Genetic Control Of Immune Response Research Articles

HLA: genetic control of immune response and disease susceptibility.

HLA: genetic control of immune response and disease susceptibility.

The genetic control of immune responses

The genetic control of immune responses

From synthetic antigens to synthetic vaccines

The availability of synthetic antigens permitted a systematic elucidation of the molecular basis of antigenicity, as well as of other phenomena, and to establish the genetic control of immune response and its link to the major histocompatibility region of the species. Moreover, it allowed a conceptual approach to production of vaccines made up of synthetic fragments of relevant virus antigens. This was first demonstrated with a bacteriophage, MS-2, that can be efficiently inactivated with antibodies obtained with an immunogen in which a synthetic peptide corresponding to a sequence of 20 amino acid residues within its coat protein was covalently linked to a polymeric synthetic carrier. When the synthetic adjuvant N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) was chemically linked to the same molecule, the resulting immunogen was effective in aqueous solution. This approach has now been used for diphtheria: a synthetic peptide from the A-chain of the toxin, covalently attached together with MDP to the synthetic carrier multichain poly(DL-alanine) induced antibodies cross-reactive with the diphtheria toxin as well as protection against the dermonecrotic activity of the toxin. A similar approach has been described also by R. Arnon and her colleagues in our laboratory for influenza virus, making use of a peptide with sequence 91–108 of the hemagglutinin of type A H3N2 strains attached to tetanus toxoid. The results indicated that the conjugate led to partial protection against A/Texas mouse-adapted influenza virus.

Genetic determinants of autoimmune chronic active hepatitis.

There has been a remarkable vindication over the past 15 years of Burnet’s forecast, with two particular themes of dominant interest to research on immunogenetics. The first is the association in inbred animals between genetic control of immune responses to antigens of limited heterogeneity and genes (Ir genes) of the major histocompatibility complex (MHC) [2, 39]. The second is the increasing refinement of typing methods for human histocompatibility antigens, of relevance to tissue transplantation, and associations between certain immunopathic diseases and HLA specificities [26, 31]. However, despite much experimental work and theoretical speculation, no unifying concept relating MHC-linked Ir genes effects and MHC- linked disease susceptibility has yet emerged.

Gene complementation: A mechanism for genetic control of immune responses to synthetic polypeptides in humans

Gene complementation: A mechanism for genetic control of immune responses to synthetic polypeptides in humans

Antigen-specific T-cell factors.

Antigen-specific T-cell factors are mediator molecules which are produced by helper and suppressor T cells and which can perform the function of those cells in an antigen-specific manner. They probably play an important part in immunoregulation. The major histocompatibility complex has a controlling influence on their structure and activity, while their antigen-recognition properties may be conferred by immunoglobulin V regions. Interest in the factors derives from three related areas of research, namely (i) the problem of T-cell recognition of antigen; (ii) the mechanisms of cellular interactions in antibody production and cell-mediated immunity; and (iii) the genetic control of immune responses. This review discusses the literature up to June 1980 on their production, structure, genetic restriction and mechanism of action.

Macrophage-lymphocyte interaction and genetic control of immune responsiveness.

We have reviewed briefly some of the diverse functions of macrophages in the immune response. Clearly, this population of cells interact physically with lymphoid cells, are required for activation of T cells, and process various protein antigens. Finally, we have studied the immune response to insulin in order to unify these previous data in such a way to demonstrate the active role of macrophages in the regulation of the immune response. The function of the Ir gene in the guinea pigs appears to be an intramolecular selection of discrete regions within the antigen for recognition by the T cell. The data presented suggest that this function operates at the level of the macrophage.

Functional Analysis of H-2-Linked Genetic Control of Immune Responsiveness to TNP-MSA

Abstract The antibody response to trinitrophenyl-conjugated mouse serum albumin (TNP-MSA) in inbred strains of mice is regulated by a gene(s) in the I-B subregion of the H-2 complex. High responsiveness in low H-2k × high H-2b F1 hybrids is inherited as a recessive trait. Various parameters of the immune response to TNP-MSA were investigated to determine whether specific Ir gene activation by TNP-MSA leads to a similar or different type of regulation compared to dominant H-2-linked Ir genes. Analysis of high and low responder sera by radioimmunoassay and isoelectric focusing revealed that Ir-6 controls the production of IgG antibodies in high responder mice. Although both high and low responder immune sera contained equivalent amounts of IgM TNP-antibody, IgG anti-TNP activity was found only in high responder sera. However, low responders could be induced to produce high levels of IgG TNP-antibody after immunization with TNP-MSA complexed to a xenogeneic carrier (MBSA). Adult thymectomy and rabbit antimouse T cell serum treatment of high and low responder animals demonstrated that TNP-MSA is capable of eliciting both a T-independent IgM response and a T-dependent IgG response. The thymus-dependent IgG produced by high responder animals is of restricted heterogeneity as revealed by isoelectric focusing. High responsiveness to TNP-MSA displays either dominant or recessive inheritance in F1 progeny depending on the H-2 haplotype combination. This finding is interpreted in terms of Ir-6 gene product interaction and hierarchical or partial dominance among multiple alleles.

