Jane S. Schultz

The genetics of the Lp antigen. I. Its quantitation and distribution in a sample population.

The frequency distribution of the quantitative activity of the Lp antigen was found to be bimodal. It is hypothesized that a major genetic factor is operating to determine the modes.

Tissue graft rejection in mice: I. Contributions ofH-2 and Non-H-2 genetic barriers

A liver-slice to kidney-bed grafting system was used to study the course of rejection of a specific tissue across various genetic barriers in inbred strains of mice. Rejection or survival, scored histologically at various times after grafting, demonstrated that multiple nonH-2 differences cause rejection at least as rapidly asH-2 differences. Differences at theK end of the mouse major histocompatibility complex cause tissue rejection more rapidly than do differences at theD end of the complex. The latter differences cause chronic rejection similar to that found across several minorH locus barriers. TheH-2 haplotype carried by the recipient or the strength of theH-2 antigens of the donor affect the survival time in liver tissue grafts. Studies employing this model system will contribute to the definition of different immunogenetic parameters affecting survival of various tissues in a genetically well-defined animal model.

The distribution of la antigens of the H-2 complex on lymph node cells by immunoferritin labelling

Abstract The distribution of Ia antigens on the surfaces of lymph node lymphocytes of several mouse strains was investigated using indirect immunoferritin labeling and electron microscopy. The immunoferritin labeling results agreed with results of cytotoxic tests in strain distribution of reactivity, proportion of cells showing label, and cell populations reacting. Capping was induced by increased incubation temperature but conditions for Ia antigen mobilization varied somewhat between the two anti-Ia antisera employed. Uncapped specimens generally showed a denser, more evenly distributed antigen coating than is the case for H-2 antigens labeled by the same indirect immunoferritin method.

Studies on the Heterogeneity of Human Serum Lp Lipoproteins and on the Occurrence of Double Lp Lipoprotein Variants

Lp lipoproteins have been prepared by a mild method from the serum of a large number of individuals. Approximately 25% of the individuals tested showed the presence of a double Lp peak in analytical ultracentrifuge diagrams. These double peaks were designated Lp(a)-1 and Lp(a)-2 to distinguish them from the single Lp(a) peak. The mean viscosity-corrected sedimentation coefficient, S1.004, 20C and density of the single Lp(a) peak were 15.8±1.8s (n=32) and 1.076±0.01 g/ml, of the Lp(a)-1 peak were 13.5±1.1s (n=14) and 1.064±0.007 g/ml, and of the Lp(a)-2 peak were 16.8±1.7s (n=14) and 1.074±0.009 g/ml. Absorption tests using a double and single Lp preparation showed that both Lp peaks in the double variants possess Lp(a) specificity. Evidence is lacking as yet for individual specificities for either Lp(a)-1 or Lp(a)-2. Interand intra-individual heterogeneity among Lp lipoproteins is discussed.

C2 Deficiency and a Lupus Erythematosus-Like Illness: Family Re-evaluation

Excerpt To the editor: A family with inherited C2 deficiency (C2D) and systemic lupus erythematosus was previously described by one of us in the March 1975 issue (1). Subsequent to this report, the...

Accelerated autoimmune disease and lymphoreticular neoplasms in F1 hybrid PN/NZB and NZB/PN mice

This report describes the first studies of inheritance of autoimmunity in inbred Palmerston North (PN) mice, a model of systemic lupus erythematosus (SLE). Mating of PN mice with the nonautoimmune DBA/2 strain produced evidence that PN disease had a recessive mode of inheritance. When PN mice were crossed with autoimmune NZB mice, female offspring from both crosses developed anti-DNA antibodies and died prematurely with vasculitis, renal disease, and lymphomas. In contrast, reciprocal hybrid males had different patterns of mortality; PN/NZB males from the PN female X NZB male mating had moderately prolonged life spans, whereas NZB/PN males from the opposite cross (NZB female X PN male) had prolonged survival to the mean age of 104 weeks. To determine if testicular hormones were solely responsible for increased longevity in hybrid males, PN/NZB and NZB/PN mice were castrated at 2 weeks of age and compared to sham-operated littermate controls. Prepubertal castration did not influence longevity in PN/NZB males, but loss of gonadal hormones significantly reduced life spans in reciprocal NZB/PN males. Female hybrids were not affected by oophorectomy. Because castration changed disease expression only in male hybrids from the NZB female X PN male cross, it was concluded that parentage influenced sensitivity to the protective effects of male hormones. Although surgical sterilization had disparate effects on males, castrated PN/NZB and NZB/PN males consistently outlived oophorectomized females. The lack of clear-cut reversal of disease in males subjected to early castration suggested that nonhormonal, possibly genetic, factors contributed to longevity in both groups of male hybrids.

