Specific Immune Response Genes Research Articles

Histocompatibility-Linked Genetic Control of the Immune Response to Hapten Guinea Pig Albumin Conjugates in Inbred Guinea Pigs

Abstract The immune response of inbred guinea pigs to low doses of hapten-guinea pig albumin conjugates is controlled by a specific immune response gene closely linked to the gene complex controlling strain 13 histocompatibility antigens. Thus, strain 13 guinea pigs make significant anti-dinitrophenyl (anti-DNP) antibody responses to 1 μg of DNP-guinea pig albumin (GPA) while strain 2 guinea pigs make little or no response and are not prepared for secondary anti-DNP responses. Progeny of (2 × 13) F1 × 2 matings which possess strain 13 histocompatibility antigens are good responders to a low dose of DNP-GPA while offspring lacking strain 13 antigens are poor responders. The differential response of strain 2 and 13 animals to DNP-GPA is also observed with p-iodophenylsulfonyl-GPA and a 3-(2,4-dinitrophenylamino)-propylamide derivative of GPA. These observations indicate that this immune response gene is involved in carrier recognition and suggest that it operates in thymus-derived lymphocytes.

Specific immune response genes of the guinea pig. V. Influence of the GA and GT immune response genes on the specificity of cellular and humoral immune responses to a terpolymer of L-glutamic acid, L-alanine, and L-tyrosine.

The ability of guinea pigs to make immune responses to the random linear copolymer of L-glutamic acid and L-alanine, GA, and to L-glutamic acid and L-tyrosine, GT, is each controlled by a different immune response gene. On the other hand, the random linear terpolymer of L-glutamic acid, L-alanine, and L-tyrosine, GAT, which contains both GA and GT antigenic determinants, is immunogenic in all guinea pigs. After GAT immunization, all animals develop delayed hvpersensitivity and serum antibody specific for GAT. However, only those guinea pigs possessing the GA immune response gene demonstrate cross-reactive delayed hypersensitivity when challenged with GA. In addition, the anti-GAT antisera produced by those animals having the GA gene contain cross-reacting anti-GA antibodies. The sera from guinea pigs lacking the GA gene have no anti-GA antibody activity. Thus, we have demonstrated that a specific immune response gene controlling responsiveness to a "simple" antigen can determine the specificity of both cellular and humoral immune responses to a more complex antigen.

Specific immune response genes of the guinea pig. 3. Linkage of the GA and GT immune response genes to histocompatibility genotypes in inbred guinea pigs.

The ability of guinea pigs to form immune responses specific for each of the random copolymers, L-glutamic acid and L-alanine (GA) and L-glutamic acid and L-tyrosine (GT), is under the control of distinct autosomal dominant genes. By testing for the ability to respond to these copolymers among the progeny from the reciprocal backcross mating of responder (2 x 13)F(1) animals with the appropriate nonresponder parental strain, we have demonstrated that different unigenic autosomal dominant traits control the ability to respond to GA and GT respectively. The data further shows that the GA gene is linked to the poly-L-lysine (PLL) gene and to the locus determining the major strain 2 histocompatibility specificities and that the GT gene is linked to the locus controlling the expression of major strain 13 histocompatibility specificities. Analysis of the inheritance of the GT and PLL genes among the offspring from a mating of responder (2 x 13)F(1) guinea pigs with random-bred guinea pigs unable to respond to GT or PLL demonstrate that these genes segregate away from each other. Thus, the PLL gene and the genes to which it is linked, the GA gene and the major strain 2 histocompatibility locus, behave as alleles or pseudoalleles to the GT gene and the major strain 13 histocompatibility locus.

Specific immune response genes of the guinea pig. II. Relationship between the poly-L-lysine gene and the genes controlling immune responsiveness to copolymers of L-glutamic acid and L-alanine and L-glutamic acid and L-tyrosine in random-bred Hartley guinea pigs.

