The Histocompatibility-Linked Immune Response Genes

Benacerraf, Baruj; Katz, David H.

doi:10.1016/s0065-230x(08)60972-0

Cited by 287 publications

(195 citation statements)

References 70 publications

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“…Based on studies of mice with recombinational events in this region, it has been possible to define five I subregions, now designated I-A, I-B, I-J, I-E, and I-C, and to assign certain distinct roles in immunity to one or more subregions (2). Thus, the I-A, I-B, and I-E or I-C subregions contain genes regulating specific immune responses (Ir genes) (3,4), whereas the I-A or I-B and I-C or S regions control specific immune suppression (Is genes) (5). The I-A, I-J, and I-E-I-C subregions also contain genes controlling mixed lymphocyte and graft-vs-host reactions (2); the I-A subregion has been shown to also code for cell-surface components responsible for determining efficient T cell-B cell (6) or T cell-macrophage (7,8) interactions.…”

mentioning

confidence: 99%

Potentiation of a primary in vivo antibody response by alloantisera against gene products of the I region of the H-2 complex.

Pierres¹,

Germain²,

Dorf³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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mentioning

confidence: 99%

Potentiation of a primary in vivo antibody response by alloantisera against gene products of the I region of the H-2 complex.

Pierres¹,

Germain²,

Dorf³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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“…A summary of the data is shown in Fig. 1 (40). Identical linkage between guinea pig Ir genes and MHC specificities in that species was documented in our laboratory (41).…”

Section: Linkage Of Ir Genes To the Major Histocompatibility Complexmentioning

confidence: 64%

The Role of MHC Gene Products in Immune Regulation and its Relevance to Alloreactivity

Benacerraf¹

1992

Scand J Immunol

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The immune system has evolved the capacity to react specifically with a very large number of foreign molecules with which it had no previous contact, while avoiding reactivity for autologous molecules, naturallyantigenic in other species or in other individuals of the same species.Immunological research has been directed to the elucidation of this phenomenon ever since Ehrlich (1) proposed that immunocompetent cells bear receptors for antigen identical with the antibodies to be produced. Gowans (2) identified lymphocytes as the cells responsible for immune phenomena. Burnet (3) proposed the clonal selection theory of immunity which postulated that: 1) lymphocytes differentiate as clones bearing antibody receptors of unique specificity, 2) antibody responses reflect the selective expansion of specific lymphocytes, following the binding of antigen, and their differentiation as secretors of antibody, identical in specificity with the antigen binding receptors on the original clones. The Burnet hypothesis was verified experimentally (4,5,6) and was accepted as a major advance, concerned primarily with the response of antibody producing cells, later identified as B lymphocytes (7) and plasma cells. Accordingly, studies on the specificity of antibodies and on the structure of immunoglobulins revealed that these molecules (8,9) and their structural genes (10,ll) evolved in a way that ensures the enormous diversity of antibody combining sites observed.The discovery by Miller (12) and by Good (13) that lymphocytes differentiate into two separate classes of cells (T and B) with distinct functions, the identification of cellular immune phenomena mediated by T cells (14) and the demonstration that immune responses are regulated by helper (15,16,17) and suppressor (18,19) cells and by macrophages (20) emphasized the complexity of the immune system and the critical role played by T lymphocytes in the regulation of immunity.It became increasingly apparent that the clonal selection theory, although correct, did not take into account the complex cellular and molecular interactions essential to immune phenomena or the restrictions these interactions dictate in the specificity of T cells. An additional system, beside specific immunoglobulins, involving the products of the major histocompatibility complex (MHC) was shown to be critically involved in the manner by which T cells 597

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“…Major histocompatibility complex (MHC)-linked immune response (Ir) genes encoding recognition of various synthetic polypeptide antigens and native proteins have been welldocumented in laboratory animal species (1,2). In 1981 we reported similar Ir genes in man (3).…”

mentioning

confidence: 99%

Genetic control of major histocompatibility complex-linked immune responses to synthetic polypeptides in man: poly(L-phenylalanine, L-glutamic acid)-poly (DL-alanine)--poly(L-lysine) and L-glutamic acid, L-alanine, L-tyrosine (60:30:10).

