Genetic control of experimental autoimmune myasthenia gravis in mice. III. Ia molecules mediate cellular immune responsiveness to acetylcholine receptors

When MHC congenic and recombinant mice are inoculated with Torpedo acetylcholine receptors (AChR) with adjuvants, the magnitude of autoantibody responses to muscle AChR and the defect of neuromuscular transmission closely parallel in vitro lymphocyte proliferative responses to Torpedo AChR. All of these responses are controlled by gene(s) at the I-A subregion of the H-2 complex. Data presented in this report confirm in back-cross mice that T lymphocyte proliferative responses to AChR are controlled by a Mendelian dominant gene linked to H-2, at the I-A subregion. Lymphocyte responses were eliminated by blocking Ia antigens on lymph node cell surfaces with appropriate anti-I-A alloantisera and by removal of adherent cells. A spontaneous mutation at the I-A subregion in the B6 strain, which resulted in structural alteration of the A beta chain of Ia, converted high responsiveness to AChR to a state of low responsiveness. These data implicate a macrophage-associated Ia molecule in induction of autoimmune responses to AchR, probably in the presentation of AChR to helper T lymphocytes that thereby help B lymphocytes to differentiate into anti-AChR antibody-forming cells.     

Genetic control of the immune response of mice to type III pneumococcal polysaccharide

BALBc mice immunized with Type III pneumococcal polysaccharide (SIII) had higher numbers of IgM plaque-forming cells (PFC) in the spleen than similarly immunized C57BL/Ks mice. The F₁ hybrids of these two strains had intermediate numbers of SIII-specific PFC. Analysis of the responses of F₂ and backcross strains indicated that the observed responses were compatible with results expected for control of the immune response to SIII at a single autosomal locus.     

Genetic control and dynamics of the cellular immune response to the human T-cell leukaemia virus, HTLV-I.

About 1% of people infected with the human T-cell leukaemia virus, type 1 (HTLV-I) develop a disabling chronic inflammatory disease of the central nervous system known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have a vigorous immune response to HTLV-I, and it has been widely suggested that this immune response, particularly the HTLV-I-specific cytotoxic T-lymphocyte (CTL) response, causes the tissue damage that is seen in HAM/TSP. In this paper we summarize recent evidence that a strong CTL response to HTLV-I does in fact protect against HAM/TSP by reducing the proviral load of HTLV-I. We conclude that HTLV-I is persistently replicating at a high level, despite the relative constancy of its genome sequence. These results imply that antiretroviral drugs could reduce the risk of HAM/TSP by reducing the viral load, and that an effective anti-HTLV-I vaccine should elicit a strong CTL response to the virus. The dynamic nature of the infection also has implications for the epidemiology and the evolution of HTLV-I.     

Genetic control of immune responsiveness to poly (LPro)--poly (LLys)-derived polypeptides by histocompatibility-linked immune response genes in the rat.

In rats responsiveness to branched synthetic polypeptides carrying a Pro--L backbone, such as (T,G)-Pro--L or (Phe,G)-Pro-L and to Pro--L itself is controlled by Ir genes which are linked to the major histocompatibility genes. The level of antibody production to these polypeptides does not fall into strict high or low responder categories but covers the range in between. (T,G)-pro--L and Pro--L elicit a very similar response pattern which, however, differs from that obtained with (Phe,G)-Pro--L. Anti-(T,G),Pro--L antibodies do not cross-react with (T,G)-A--L, but do so extensively with Pro--L. Anti-(Phe,G)-Pro--L antibodies show cross-reactivity to (Phe,G)-A--L only when the antibody-producing strain is a high responder to (Phe,G)-A--L. These results when considered in view of data obtained in mice on genetic control of the immune response to (T,G)-Pro--L suggest that at least two unlinked Ir genes are involved in controlling anti-Pro--L responsiveness.     