Genetic Control of Immune Response to Sperm Whale Myoglobin in Mice

Abstract The genetic control of T lymphocyte proliferative response to the five synthetic antigenic sites of myoglobin, two synthetic nonantigenic control peptides, and one “nonsense” peptide was determined in independent and recombinant strains of mice. In all the strains examined, the nonantigenic control peptides and the “nonsense” peptide did not invoke a response in myoglobin-primed mice. Further, when mice were not primed with whole myoglobin, no response was obtained with any of the antigenic sites. Haplotypes H-2d, H-2f, and H-2s are higher responders to sites 1 and 2, whereas haplotypes H-2d and H-2s are high responders to site 5. Response to site 3 may be controlled by a non-H-2-linked gene. Site 4 can stimulate H-2b and H-2k haplotypes that are nonresponders to the whole myoglobin. Studies with the recombinant strains suggested that Ir genes to sites 1 and 2 map in the I-A subregion and I-C subregion and were designated Ir-Mb-1,2(A) and Ir-Mb-1,2(C). Ir genes to sites 4 and 5 mapped only in the I-A subregion and were designated Ir-Mb-4(A) and Ir-Mb-5(A). These studies suggest that individual antigenic sites in a molecule are controlled by unique Ir genes.

Structural polymorphism of human DR antigens

DR ANTIGENS are polymorphic cell surface molecules whose expression is controlled by a locus closely linked or identical to the D locus of the major histocompatibility complex (MHC) of man (for reviews see refs 1, 2). They are functionally and structurally homologous to the murine la antigens determined by the I-E subregion of the MHC, a region which has been implicated in the genetic control of immune responses(3,4). Both sets of antigens are mainly expressed on cells associated with immune function (for reviews see refs 1, 2, 5), and are involved in mediating T-cell, B-cell and macrophage interactions required for the generation of immune responses(6-9). In addition, both consist of two non-covalently associated polypeptides, designated alpha and beta, with molecular weights of 34,000 and 28,000, respectively(10). The association of some DR antigens with increased susceptibility to certain diseases (for review see ref. 1) and the genetic restrictions imposed on cellular interactions by the HLA-D region(9,11) may represent the effects of structural variability among DR antigens. The aim of the studies reported here was to examine the nature and degree of structural variation among DR antigens isolated from cultured lymphoid B cells with different DR phenotypes. Such information may provide an understanding of the molecular mechanisms by which DR antigens mediate their function.

Close association between particular I region‐determined cell surface antigens and Ir gene‐controlled immune responsiveness to synthetic polypeptides in wild rats

The relationship between major histocompatibility complex (MHC) and genetic control of immune responsiveness to the synthetic polypeptides (T,G)-A--L [poly-(LTyr,LGlu)-poly(DLAla)--poly(LLys)] and (H,G)-A--L [poly(LHis,L-Glu)-poly-(DLAla)--poly(LLys)] has been studied in 26 wild rats. The major histocompatibility complex (MHC) genotype frequencies observed were not different from those expected according to the Hardy-Weinberg formula. More than half of the wild rats carried MHC-linked responder Ir-TGAL and Ir-HGAL genes. High or intermediate responsiveness to (T,G)-A--L and high responsiveness to (H,G)-A--L were always found to be associated with particular I region-determined cell surface antigens. These antigens could be identified serologically and by primary and secondary mixed lymphocyte reactions, and were similar or identical to I region products of (T,G)-A--L high responder or (H,G)-A--L intermediate responder inbred rat strains. The strong association between cell surface antigens and immune responsiveness could be due to linkage disequilibrium or to pleiotropy. Since the same I region-determined cell surface structure could be associated either with high or intermediate anti-(T,G)-A--L antibody titers, the presence of the Ia antigen(s) identified did not seem to guarantee high antibody responsiveness to the test antigen.