Chan¹,

Bias²,

Hsu³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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Vigorous lymphoproliferative responses to synthetic polypeptides poly(L-phenylalanine, L-glutamic acid)-poly(DL-alanine)--poly(L-lysine) [(Phe,G)-A--L], and L-glutamic acid, L-alanine, L-tyrosine (60:30:10) (GAT) were observed in cells from 92 unrelated subjects. Thirty-three percent responded to (Phe,G)-A--L and 77% to GAT. No HLA association was observed with responses to these two antigens. Family studies indicated that two complementary immune response (Ir) genes are required for response to each antigen. Eleven matings were informative for linkage analysis between HLA and these Ir genes. Families in which the complementary genes are in coupling gave maximal lod scores (log of the odds) of 4.50 for (Phe,G)-A--L and 7.57 for GAT for 0 = 0. In a HLA-BID recombinant family, the Ir-PheGAL genes are mapped towards the HLA-D region. MATERIALS AND METHODSSubjects. Cell donors were 92 healthy, unrelated volunteers selected to include all known HLA-A, -B, -C and DR specificities and members of 35 nuclear families with 3 or more children. Eight of the families had an offspring who carried an intra-HLA recombinant haplotype.Antigens. Synthetic polymers (Phe,G)-A--L (lot MP1, Mr 260,000) and GAT (lot GAT 12, Mr 46,200) were obtained from Miles-Yeda (Elkhart, IN). Both antigens were readily soluble in RPMI 1640 medium. Before use, the pH of each antigen solution was adjusted to 7.2 and the solution was filter-sterilized (Millipore, 0.45 ,um). As described previously (3), each antigen preparation was tested for contamination with mitogenic material by coculturing with human cord blood lymphocytes and with spleen cells from unimmunized female mice of nonresponder and high-responder strains.In Vitro Lymphocyte Stimulation. Human peripheral blood lymphocytes were isolated by the standard Ficoll-Hypaque gradient technique. Varying concentrations of each antigen were cultured in triplicate with 8 x 104 peripheral blood lymphocytes in 0.2 ml of RPMI 1640 medium with 10% (vol/vol) human group AB serum, in round-bottom microtiter plates (Linbro). On day 7, 1 ,uCi of [3H]thymidine (specific activity, 6.7 Ci/mmol; 1 Ci = 37 GBq) was added to each well. The cultures were harvested 16-18 hr after labeling and samples were assayed for radioactivity in a Beckman model LS 7000 liquid scintillation counter. Results were expressed as the stimulation index (SI): SI = mean cpm of culture with antigen/mean cpm of culture without antigen.Each subject was tested at least twice with seven serial dilutions of each antigen. As previously reported, the antigen concentration eliciting maximal response varied from individual to individual (3). For the majority of subjects tested, the optimal antigen concentration was 80 gg per well for both (Phe,G)-A--L and GAT. The mean maximal SI obtained for each antigen was used to classify the subjects into responder and nonresponder groups. Subjects with SI >3 were considered as responders, in accordance with accepted procedures (4-6). There was a small number of subjects [12 for (Phe,G)-A--L and 9 ...

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The Histocompatibility-Linked Immune Response Genes

Cited by 287 publications

References 70 publications

Potentiation of a primary in vivo antibody response by alloantisera against gene products of the I region of the H-2 complex.

Potentiation of a primary in vivo antibody response by alloantisera against gene products of the I region of the H-2 complex.

The Role of MHC Gene Products in Immune Regulation and its Relevance to Alloreactivity

Genetic control of major histocompatibility complex-linked immune responses to synthetic polypeptides in man: poly(L-phenylalanine, L-glutamic acid)-poly (DL-alanine)--poly(L-lysine) and L-glutamic acid, L-alanine, L-tyrosine (60:30:10).

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