Polygenic control of the immune response to F antigen

The ability to produce an autoimmune response to F antigen in mice is underH-2-linked and non-H- 2-linkedIr-gene control. There is an absolute requirement for ak allele atH-2K orI-A in order to produce anti-F antibodies. Low and high responsiveness is controlled by a non-H-2-linkedIr gene which behaves in a similar fashion toIr-3, in that as the dose of F-antigen is lowered, low responders behave as high responders and vice versa. This conversion from low to high responsiveness also occurs within a month after ATX.— Most F₁ hybrids derived from (responder x nonresponder) parents bearing identical F-types behave as dominant nonresponders. As a result of ATX, such F₁ mice convert to high responders. This conversion occurs if the animals are not immunized before day 90. If they receive F antigen prior to that time, they remain nonresponders for 7–9 months. One F₁ combination — AKD2 — behaves as a dominant high responder. Genetic analysis showed that in the presence of ak allele atH-2K orI-A, a non-H-2-linkedIr gene inherited from the AKR mice determined dominant responsivenss. No manipulation of the immune response or combination of genes converted nonresponders lacking ak allele into responders. Such complex genetic control suggests regulation by a number of independently segregating loci whose function it is to limit the autoimmune response to F antigen.     

Genetic regulation of the immune response to hepatitis B surface antigen (HBsAg). V. T cell proliferative response and cellular interactions

We previously demonstrated that in vivo antibody production to HBsAg in the mouse is regulated by at least two immune response (Ir) genes mapping in the I-A (HBs-Ir-1) and I-C (HBs-Ir-2) subregions of the H-2 locus. To confirm that H-2-linked Ir genes regulate the immune response to HBsAg at the T cell level and to determine if the same Ir genes function in T cell activation as in B cell activation, the HBsAg-specific T cell responses of H-2 congenic and intra-H-2 recombinant strains were analyzed. HBsAg-specific T cell proliferation, IL 2 production, and the surface marker phenotype of the proliferating T cells were evaluated. Additionally, T cell-antigen-presenting cell (APC) interactions were examined with respect to genetic restriction and the role of Ia molecules in HBsAg presentation. The HBsAg-specific T cell proliferative responses of H-2 congenic and intra-H-2 recombinant strains generally paralleled in vivo anti-HBs production in terms of the Ir genes involved, the hierarchy of responses status among H-2 haplotypes, antigen specificity, and kinetics. However, the correlation was not absolute in that several strains capable of producing group-specific anti-HBs in vivo did not demonstrate a group-specific T cell proliferative response to HBsAg. The proliferative responses to subtype- and group-specific determinants of HBsAg were mediated by Thy-1+, Lyt-1+2- T cells, and a possible suppressive role for Lyt-1-2+ T cells was observed. In addition to T cell proliferation, HBsAg-specific T cell activation could be measured in terms of IL 2 production, because anti-HBs responder but not nonresponder HBs-Ag-primed T cells quantitatively produced Il 2 in vitro. Finally, the T cell proliferative response to HBsAg was APC dependent and genetically restricted in that responder but not nonresponder parental APC could reconstitute the T cell response of (responder X nonresponder)F1 mice, and Ia molecules encoded in both the I-A and I-E subregion are involved in HBsAg-presenting cell function.     

Genetic control of the immune response

(1) Inbred strains of mice when immunized withp-aminobenzoic acid and sulphanilic acid bound by diazo-linkage to the same protein carrier molecule (bovine gamma globulin) differ in their ability to respond by antibody formation. The strains A and CBA/J form only low levels of antibodies to the haptens after immunization; in strains ScSN and B10.LP the same high titers of antibodies to both haptens were found under these conditions. The strain B10.D₂ forms antibodies well to sulphanilic acid, antip-aminobenzoic acid antibodies are formed only in very low quantity. (2) Individual mice of an inbred strain form a homogeneous population in respect of their capability or inability to form a particular antihapten antibody. The individual titers in a given inbred strain vary only slightly. On the contrary the noninbred strain H shows great variability both in quantity and quality of the immune response to the haptens. (3) The crossing of good and poor anti-hapten antibody producing strains shows in F₁; F₂ and B₁ generation, that the ability to produce antibodies againstp-aminobenzoic and sulphanilic acid depends on the genotype of a given individual. The ability to respond is transmitted to the offspring as a dominant trait. (4) There is no difference in the response to the haptens between males and females of the same strain. (5) The antibodies to the haptens in different strains of mice differ in the ratio of 2-mercaptoethanol sensitive and 2-mercaptoethanol resistant antibody. Dedicated to Academician Ivan Málek on the occasion of his 60th birthday     