Complex Genetic Control of Immune Response to Lysozymes in Mice

Abstract H-2b mice fail to respond to some bird lysozymes (prototype: hen egg-white lysozyme (HEL)) while showing normal responsiveness to other closely related bird lysozymes (prototype: ringed-neck pheasant lysozyme (REL)). H-2b mice also fail to respond to human lysozyme (HUL). Previous studies have shown that differential HEL:REL responsiveness is associated with two genetic loci within H-2, one mapping to the left of I-B and one to the right. Present studies, in which equal positive response is found to HEL and REL in H-2ba and H-2bf mice, indicate that a mutation at H-2K is associated with the loss of ability to discriminate between HEL and REL. The presence of at least one controlling locus outside H-2 is suggested by studies with recombinant inbred strains (RI) of C57BL/6 and C57L (a strain which responds to HEL although H-2b). Two such RI with H-2 derived from the C57BL/6 parent respond to HEL while one RI with H-2 derived from C57L does not respond.

Genetic Control of Immune Response to Sperm Whale Myoglobin in Mice

Abstract Studies on the genetic control of immune response to sperm whale myoglobin were initiated. As demonstrated in this paper, the T lymphocyte proliferative response to whale myoglobin is under H-2-linked Ir gene control. Mice of H-2d, H-2f, and H-2s haplotypes were high responders to the myoglobin, whereas haplotypes H-2b, H-2k, H-2p, H-2q, and H-2r were low responders. The Ir gene(s) was localized between H-2K and H2D regions, since the recombinant strain A.TL (KsIkSkDd) was a low responder and A.TH (KsIsSsDd) was a high responder. Further studies with recombinant strains revealed that the expression of the high-responder I-Ad or I-As alleles was sufficient to give a good response, since strains D2.GD (d d b b b b b b) and B10.HTT (s s s s k k k d) were high responders. The expression of the I-Cd allele in strains B10.A (k k k k k d d d) and B10.A(5R) (b b b k k d d d) also gave high response, and thus suggested a second Ir gene, derived from the H-2d haplotype. The finding that expression of the I-Cs allele in B10.S(8R) (k k ? ? s s s s) did not result in high response suggests the lack of the second Ir gene in the high-responder H-2s haplotype.

Genetic Control of Immune Responses to Moloney Leukemia Virus in Rats 2

When BN and LEW rats were immunized with untreated or with inactivated Moloney murine leukemia virus (M-MuLV), BN rats produced high antibody responses to the p15, p30, and gp70 antigens of the virus, whereas LEW rats were low responders to these antigens. BN rats also exhibited a high response and LEW rats a low response when the two strains were immunized with purified p30. Studies of (LEW X BN)F1 and backcross rats suggested that factors associated with AgB exerted major influences on responses to antigens of M-MuLV and that other factors were also important. When other rat strains representing 5 AgB alleles were tested, some were high and some were low responders to M-MuLV, and responses to p15, p30, and gp70 were not always parallel. Since M-MuLV replication was greater in cells of BN rats than in cells of LEW rats, replication of M-MuLV may have influenced the levels of responses to some viral antigens. Control of virus replication appeared to be due to cell mechanisms rather than to the environment of the host.

Immunogenetic Profile of the Axolotl: 1977

SYNOPSIS. As with mammals, the ability to test questions of an immunogenetic nature in the axolotl and other amphibia is greatly enhanced by the use of defined, inbred genetic lines. These have been developed and at present qualify as partially inbred strains; there are 7, with the most highly inbred being at present at F13. During the development of these strains, several questions have been tested. A question of evolutionary interest is whether the amphibia show the equivalent of a major histocompatibility complex (MHC). The anurans do but there remains a question of whether any one histocompatibility locus is predominant in urodeles; suggestive but not definitive data support the idea that one locus may be predominant. Analysis of genetic control of immune responses has been done both in vivo through allograftings and in vitro through mixed lymphocyte culture (MLC) and through responsiveness to mitogens. The axolotl responds to MLC with low but statistically significant stimulation indices and to mitogens in such a way that it is difficult clearly to distinguish between B and T cells. A technique has been developed that leads to failure of thymus differentiation and this may help to clarify the question of lymphocyte cell types inasmuch as thymectomy greatly reduces allograft rejection and permits growth of an allogeneic lymphosarcoma. Evidence is presented suggesting that immune responsiveness is capable of developing at the localized site of immune stimulation rather than requiring movement to foci such as lymph nodes, which are absent in the axolotl. Evidence also is presented that the nature of the allograft can alter the overt expression of the immune response. Lastly, it is shown that while several kinds of neoplasms are seen in older axolotls, these animals tend to respond to allograft challenge more rapidly and more vigorously and thus, for this age group at least, seem to be inconsistent with some theories of aging.

