GENE COMPLEMENTATIONS TO GENERATE Ia ANTIGENS (Ia.23) ON HYBRID MOLECULES

Lafuse, William P.; McCormick, John; Corser, Paula S.; David, Chella S.

doi:10.1097/00007890-198011000-00007

Cited by 15 publications

(5 citation statements)

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“…Heterozygous patients may possess unique Ia determinants as a result of combinatorial a-chain and ,B-chain associations (21,22) or alternatively, the LD"40" specificity alone may confer significant increased disease susceptibility. In another patient population, namely children with juvenile onset diabetes (insulin-dependent diabetes mellitus), it has been shown that the relative risk for DR3/DR4 heterozygosity is greater than the relative risk for either DR3 or DR4 homozygotes (23).…”

Section: Resultsmentioning

confidence: 99%

Specific HLA-DR4-associated histocompatibility molecules characterize patients with seropositive juvenile rheumatoid arthritis.

Nepom¹,

Nepom²,

Mickelson³

et al. 1984

J. Clin. Invest.

118

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A bstract. The structural and functional heterogeneity of HLA-DR4-associated specificities was investigated in patients with seropositive juvenile rheumatoid arthritis, a DR4-associated disease. Using a combination of HLA-D analysis by mixed lymphocyte culture and electrophoretic analysis of immunoprecipitated Ia molecules by two-dimensional polyacrylamide gels, we observed a surprisingly homogeneous pattern of HLA-D antigen expression. All patients expressed common structural products of the DR and DS loci, and 7/12 homozygous DR4 patients expressed a rare and subtle HLA-D heterozygous phenotype.

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Section: Resultsmentioning

confidence: 99%

Specific HLA-DR4-associated histocompatibility molecules characterize patients with seropositive juvenile rheumatoid arthritis.

Nepom¹,

Nepom²,

Mickelson³

et al. 1984

J. Clin. Invest.

118

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“…If I-region-encoded (Ia) molecules of infected macrophages influence the expression of resistance-promoting T cells, then observations on the dominance of susceptibility or resistance in F, mice may open up both genetic and immunochemical approaches (Handman et al, 1981) to analyses of relevant Ia molecules. Differences in expression of H-2, including Ia, molecules or epitopes in F, hybrids relative to parental strains have been demonstrated in numerous laboratories (O'Neill & Blanden, 1979a,b;Jones et al, 198 1;Lafuse et al, 1980;Fathman & Nabholz, 1977;Sandrin et al, 1981). The results of experiments in various F, hybrids and parental mice injected with promastigotes of clone V121 indicate a dominant or co-dominant mode of inheritance of resistance in F, mice; of course, if resistance is co-dominant then susceptibility is also co-dominant.…”

Section: Discussionmentioning

confidence: 99%

MURINE CUTANEOUS LEISHMANIASIS: RESISTANCE IN RECONSTITUTED NUDE MICE AND SEVERAL F₁ HYBRIDS INFECTED WITH LEISHMANIA TROPICA MAJOR

Mitchell

1983

Int J Immunogenetics

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SUMMARY After cutaneous injection of promastigotes of an isolate of the intramacrophage protozoan parasite, Leishmania tropica major, mouse strains develop chronic cutaneous lesions or show a resolving pattern of disease. On this basis, they can be classified as resistant (e.g. CBA/H and C57BL/6) or susceptible (e.g. BALB/c, BALB/c.H‐2b and BALB/c.H‐2k). Hypothymic nude (nu/nu) mice of either BALB/c, CBA/H or C57BL/6 genotype are susceptible to chronic disease. However, nude mice of these genotypes, including BALB/c, are resistant to chronic cutaneous leishmaniasis when injected at the time of parasite challenge with small numbers of H‐2 compatible lymphoid cells from normal mice. Nude mice remain susceptible when injected with fully H‐2 incompatible cells. Using cells from H‐2 mutant mice for reconstitution of resistance in C57BL/6.nu/nu mice, evidence was obtained that I region compatibility is necessary for cells to mediate host‐protective effects. Cells from chronically‐diseased BALB/c mice do not have protective effects in BALB/c.nu/nu mice at any cell dose and will abrogate the resistance‐promoting effect of lymphoid cell populations from chronically‐diseased BALB/c.H‐2k and BALB/c.H‐2b mice can be demonstrated when assayed at certain cell doses in H‐2 compatible CBA/H.nu/nu and C57BL/6.nu/nu mice, respectively. The data suggest that chronically‐diseased (genetically‐susceptible) mice contain a mixture of resistance‐promoting and disease‐promoting T cells in their peripheral lymphoid organs and that expression of the resistance‐promoting subset can occur in nude mice of resistant genotype. Previous data have indicated that Lyl+2− T cells are efficient mediators of both T cell‐dependent activities. No evidence for the operation of disease‐promoting or resistance‐promoting antibodies in perpetuation or resolution of disease has been obtained in extensive serum transfer experiments. Some discrepancies exist in the literature on the question of the dominance of susceptibility or resistance in F1 hybrid mice. A re‐examination of susceptibility/resistance in F1 hybrids between BALB/c and several other parental strains was undertaken using cloned pathogenic promastigotes derived from a heterogeneous L. t. major isolate in order to reduce effects of parasite heterogeneity in the analysis. Resistance was dominant in some but not all F1 hybrids, with most showing a delayed healing pattern of disease relative to the resistant parental strain. Despite the use of genetically‐homogeneous parasites, the analysis was complicated by variability within groups of F1 hybrid mice as well as between males and females and between F1 hybrids of reciprocal crosses. A hypothesis based on antigen and H‐2 expression on infected macrophages is advanced to account for the balance between the effects of resistance‐promoting and disease‐promoting Lyl+2− T cells in mice of various genotypes.