Genetic control of the immune response

(I) The influence of the dose of antigen on the amount of antibodies produced was studied in two inbred strains of mice that were different with respect to the ability to produce antibodies top-aminobenzoic acid, i.e. well responding strain B10.LP and poorly responding CBA/J strain. Similar dependence between the dose of antigen and the antibody titre was demonstrated in both strains. (2) It was found that the type of reaction to the antigenic determinant (i.e. hapten) appeared to be a constant property of the inbred strain and that it did not change during the long period of the immunological maturity of the organism. (3) Antibodies of 19S type (2-mercaptoethanol sensitive) were formed in sera of both inbred strains, particularly in strain B10.LP, even after the third adjuvant immunization. Antibodies of 7S type appeared to be partially 2-mercaptoethanol sensitive, however, the major part was resistant to this agent. No 7S, 2-mercaptoethanol resistant antibodies were found in sera of the poorly responding strain CBA/J.     

Genetic control of the immune response

The participation of cells from bone marrow and thymus in the antibody response to haptens was studied in two inbred strains of mice: poorly (CBA/J) and well (B10.LP) responding to immunization. The cell transfer experiments showed that the genetic regulation of the antihapten response under study, was bound directly to lymphatic cells of the immune system. For transfer of the good response it was essential that the thymus and bone marrow cell mixture contained bone marrow cells from well responding donors. Furthermore, the effect of endotoxin on antibody formation was studied in both well and poorly responding strains. It was found that endotoxin enhanced the antibody formation in both strains similarly so that the finεl differences between the levels of antibodies formed in both strains remained unchang d. Finally, it was demonstrated that endotoxin played the most important role in the primary stimulation, where the highest increase of the antibody response was obtained.     

Genetic control of the immune response to staphylococcal nuclease

Summary Antibody responses of inbred strains of mice to staphylococcal nuclease were studied by isoelectric focusing in polyacrylamide gels followed by in situ labeling of focused antibodies with radioactive antigen. All A/J mice examined produced antinuclease antibodies of limited heterogeneity, and although there was individual variation in the focusing patterns observed, a characteristic spectrotype produced by all of the animals could be discerned. In order to determine the possible relationship between this characteristic spectrotype and the cross-reactive idiotypes of A/J antinuclease antibodies previously described (7), focused antibodies were also examined with a radioactively labeled pig anti-(A/J antinuclease) anti-idiotypic antibody preparation. Using this reagent, similar spectrotypes to those observed for antigen binding were seen in all of the individual A/J sera, suggesting that cross-reactive idiotype expression is a reflection of the characteristic spectrotypes observed. The same labeled anti-idiotypic reagent revealed characteristic but different spectrotypes when used to develop focused antinuclease antibodies from individual mice of other strains, suggesting that the use of similar variable region structures may be a common feature of the antinuclease response in mice of different allotypes. These studies thus provide a structural basis for the genetics of idiotype expression defined previously by serologic analysis.     

Genetic control of the murine T lymphocyte proliferative response to collagen: analysis of the molecular and cellular contributions to immunogenicity

The genetic control of the murine immune response to denatured beef type II collagen was examined in an antigen-presenting cell-dependent T cell proliferation assay. It was found that the response to collagen is under the control of H-2-linked Ir genes, possibly operating at the level of the antigen-presenting macrophage. Utilizing in vitro cross-stimulation with synthetic collagen-like polypeptides, the data suggest that the antigenic determinants stimulating collagen immune T cells are more dependent on primary amino acid sequence and less on conformation. The implications of such findings for Ir gene specificity and other related immunologic functions is discussed.     

Induction of a cellular immune response to a foreign antigen by a recombinant Listeria monocytogenes vaccine.

