The discovery of linkage between the MHC and genetic control of the immune response

Summary: Immunization of rabbits, and inbred strains of mice with branched, multichain, synthetic polypeptides, such as (T, G) − A--L and (H, G) − A--L, revealed striking differences in the ability of different strains of mice to produce specific antibody. F1 and F1 × parental backcross mice revealed clear genetic control. Initial attempts to link this genetic control to known genetic markers were unsuccessful. The second approach, which attempted to transfer response from high or immediate responders into low responder recipients, initially encountered graft vs. host and host vs. graft reactions. The transfer of F1 spleen cells into the low responder parent demonstrated that ability to respond was a property of immunocompetent cells (spleen cells), not of the recipient's background genes. Mapping studies with recombinant H2 haplotype congenic strains, and a classic 4-point mapping cross were concordant in placing the gene controlling this trait within the H2 complex, between the K and Ss loci. Subsequent studies mapped the genes for stimulation in the mixed lymphocyte culture reaction to the same position, suggesting cell surface expression. Production of antisera to 'I-region' products defined 'Ia' antigens, the 2-chain α/β MHC class II molecules.     

Genetic control of the humoral immune response to rabbit erythrocyte isoantigens

Blood group Hg^A negative rabbits were injected with 2 × 10⁹ Hg^A positive erythrocytes from a donor rabbit. Assortative matings were set up between those rabbits which produced detectable anti-Hg^A (responders) and those which did not (non-responders). The progeny were injected with 2 × 10⁹ Hg^A positive erythrocytes 3 months after birth and their anti-Hg^A response measured. It was found that 20/24 (83 per cent) of the offspring of responder parents, but only 4/26 (15 per cent) of the offspring of non-responder parents, produced detectable anti-Hg^A. No difference was found between the ability of responders and non-responders to produce haemagglutinins to various doses of sheep erythrocytes. In contrast, non-responder rabbits rarely responded to non-Hg^A blood group isoantigens on the donor erythrocytes whereas rabbits which responded to Hg^A after injection of the donor erythrocytes often responded to non-Hg^A isoantigens. Typing the cells of non-responder rabbits with the sera from responder rabbits containing non-Hg^A antibodies showed that the non-responder cells were antigenically more like the donor cells than were the cells from responder rabbits. The ability to respond to Hg^A was not associated with any particular heavy or light chain immunoglobulin allotype specificities. It is considered that Hg^A has an important helper function in regard to the antibody response to non-Hg^A antigens but the latter probably also have a similar but less marked effect in relation to the Hg^A antibody response. The genetic control observed is thought to operate through T cell recognition and reaction with Hg^A and other blood group determinants.     

Genetic control of immune response and disease susceptibility by the HLA-DQ gene.

The particular alleles of the HLA-DQ locus may control the low immune response to natural antigens by a dominant genetic trait through the immune suppression mediated by CD8+ suppressor T cells. The suppressor T cells may be activated by DQ-restricted and antigen-specific CD4+ suppressor/inducer T cells, because (1) a statistically significant association and linkage between low immune responsiveness to the natural antigens and the HLA-DQ gene were observed; (2) antigen-specific CD4+ T cells restricted by the DQ molecules encoded for by the HLA-DQ allele associated with low responsiveness were evidenced in many low responders; and (3) anti-HLA-DQ mAb restored the immune response to natural antigens, in some low responders. This HLA-DQ-controlled polymorphism of immune response to the natural antigens may account for the association between HLA-DQ alleles and organ-specific autoimmune diseases.     

Genetics of the immune response: identifying immune variation within the MHC and throughout the genome

Summary: With the advent of modern genomic sequencing technology the ability to obtain new sequence data and to acquire allelic polymorphism data from a broad range of samples has become routine. In this regard, our investigations have started with the most polymorphic of genetic regions fundamental to the immune response in the major histocompatibility complex (MHC). Starting with the completed human MHC genomic sequence, we have developed a resource of methods and information that provide ready access to a large portion of human and nonhuman primate MHCs. This resource consists of a set of primer pairs or amplicons that can be used to isolate about 15% of the 4.0 Mb MHC. Essentially similar studies are now being carried out on a set of immune response loci to broaden the usefulness of the data and tools developed. A panel of 100 genes involved in the immune response have been targeted for single nucleotide polymorphism (SNP) discovery efforts that will analyze 120 Mb of sequence data for the presence of immune‐related SNPs. The SNP data provided from the MHC and from the immune response panel has been adapted for use in studies of evolution, MHC disease associations, and clinical transplantation.     

Genetic control of the immune response to ferritin in F1 hybrid mice.

The immune response to the antigen horse spleen ferritin, has been investigated in ten inbred parental strains and seven different F1 hybrid strains of mice, using an antigen excess technique. The degree of dominance in an F1 hybrid system can be estimated by using the Fisher dominance index. The responses in F1 hybrid animals, obtained from crosses of high and low responder parents, varied from dominant to recessive but the overall mean dominance index for the ferritin immunogenetic system was found to be -0.0467 +/- 0.0083 (mean +/- s.e.), a value close to zero, which suggests a codominant mode of inheritance of IR-genes to ferritin and this is consistent with most published data in other F1 IR-gene systems.     

