Immune responses to complex protein antigens I. MHC control of immune responses to bovine albumin

Murine T cell proliferative and antibody responses to the multi-determinant protein bovine serum albumin (BSA) are controlled by Ir genes mapping within the H-2 gene complex. Strains possessing the H-2k, H-2a, and H-2d haplotypes are classified as high responders to BSA. In contrast, H-2b strains are low responders to BSA. Genetic mapping experiments employing strains with recombinant H-2 haplotypes indicate that both T cell proliferative and antibody responses are at least in part regulated by genes within the I-A subregion. Studies on the inhibition of T cell proliferation by monoclonal anti-Ia antibodies are consistent with the assignment of an Ir gene for BSA to the I-A subregion and strongly suggest a role for genes within the I-E/C subregions as well. The MHC-mediated control of antibody responses did not affect the affinity or the isotype of the antibody produced. The relative quantities of antibody specific for each of the three domains of BSA appears to be regulated by H-2-linked BSA Ir genes, and domain III antigenic determinants were found to be dominant in the responses of low-responder mice and in the early response of high-responder mice. This domain III epitope dominance essentially disappears by the tertiary response of high-responder mice.     

Neonatally induced tolerance to soluble protein antigens. I. Analysis of B-cell and T helper cell function in mice tolerant to bovine serum albumin or fowl gamma-globulin

High dose tolerance to either bovine serum albumin (BSA) or fowl γ-globulin (FGG) was induced in CBA mice by neonatal injection. Tolerance to BSA lasted about 9 weeks, and that to FGG, about 18 weeks. Splenic B-cell function was analyzed using quantitative in vivo assays and in vitro limiting dilution analysis. Tolerogen-specific IgM- and non-IgM-producing B cells are depleted at least threefold in the spleens of tolerant mice. Tolerogen-specific T-helper-cell function was examined by immunization with haptenated antigens. Analysis of the recovery from tolerance indicates that the return to normal function in the tolerogen-specific B-cell and T helper fractions coincides with the return to normal responsiveness by the whole animal.     

Genetic and cellular requirements for primary antibody immune response to Thy-1 antigens in mice.

An effective anti-Thy-1 response requires at least three conditions to be simultaneously fulfilled--1) The responder has to share an H-2 haplotype, or at least K and D alleles, with the donor of the Thy-1 disparate thymocytes, 2) The responder has to differ from the donor by some non-H-2 cell-surface antigens, and 3) The responder has to possess functionally capable T cells. All these requirements are consistent with the hypothesis that Thy-1 antigens and the non-H-2 antigen(s), the latter serving as carrier, form a complex that is viewed as a variant of self and then recognized in the context of the H-2 molecules by the responder's T cells. An attractive feature of the proposed hypothesis is that it could be applicable to a variety of cell-surface and also exogenous antigens.     

Genetic control of the immune response of mice to highly dinitrophenylated human gamma-globulin (DNP56HGG)

The immune response to highly dinitrophenylated human gamma-globulin (DNP56HGG) was tested in inbred strains of mice. Significant differences in the anti-DNP response among inbred strains were found, including the magnitude of serum antibody and the location of plaque-forming cells (spleen or lymph nodes). The strain differences persisted when the dose and adjuvant were changed. The genetic control of the anti-DNP response to DNP56HGG was investigated. The analysis of the response of congenic and F1 hybrid mice to DNP56HGG suggests that at least two genes are involved in the control of the anti-DNP response. The two genes are demonstrated by complementation in the F1 generation, and show no correlation with H-2 haplotype or IgG2a allotype. A third gene may be implicated by differences in response observed between male and female mice.     

Genetic control of tolerance induction to human gamma-globulin in mice.

Susceptibility to tolerance induction with monomeric human gamma-globulin (HGG) was tested in different inbred strains of mice. The results indicated a differential tolerance susceptibility among the strains and that the basis for the variation is genetic in nature. By using a protocol that permits genetic analysis, F1, F2, and backcross generations of the parental strains SJL/J and C3H/Bi were examined. A multigenic control model by H-2-linked and non-H-2-linked genes showing Mendelian autosomal inheritance is proposed.     

Adjuvant actions of polyclonal lymphocyte activators. I. Comparison and characterization of their actions in antibody response to deaggregated bovine serum albumin.

Various polyclonal lymphocyte activators (PLA) were compared in their effects to trigger the initiation of the immune response and the amplification of the once-initiated immune response. When PLA were injected into mice subcutaneously together with deaggregated bovine serum albumin (DBSA), all of the nine kinds of PLA tested, such as capsular polysaccharide of Klebsiella pneumoniae (CPS-K), lipopolysaccharide, dextran sulfate, concanavalin A, pokeweed mitogen, phytohemagglutinin, polyadenylic-uridylic acid, and polyinosinic-cytidylic acid, exhibited more or less the adjuvant action to trigger the antibody response and to increase immunological memory to DBSA. Among the PLA tested the action of CPS-K was the strongest. On the other hand, none of these PLA, including CPS-K, acted to augment the secondary antibody response to the optimal dose of DBSA in mice primed with DBSA together with CPS-K. It was concluded that PLA act generally to trigger the initiation of the antibody response, although the intensity of their actions distributes in a wide range of diversity, but that they do not stimulate the amplification of the response.     

Genetic control of the immune response in mice: V. Minor genes involved in the response to H-Y and Ea-1 antigens

Murine responses to both the male specific histocompatibility antigen H-Y and the erythrocyte alloantigen Ea-1 are regulated by genetic factors. In each case a single major gene that controls the immune response has been identified, but additional modifying factors can be demonstrated if appropriate strain combinations are studied. A single gene controlling the response to Ea-1 antigens, which segregates when strains YBR and B10.D2 are crossed, has been shown not to be an allele of theIr-2 locus. A new phenomenon has also been observed in the control of anti-Ea-1 antibody production in that the mating of two responding strains, YBR and HTG, produces an F₁ generation of complete nonresponders. By linkage tests it was shown that the responding strain HTG possesses the nonresponder allele at theIr- 2 locus, so there appear to be recessive genes in the background which are able to overcome the suppressive influence of this allele.     

Genetic control of immune responses to parasites: selection for responsiveness and non-responsiveness to Trichuris muris in random-bred mice.

Populations of Schofield strain, random-bred mice were shown to have a bimodal variation in ability to bring about immune expulsion of the nematode Trichuris muris. This variation was genetically determined and independent of the size of infection experienced. The proportion of mice unable to achieve worm expulsion (non-responders) was relatively constant in various populations of the strain but was increased by selective breeding from mice of known status. Crosses made between non-responder and responder mice produced progeny that were almost all (92%) of responder phenotype, showing that the ability to achieve worm expulsion was inherited as a dominant characteristic. It is suggested that the genetic control involves a small number of genes; the possible immunological mechanisms by which control is mediated are briefly discussed.