A recombinant strain of Listeria monocytogenes that stably and constitutively expresses Escherichia coli beta-galactosidase was used as a live vaccine vector. BALB/c mice were immunized orally or parenterally with the recombinant L. monocytogenes, and their cellular and humoral immune responses to beta-galactosidase were measured. Spleen cells taken 1 week after oral inoculation or 5 weeks after oral or parenteral inoculation (with a boost at 4 weeks) showed beta-galactosidase-specific CTL responses. The CTL line derived from mice immunized i.p. was also shown to be class I restricted and Thy-1.2+, CD8+, and TCR alpha beta+. All mice immunized with the recombinant L. monocytogenes had positive delayed-type hypersensitivity responses to heat-killed L. monocytogenes, but only 15% had a positive delayed-type hypersensitivity reaction to beta-galactosidase. Individual serum samples from mice immunized i.p. or i.v. were tested for antibody to beta-galactosidase. Approximately 11% had low positive titers for beta-galactosidase antibodies. These results demonstrate that both oral and parenteral immunization with recombinant L. monocytogenes results in a cellular immune response to the foreign protein, which is primarily a specific CD8+ CTL response.     

Genetic control of the murine immune response to cholera toxin

This study was undertaken to determine whether previously noted differences in the immune response of inbred strains of mice to cholera toxin (CT) might be under immune response gene control. A series of inbred, congenic, and intra-H-2I region recombinant mouse strains were tested for responsiveness to CT after i.p. immunization with 0.1 micrograms CT in alum. Samples of plasma were collected at intervals before and after priming and boosting. IgG and IgA anti-CT were measured by ELISA. In three different sets of congenic strains, the level of IgG anti-CT clearly depended on the H-2 haplotype of the strain rather than on any background or Igh genes. Strains with the H-2b and H-2q haplotypes were high responders, and strains with the H-2k, H-2s and H-2d haplotypes were low responders. Within the H-2 complex, the IgG anti-CT response was mapped to the I-A subregion with the use of congenic intra-H-2I region recombinant strains. In contrast to these results with IgG anti-CT, plasma IgA anti-CT levels were uniformly low and indeterminate. We conclude that the murine IgG anti-CT response is controlled by a locus within the I-A subregion of H-2--a remarkable finding, considering the known abilities of this toxin to bind to and to directly stimulate lymphocytes.     

Borna disease: association with a maturation defect in the cellular immune response.

Borna disease virus (BDV) is a negative-strand RNA virus which produces persistent infection in a variety of experimental animals. In the rat, the presence or absence of clinical signs of Borna disease, a characteristic, biphasic neurobehavioral illness, depends on host-related factors. A window of opportunity exists after birth wherein inoculation with BDV produces a persistently infected rat without signs of Borna disease or encephalitis (persistent, tolerant infection-newborn [PTI-NB] rat). Although immunopathological destruction of the nervous system does not occur in the PTI-NB rat, significant alterations in the development of the nervous system were noted, including site-specific lysis of neurons. Unlike the case with other pharmacologically produced, persistent, tolerant BDV infections, adoptive transfer of spleen cells from BDV-infected rats did not produce disease in the PTI-NB rats. PTI-NB rats developed Borna disease after being connected by parabiosis to rats with Borna disease. Bone marrow transplantation experiments revealed that bone marrow cells from PTI-NB rats produced Borna disease in lethally irradiated, BDV-infected recipient rats. Bone marrow from PTI-NB rats contained a complement of inflammatory cells capable of inducing Borna disease. Thus, the loss of BDV-specific cellular immunity appeared to occur after the release of cells from the bone marrow.     

Antigen-specific T-cell factor in cell cooperation and genetic control of the immune response.

Cell interactions between thymus-derived (T) and bone marrow-derived (B) lymphocytes in the antibody response appear to involve soluble T-cell mediators known as 'factors.' This paper describes the properties of a T-cell factor that has specificity for the inducing antigen, a synthetic polypeptide (T, G)-A--L, and is able to replace T cells in the thymus-dependent antibody response to (T, G)-A--L. Besides antigen specificity, the main features of the molecule are that it is nonimmunoglobulin; it has a molecular weight of about 50,000; and it is a product of the I-A subregion of the H-2 complex (the mouse major histocompatibility complex). These properties suggest that the factor is closely related to the T-cell receptor, which may, by inference, also be a product of the H-2 complex. The factor cooperates well with allogeneic B cells. It can also be absorbed by bone marrow cells and B cells. Studies on the genetic control of the immune response to (T, G)-A--L using the T-cell factor indicate that two immune response genes in the H-2 complex are involved in genetic control, one expressed in T cells and the other in B cells. This two gene hypothesis has been confirmed by showing that an F1 between two low responders to (T, G)-A--L can be a high responder.