An immune response gene linked to MHC in man

With a view to finding a relationship between immune response and MHC in man, 83 D negative mothers with allo-into-D antibodies and 26 PLA1 negative mothers with allo-anti-PLA1 antibodies were investigated as regards their HLA-A, B and DR antigens. We have found that there is a highly significant relation between the DR3 antigen and an immune response to the PLA1 antigen, but none to the D antigen.     

Genetic control of immune response to staphylococcal exfoliative toxin A in mice.

Different inbred and congenic resistant strains of mice were immunized with staphylococcal exfoliative toxin A (ETA). In antibody responses measured in sera of mice by a passive hemagglutination technique, A/J, DBA/2, BALB/c, B10A, B10D2, B10S, and A.SW were high responders. C57BL/10 (B10), A.BY, and DBA/1 were low responders. The congenic C3H/HeJ and C3H.SW mice were, respectively, high and low responders. The observation that the immune responses of the mice to ETA were closely linked with the haplotypes of their H-2 complexes suggests the existence of an H-2-linked immune response (Ir) gene coding for the production of humoral antibodies to ETA. Four B10A recombinants were used to map this gene within the H-2 complex. The finding that B10A(2R) and B10A(4R) were high responders, whereas B10A(3R) and B10A(5R) were low responders, indicates that the gene controlling antibody response to ETA is located in the I-A subregion or the H-2K end within the H-2 complex. We wish to propose the name Ir-ETA for this gene. The function of Ir-ETA seems to be at least related to antigen recognition at the T-lymphocyte level. Neonatal mice are generally susceptible to ETA regardless of their H-2 haplotypes. However, the neonatal mice born to a high-responder mother immunized with ETA were resistant to the subcutaneous challenge of ETA, but those born to an immunized low-responder mother were susceptible to the challenge. This result suggests that if the mother is a high responder to ETA and is effectively immunized with ETA, the maternal immunity makes it possible to neutralize this toxin in neonatal mice.     

Features of the immune response to DNA in mice. I. Genetic control.

The genetic control of the immune response to DNA was studied in various strains of mice F1 hybrids and corresponding back-crosses immunized with single stranded DNA complexed to methylated bovine serum albumin. Anti-DNA antibody response was measured by radioimmuno-logical technique. High responder, low responder, and intermediate responder strains were found and the ability to respond to DNA was characterized as a dominant genetic trait which is not linked to the major locus of histocompatibility. Studies in back-crosses suggested that this immune response is under multigenic control. High responder mice produce both anti-double stranded DNA and anti-single stranded DNA 7S and 19S antibodies, while low responder mice produce mainly anti-single stranded DNA 19S antibodies.     

Dendritic cells and the control of the immune response

Cells of the dendritic family are suited to perform two distinct functions at two discrete locations. In the peripheral tissues, DC act as sentinels for "dangerous" antigens. They then migrate into the lymphoid organ, where they initiate activation of T lymphocytes which are specific for these antigens. During their migration, DC shift from an antigen-capturing-mode to a T cell sensitizing mode. In addition to switching on the immune response, subtypes of DC appear to influence the character of T cell differentiation, i.e. the Th1/Th2 balance.     

Genetic control of the immune response to mammalian chymotrypsins in mice. I. The immune response to high doses of bovine alpha-chymotrypsin.

The primary and secondary immune response to the antigen bovine pancreatic alpha-chymotrypsin was investigated in inbred mice. It was found that strain differences in the immune response only became apparent after secondary immunization. The genetic control of the immune response was investigated in twelve different strains of mice, F1, F2 and F1 backcross hybrids, following secondary immunization. A continuous distribution for the mean antibody responsiveness was obtained. High responsiveness was associated with both the H-2 haplotype and three non-H-2 loci. Furthermore the F1 hybrids produced a greater quantitative antibody response to chymotrypsin than either of the corresponding parental strains.     

Genetic control of the immune response to mammalian chymotrypsins in mice. II. The immune response to low doses of bovine alpha-chymotrypsin.

The immune response to the antigen bovine pancreatic alpha-chymotrypsin was investigated in ten recombinant strains of mice. Using a fixed antigen-percentage bound isotope technique, it was found that the quantity of antibody produced was related to the H-2 haplotype of the responding animal. A continuous distribution for the mean antibody responses was obtained for the ten strains of mice. High responsiveness was associated with the H-2 haplotype gamma2. The genetic control of the immune response to this immunogen was found to be both quantitative and qualitative.     

Genetic aspects of cellular interactions in the immune response

Our understanding of the complex cellular interactions responsible for mediating effective immune responses has increased substantially in recent years. It is now clear that the genetic loci that control the interaction of the cells of the immune response encode groups of closely related cell-surface molecules. These molecules are the class I and class II antigens of the MHC, the differentiation antigens on lymphocyte subpopulations, and the receptors of various types, including the membrane immunoglobulin of B lymphocytes and the antigen receptors of T lymphocytes. Biochemical analysis of these cell surface molecules has demonstrated that they display important DNA sequence homologies. A polypeptide of approximately 110 amino acids comprises the basic building block for many of the cell surface molecules. Gradually, as a consequence of evolutionary development, the immune system has expanded its ability to respond to the external environment by an increased complexity of lymphocyte subpopulations and the surface structures that modulate their interaction. These cell surface molecules provide the structures that allow collaborative interaction of different cell types and that form the multiprotein receptor complexes involved in the recognition of, and specific response to, foreign antigens. Our future understanding of the control of the immune response will depend upon establishing the biochemical nature and the multifaceted interactions of these important molecules.