The H-2 haplotype of the PN (Palmerston North) inbred strain

Inbred Palmerston North (PN) mice have been established as an animal model of the multisystem autoimmune disease, systemic lupus erythematosus. Disease in these animals is characterized by the presence of antibodies to nuclear antigens and immune complex glomerulonephritis (Walker et al. 1978). Because of the usefulness of this animal model for further studies of autoimmune disease, and because of the well-known relationship between the major histocompatibility complex (MHC) and autoimmune disease development, it is of considerable interest to determine the H-2 haplotype carried by this strain. To accomplish this identification, antigens in the K, D, and I regions of the MHC were determined by microcytotoxic assay (Frelinger et al. 1974) in the laboratory of one of us (C. S. David). PN mice are descendents of albino mice purchased in a New Zealand pet shop in 1948. The offspring of these albinos were raised at Palmerston North Hospital in Palmerston North, New Zealand, and were then taken to Massey University and subsequently sent to the Glaxo Laboratories of New Zealand. Breeding pairs were returned to Dr. Richard D. Wigley at the medical research department of Palmerston North Hospital. In 1964 a brother-sister mating program was begun with selection for positivity for anti-nuclear antibody (ANA). The resulting strain was called PN/nA. At the F9 generation a subline (PN/nB) was begun from a first cousin mating and was continued with brother-sister matings. In March 1975, when the A subline was in the F28 generation and the B subline in the F23 generation, breeders of both sublines were shipped to the United States. Animals currently in use are from the B subline. Initially, three PN mice were killed and their spleen cells tested by the microcytotoxieity test with a battery of anti-H-2 and anti-Ia sera. We noticed that whenever an H-2 q strain was one of the recipients used for the antiserum production, the PN mice failed to react. This suggested that strain PN could possibly carry the H-2 q haplotype. Next, antisera directed against most of the private antigens of the H-2, K, D, and I regions were tested against cells of three more PN mice. The results with two of these mouse cells are shown in Table 1.

Liver Tissue Graft Rejection in Murine Major Histocompatibility Complex Mutants

Liver tissue grafts between seven H-2 mutants and their parental strains have been studied. Each of these mutants was originally identified by reciprocal mutant—parental strain skin graft rejection. However, liver grafts among mutants and parental standard strains are not uniformly rejected. Liver graft rejection also fails to correlate with mutant—parental stimulation in CML and MLC. In addition, the immune reaction pattern of female mutant animals against grafts of male liver differs from the reaction pattern found in parental standard strains. Several explanations for the differences between immune response to liver and skin grafts are proposed, including different T cell subsets involved in recognition, availability of antigenic sites to immunocompetent cells, and structural differences between mutant and parental H-2 antigens.

Hybrid immune response to parental liver tissue grafts

Parental-to-F1-hybrid liver tissue grafts in like-sex donor-recipient combinations survive indefinitely, although several F1 recipients demonstrate an immunological response to the parental graft. Female F1 recipients, particularly those carrying theH-2b haplotype, respond vigorously to male parental liver grafts. However F1 female responses to male parental liver tissue grafts differ substantively from the responses of parental females to syngeneic male grafts. C3H male liver grafts are rejected vigorously by F1 females as long as the F1 carries theH-2b haplotype. These findings support previous reports of strong immunological responses to C3H H-Y antigen in female F1 and C3H.SW animals, a response which is absent in C3H females. Female F1 hybrids carrying theH-2b haplotype do not reject grafts of B10 or B6 male liver as rapidly as do B10 or B6 parental females. This reduced F1 response may be related to the formation of hybrid antigens and consequent alteration of the anti-H-Y response. Alternatively, cells that specifically suppress the anti-H-Y response may be present in F1 hybrids. Factors responsible for suppression appear to be controlled by non-MHC antigens, at least in (OH x B6 or B10) F1 hybrids.