Genetic control of immune responses in chickens

Genetic control of immune responses in chickens

Genetic Control of Immune Response to the H-2Dk Private Specificity, H-2.32

Abstract A variety of congenic resistant strains of mice sharing the B10 background have been examined for humoral responsiveness to the H-2D region private specificity H-2.32. All of these strains were found to produce little or no anti-H-2.32 antibody, confirming previous indications that the B10 background is defective with respect to this response (1). However, both strain B10 (H-2b) and strain B10.D2 (H-2d) did produce reasonable titers of antibodies reactive with public H-2D region specificities of H-2k. In the case of B10.D2, this response could be shown to be due to a response to the D region product itself rather than a cross-reaction with public specificities shared in both K and D regions. By using sera to public and private H-2Dk specificities sequentially to precipitate radiolabeled solubilized H-2 antigen preparations, both private and public specificities were shown to be present on the same molecules. Thus, the failure of B10 background mice to respond to the private specificity H-2.32 appears to be peculiar to this specificity and not to all specificities on the H-2Dk molecule. Analysis of (AKR.M × B10.AKM)F1 × B10.AKM backcross mice revealed that the magnitude of the antibody response to H-2d antigens did not correlate with that of the anti-H-2.32 response, indicating the specific nature of the anti-H-2.32 low responsiveness of B10 congenic mice.

Genetic Control of Immune Response to Protein Antigens

Abstract A high (H/p) and a low (L/p) responder line of mice have been produced by selective breeding for the character “quantitative antibody responsiveness” to BSA and RgG. These two Ag were administered at optimal immunizing doses and alternated at each generation in order to avoid the interference of maternally transmitted antibodies. H/p and L/p diverged progressively during the first seven generations of selective breeding, suggesting a polygenic regulation of the character investigated. The maximal interline separation (RT) was reached after seven consecutive generations of selective breeding (F7). The continuation of the selection until the F15 generation did not significantly modify the RT value of F7. At the maximal interline separation (F7 to F15) the titer of antibody measured in terms of passive hemagglutinins was about 250 times higher in H/p than in L/p. The decrease of phenotypic variance during the selective breeding shows that 76% of the phenotypic variance of the foundation population (F0) is due to genetic factors: VG, and that 24% is produced by environmental effects: VE. The heritability of the character (h2) measured by the linear regression between the selection differential (S) and the response to selection (R) during the first seven generations is 0.22 ± 0.06. A provisional estimation that needs to be confirmed by experiments under way indicated that the character investigated may be controlled by two or three independent loci.

Textbook of Immunopathology

The second edition of this textbook of immunopathology is a welcome addition to a number of new and revised texts on immunology. It has been considerably enlarged and the number of contributors increased. The first chapters deal with the fundamentals of immunology, namely, the cellular basis of immune responses, immunoglobulins, complement, genetic control of immune responsiveness, anaphylaxis, antigen-antibody complexes, and delayed hypersensitivity. These have been brought to date and are excellent. Because the coagulation mechanism is so important in the inflammatory process, a new chapter dealing with this theme is a very worthwhile addition. However, I do find fault with the organization of the rest of the text. The chapters on experimental immune diseases such as of the CNS, thyroid, and kidney could perhaps have been combined with the ones dealing with the clinical immunopathology of these organs. There is considerable redundancy at present. A discussion of HLA antigens can

Genetic Control of Immune Responsiveness in Man

Interest in immunogenetics originated from two streams: (a) histocompatibility in mouse and man, and (b) inheritance of specific immune responses in the guinea pig and mouse. In the mouse, there are genes associated with the major histocompatibility complex (MHC) which (i) code for antigens determining allograft responses and mixed lymphocyte reactions, (ii) control responses to certain antigens (Ir genes), and (iii) code for cell-surface antigens which elicit specific antisera (anti-la). In man, there is genetic control, in part X-linked, over levels of immunoglobulins and immunoglobulin classes. Evidence for MHC-linked genetic control is derived from immune responses to (i) micro-organisms, (ii) pollen antigens, (iii) food antigens, (iv) vaccines, (v) innocuous test antigens, and (vi) autoantigens. Some evidence exists for allotype-linked genetic control. Practical aspects concern influences of the MHC on susceptibility to disease, within individuals and populations.