A. L. M. Watson

A putative gene causes variability in lifespan among genotypically identical mice

Ageing is a complex process during which damage to multiple organ systems accumulates1. The time at which impairment of critical bodily functions becomes incompatible with life determines organismal longevity and is usually measured in a population as mean or maximal lifespan. Our current understanding of the genes affecting longevity, particularly in mammalian species, is rudimentary at best2. Here we studied the range of lifespans among individual animals within genetically identical recombinant inbred (RI) strains of mice. We found that the time between the deaths of the first and last members of a given strain fell into two temporal groups, despite the fact that strains may have had similar mean or maximal lifespans. The segregation of RI strains into wide and narrow ranges that roughly corresponded to characteristic lifespan ranges of the progenitor strains, suggested a genetic component. We therefore mapped a putative gene accounting for more than 60% of the phenotype to a genomic segment near the centromere on chromosome 11. This locus causes variability in the rate at which genetically identical members of a population die and, from a practical standpoint, affects the slope of a death curve for a population.

Familial clustering of scleroderma spectrum disease

This is the second case report of familial scleroderma (systemic sclerosis) in South Carolina. The family includes two cases of scleroderma meeting American Rheumatism Association criteria, one of systemic sclerosis sine scleroderma, and two other cases of undifferentiated connective tissue disease with features of scleroderma spectrum disorders; there are also two cases of Raynauds phenomenon (one associated with rheumatoid arthritis), for a total of seven affected relatives. Evidence of scleroderma spectrum disorders was sought in six siblings of the two co-index cases and in 23 of the 35 offspring. Laboratory studies included antinuclear antibody determinations and typing for the following genetic markers: HLA (A, B, C, DR), complotypes, Gm and Km allotypes, and alpha-1 antitrypsin phenotypes. No common genetic markers restricted to affected members of this family were found, and no environmental exposures were detected that could explain this familial clustering of cases. This report should, however, add to the slowly accumulating information on the genetic characteristics of families at unusually high risk for scleroderma spectrum disorders. Positive antinuclear antibody tests at a titer of 1/40 or higher were present in 57 percent of the first-degree relatives of the affected cases.

Changes in the expression of HLA and β2-microglobulin by cultured lymphoid cells

Changes in the expression of HLA and beta 2-microglobulin (beta 2-m) antigens by cultured human lymphoid cell lines were investigated. HLA expression was assayed by indirect trace binding radioimmunoassay (RIA) with monoclonal antibodies and by determining sensitivity to complement-dependent lysis by alloantisera. Lymphoid cells in culture were found to undergo changes in the expression of HLA and beta 2-m antigens characterized by decreased membrane expression of these antigens at high cell densities or after a prolonged period of cultivation. The decreased expression of HLA and beta 2-m antigens apparently is due neither to a masking phenomenon nor to a lack of nutrients or an accumulation of metabolites in the culture media but is perhaps mediated by a cell-to-cell contact mechanism. Human interferon was found to enhance the expression of HLA and beta 2-m, apparently overriding the effects on major histocompatibility complex (MHC) expression induced by cell density.

Major histocompatibility complex markers and red cell antibodies to the Rh (D) antigen. Absence of association

Between 20 and 35 percent of Rh(D) antigen‐negative individuals do not develop antibodies to D even after multiple transfusions of Rh‐positive red cells. To evaluate the possibility that antibody production after exposure to the D antigen was related to a major histocompatibility complex immune response gene, analysis of the HLA genotypes of 38 Rh‐ sensitized women and their families was performed. No significant deviations were found in the frequency of any individual HLA class I, II, or III allele or of any extended haplotype (fixed allelic combinations of HLA‐B, HLA‐DR, and the complement components BF, C2, C4A, and C4B). Type 1 errors due to the extreme allelic polymorphism of the HLA system, as well as the ethnic variation in patient groups, may have contributed to HLA allele‐antibody responder relationships reported in earlier studies.

Increased fluidity of serum lipids and development of spontaneous mammary tumors in C3H mice

SummaryThe degree of lipid fluidity (LFU) was quantitatively monitored by fluorescence polarization analysis of the hydrocarbon fluorescent probe diphenylhexatriene when embedded in artificial and biological lipid complexes. The results have shown a marked increase in LFU in serum lipids associated with the development of spontaneous mammary tumors in C3H mice. An increase in serum LFU was observed during the initiation of primary tumors. The serum LFU further increases as a function of increase in the tumor volume. This increase was not observed when animals were given transplants of syngeneic, spontaneously arising mammary tumors or following implants of antigenically inert glass beads. Since the serum LFU in C57BL/6, NZB and A/JAX non-tumor-bearing mice was found to be significantly lower than in C3H non-tumor-bearing mice, it is suggested that alterations in the dynamics of serum lipids in the C3H system may have a direct relation to the induction and/or growth of spontaneous tumors in these mice. Moreover, experiments carried out with an artificial membrane model system have shown that the dynamics of a lipid complex are directly determined by its lipid composition. The three major parameters that determine the LFU of a lipid domain are: (a) the relative amounts of different phospholipids; (b) the molar ratio of cholesterol to phospholipids; and (c) the degree of saturation of the fatty acids. It is therefore suggested that alterations of this kind may occur in serum lipids during spontaneous mammary tumor development in C3H mice.