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“…A DQ ap-dimer composed of transcomplementing chains would be unique to a heterozygous individual and not expressed by either parent. In the mouse, such transcomplementation has been demonstrated structurally, and epitopes newly formed on the resulting hybrid molecules allow for an altered functional immune response different from that of either parent (7,8). Recent structural studies suggest that similar transcomplementation can occur in humans, demonstrable by two-dimensional polyacrylamide gel electrophoresis (20-PAGE) (9) and partial NH 2 -terminal protein sequencing (5).…”

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confidence: 99%

Transcomplementation of HLA Genes in IDDM: HLA-DQ α and β-Chains Produce Hybrid Molecules in DR3/4 Heterozygotes

et al. 1987

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SUMMARYThe HLA association with insulin-dependent diabetes mellitus is highest among individuals heterozygous for DR3 and DR4. To investigate potential mechanisms to account for this association, we performed two-dimensional gel-electrophoretic analysis of HLA molecules from DR3/4 heterozygous patients. These studies demonstrated hybrid molecular dimers corresponding to products of HLA-DQ genes linked to DR3 and DR4, i.e., the DQw2 and DQw3 genes, respectively. Two types of OQ molecules were found: immunoprecipitation by DQw3-specific monoclonal antibody 17.15 identified a DQw3 p-chain associating with a DQw3 a-chain and a DQw3 p-chain associating with a DQw2 a-chain. The identity of a-and p-chains comprising these hybrid molecules was confirmed by HPLC peptide-map analysis. Several characteristic peptide peaks identified both DQw2 and DQw3 a-chains associated with DQw3 p-chains. The formation of such DQa(DQw2)-DqP(DQw3) dimers potentially contributes a direct molecular mechanism for HLA-associated contributions to disease in DR3/DR4 heterozygotes. Diabetes 36:114-17, 1987 T he class II molecules of the human major histocompatibility region (HLA) are strongly associated with several autoimmune diseases (1). Several of these HLA-associated diseases show a dramatically increased relative risk for individuals possessing a particular heterozygous combination of class II antigens [e.g., DR3/4 in insulin-dependent diabetes mellitus (IDDM) (2) and Dw4/ Dw14 in seropositive juvenile rheumatoid arthritis (3) increased disease susceptibility may be related to an altered immune response resulting from the formation of hybrid class II molecules contributed from both haplotypes (3-6). We describe the identification of such hybrid molecules on cells from heterozygous DR3/4 IDDM patients, consisting of dimers containing products of genes from both DR3-and DR4-associated haplotypes.Class II HLA molecules are dimers of a-and p-polypeptide chains encoded by separate genes and function as recognition signals for activation of immune responses. These HLA gene products include both DR and DQ molecules encoded in different but linked genes. DQ a-and p-molecules are polymorphic; i.e., the DQ a-chain linked to one DR gene, such as DR3, is different from the DQ a-chain linked to another, such as DR4, and the same is true for DQ (3-chain. Thus, in a heterozygote, mixed ap-dimers potentially could form between DQ-chains from different haplotypes. Such transcomplementation of DQ a-and p-chains from opposite haplotypes would dramatically broaden the diversity of class II antigens available to participate in the immune response. The DR a-molecules are not polymorphic; i.e., DR a-molecules are invariant among haplotypes, and mixed DR ap-dimers would not result in novel HLA molecules. A DQ ap-dimer composed of transcomplementing chains would be unique to a heterozygous individual and not expressed by either parent. In the mouse, such transcomplementation has been demonstrated structurally, and epitopes newly formed on the resulting hybrid mole...

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GENE COMPLEMENTATIONS TO GENERATE Ia ANTIGENS (Ia.23) ON HYBRID MOLECULES

Cited by 15 publications

References 0 publications

Specific HLA-DR4-associated histocompatibility molecules characterize patients with seropositive juvenile rheumatoid arthritis.

Specific HLA-DR4-associated histocompatibility molecules characterize patients with seropositive juvenile rheumatoid arthritis.

MURINE CUTANEOUS LEISHMANIASIS: RESISTANCE IN RECONSTITUTED NUDE MICE AND SEVERAL F₁ HYBRIDS INFECTED WITH LEISHMANIA TROPICA MAJOR

Transcomplementation of HLA Genes in IDDM: HLA-DQ α and β-Chains Produce Hybrid Molecules in DR3/4 Heterozygotes

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GENE COMPLEMENTATIONS TO GENERATE Ia ANTIGENS (Ia.23) ON HYBRID MOLECULES

Cited by 15 publications

References 0 publications

Specific HLA-DR4-associated histocompatibility molecules characterize patients with seropositive juvenile rheumatoid arthritis.

Specific HLA-DR4-associated histocompatibility molecules characterize patients with seropositive juvenile rheumatoid arthritis.

MURINE CUTANEOUS LEISHMANIASIS: RESISTANCE IN RECONSTITUTED NUDE MICE AND SEVERAL F1 HYBRIDS INFECTED WITH LEISHMANIA TROPICA MAJOR

Transcomplementation of HLA Genes in IDDM: HLA-DQ α and β-Chains Produce Hybrid Molecules in DR3/4 Heterozygotes

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MURINE CUTANEOUS LEISHMANIASIS: RESISTANCE IN RECONSTITUTED NUDE MICE AND SEVERAL F₁ HYBRIDS INFECTED WITH LEISHMANIA TROPICA MAJOR