to the VHa1 allotype-associated segments of the first and third framework regions (FR1 and FR3). cDNA sequence analysis reveals that the 5' untranslated regions of nominal and latent VHa1 cDNA were virtually identical to each other and to previously reported sequences associated with VHa2 and VHa-negative genes. Moreover, some latent VHa1 genes encode FR1 segments that are essentially homologous to the corresponding segment of a nominal VHa1 allotype. In contrast, other putative latent genes display blocks of VHa1 sequence in either FR1 or FR3 that are flanked by blocks of sequence identical to other rabbit VH genes (i.e., VHa2 or VHa-negative). These composite sequences may be directly encoded by composite germ-line VH genes or may be the products of somatically generated recombination or gene conversion between genes encoding latent and nominal allotypes. The data do not support the hypothesis that latent genes are the result of extensive modification by somatic point mutation.

Amino Acid Sequence↗