The ability of guinea pigs to make immune responses to GA, a linear random copolymer of L-glutamic acid and L-alanine, GT, a random linear copolymer of L-glutamic acid and L-tyrosine, and PLL, a linear homopolymer of L-lysine, is controlled by different autosomal dominant genes specific for each of those polymers. We have investigated the relationship between the PLL gene and the GA and GT immune response genes by simultaneously immunizing random-bred Hartley strain guinea pigs with GA and PLL, GT and PLL, or GA and GT. In most Hartley guinea pigs the ability to respond immunologically to GA and to PLL is inherited together; that is, most animals responding to GA respond to PLL and vice versa. However, a few animals respond to either GA or to PLL but not both, demonstrating that the GA and PLL immune response genes are not identical but linked in most Hartley animals. Conversely, when simultaneously immunized with GT and PLL, most Hartley guinea pigs respond to either PLL or GT but not both, indicating that GT and PLL responsiveness tends to segregate away from each other. Thus, the GT and PLL immune response genes also are not inherited independently but, rather, behave as alleles or pseudoalleles. Similar results are observed when Hartley guinea pigs are simultaneously immunized with GA and GT. The ability to respond to GA segregates away from the ability to respond to GT. Our studies demonstrated that the specific immune response genes thus far identified in guinea pigs controlling the ability to respond to GA, GT, and PLL, respectively, are found on the same chromosome. In most Hartley animals, the GA and PLL immune response genes are often linked, i.e. occur on the same chromosome strand, and tend to behave as alleles or pseudoalleles to the GT immune response gene.

Specific immune response genes of the guinea pig. I. Dominant genetic control of immune responsiveness to copolymers of L-glutamic acid and L-alanine and L-glutamic acid and L-tyrosine.

The immunogenicity of three random copolymers of amino acids with L-glutamic acid and L-alanine (GA), L-glutamic acid and L-tyrosine (GT), or L-glutamic acid, L-alanine, and L-tyrosine (GAT), administered in complete Freund's adjuvant, was studied in several inbred and random-bred guinea pig strains. The animals were tested for delayed sensitivity and their sera were assayed for the presence of antibody directed against the immunizing polymer. All of the guinea pigs developing delayed hypersensitivity also had significant antibody levels in their sera. Inbred strain 2 guinea pigs responded to immunization with GA, but failed to form detectable responses to GT. Inbred strain 13 animals, on the other hand, responded to GT, but not to GA. The (2 x 13)F(1) hybrids responded to both GA and GT with both delayed hypersensitivity and circulating antibody. Thus, the ability of these inbred guinea pigs to respond immunologically to GA or GT is controlled by distinct autosomal dominant genes. A variable percentage of random-bred guinea pigs, depending on their source as well as their strain, responded to immunization with GA and with GT. All guinea pigs, both inbred and random bred, responded to immunization with GAT. The ability to respond immunologically to GAT, therefore, does not seem to be under simple genetic control. However, the levels of anti-GAT antibody found in the sera of animals lacking the ability to respond to GA were much lower than those detected in GA responder animals.

Histocompatibility type and immune responsiveness in random bred Hartley strain guinea pigs.

Outbred Hartley strain guinea pigs capable of responding immunologically to 2,4-dinitrophenylated poly-L-lysine were shown to display a histocompatibility specificity in common with inbred strain 2 guinea pigs. This histocompatibility specificity was not detected in guinea pigs unable to respond immunologically to DNP-PLL. The result suggests that the poly-L-lysine specific immune response gene is very closely linked or even identical with a gene determining a major histocompatibility antigen in guinea pigs.

Linkage between the poly-L-lysine gene and the locus controlling the major histocompatibility antigens in strain 2 guinea pigs.

The data presented demonstrate linkage between the major histocompatibility locus of inbred strain 2 guinea pigs and a "specific immune response gene," the PLL gene, which controls responsiveness to poly-L-lysine and hapten conjugates of this polypeptide in these animals. This finding extends to another species and to a different immune system the linkage observed in mice between the H(2) locus and specific immune response genes at the Ir-1 locus. The general significance of the linkage of specific immune response genes to histocompatibility loci is discussed.