Hemophagocytic lymphohistiocytosis: pathogenesis and treatment.

Hemophagocytic lymphohistiocytosis (HLH) is not an independent disease but rather a life-threatening clinical syndrome that occurs in many underlying conditions and in all age groups. HLH is the consequence of a severe, uncontrolled hyperinflammatory reaction that in most cases is triggered by an infectious agent. Persistent stimulation of lymphocytes and histiocytes results in hypercytokinemia, leading to the characteristic symptoms of HLH. Genetic defects in familial HLH and in immunodeficiency syndromes associated with albinism affect the transport, processing, and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes. This leads to defective killing of target cells and a failure to contract the immune response. The defects are increasingly found also in adolescents and adults. Acquired HLH occurs in autoinflammatory and autoimmune diseases (macrophage activation syndrome) and in patients with iatrogenic immunosuppression or with malignancies, but also in otherwise healthy persons with infections. Treatment of HLH aims at suppressing hypercytokinemia and eliminating the activated and infected cells. In genetic HLH, hematopoietic stem cell transplantation (HSCT) is needed for the correction of the immune defect. Treatment modalities include immunosuppressive, immunomodulatory, and cytostatic drugs; T-cell antibodies; and anticytokine agents. Using immunochemotherapy, familial HLH, which had been invariably fatal, has become a curable disease with more than 50% survivors. Reduced intensity conditioning for HSCT, which is associated with less transplantation-related mortality, will further improve cure rates.

Rescue of mice homozygous for lethal albino deletions: implications for an animal model for the human liver disease tyrosinemia type 1.

Mice homozygous for specific deletions around the albino locus on chromosome 7 die within the first few hours of birth. They have a complex phenotype in liver and kidney, which includes multiple changes in gene expression and ultrastructural abnormalities. On the basis of this phenotype, it was proposed that these deletions remove a regulatory locus, alf or hsdr-1. Recently, we and others showed that the gene for fumarylacetoacetate hydrolase (Fah), an enzyme involved in tyrosine catabolism, was disrupted by the lethal albino deletion c14CoS. The finding that the Fah gene in wild-type mice is highly expressed only in cell types that develop a phenotype in mutants, and the fact that Fah deficiency determines the human liver disease hereditary tyrosinemia type 1 (HT1), suggested that disruption of the Fah gene was responsible for the lethal albino phenotype. To test this hypothesis, we have created lines of mice carrying Fah transgenes. We find that c14CoS homozygotes which express transgenic Fah are complemented for all aspects of the complex lethal albino phenotype. Moreover, the degree to which the phenotype is corrected depends on the level of transgenic Fah expression. These results unequivocally establish Fah as the gene mapping at alf/hsdr-1 and prove that the phenotype depends ultimately on the blockage of tyrosine metabolism. Finally, they suggest lethal albino mice as an animal model for HT1.

Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice.

Mice homozygous for the c14CoS albino deletion die as neonates as a result of liver dysfunction. Previous mapping studies have associated this defect with a 310-kb fragment encoding the hepatocyte-specific developmental regulation locus (alf/hsdr-1). The gene encoding fumarylacetoacetate hydrolase (Fah), a metabolic enzyme that catalyzes the last step of tyrosine catabolism, also maps to the same deletion interval. To test whether the neonatal defects found in the albino deletion mutants are attributable to loss of Fah, and not to another gene mapping to the deletion, we have generated Fah mutant mice by gene targeting in embryonic stem cells. Fah-deficient mice die within 12 hr after birth from hypoglycemia and liver dysfunction. In addition, the same pattern of altered liver mRNA expression found in the albino deletion mutants was also found in affected animals. We conclude that the neonatal lethal and liver dysfunction phenotype of the alf/hsdr-1 deletion is entirely attributable to loss of Fah.

Differential environmental effects on lesions, early growth, and mortality of imperfect albino (Sal-c) chicks.

A series of experiments investigated early pleiotropic effects of a gene for imperfect albinism (s(al-c) in a population of chickens at Jouy-en-Josas, France. An elevated incidence of lesions of the navel, hocks, and nares typical of imperfect albinos were seen on these chicks, confirming their existence in this population. Variations in hatching environment and the amount of light in the hatcher both implicated in contributing to the occurrence of lesions of the hocks and nares, but not to those of the naval. In two experiments, using batteries and cages, early growth was reduced among albinos and early mortality was increased. Significant genotype by environment interactions for weight at 4 days and growth to this time, but not thereafter, suggested that the effect is restricted to this time. Unfavorable environments were most deleterious to albinos. In a third experiment, conducted in floor pens, the gene had no effect on either early growth or mortality. There was no effect of the gene on the lesions, early growth, or mortality when carried by heterozygous males (s+/s(al-c)).

Pleiotropisms associated with alleles of the C locus in the domestic fowl.

Pleiotropisms associated with the recessive white (c) and albino (ca) alleles at the C locus of the domestic fowl were investigated. Hatchability of fertile eggs was not significantly different for the colored (C+/c, C+/ca), recessive white (c/ca), and albino (ca/ca) chicks; however, late embryonic mortality was higher in ca/ca embryos P less than or equal to .005). Albinos exhibited shorter down lengths (P less than or equal to .01), higher incidences of subcutaneous hemorrhage and inflammation (P less than or equal to .01) and an increased incidence of yolk sac protrusions (P less than or equal to .01). Suppressed body weights (P less than or equal to .01) were evident at all times, except at hatching, in both male and female albinos reared in batteries. Recessive white females also exhibited smaller body weights than colored chicks at 7 and 8 weeks of age in battery trials (P less than or equal to .01). Significant suppression of body weights occurred in albinos only at 4 weeks of age in trials where floor rearing was used. Mortality in albinos was also significantly higher, particularly under floor rearing conditions (P less than or equal to .01). In addition, both feed consumption and feed utilization were reduced in albinos (P less than or equal to .01). These data suggest that melanin synthesis is an important component in the expression of a number of important physiological traits and that the C locus exerts a previously undefined regulatory influence on such traits.

Genetic investigations in a Northern Brazilian island. II. Random drift.

18 albinos were born on Lençóis island. Since 3 of them died and 5 emigrated, the prevalence of albinism is about 3% in the island. 2 inbred brothers with brachydactyly of the index fingers and 1 case of 'achondroplasia' were also found. The analysis of the population structure of the island suggests that its high frequency of albinism may have been produced by random drift. The index of isolation of its present population is roughly 17--27. Genealogical, clinical and histological data are presented and anslyzed. Natural selection is not acting against the albinism gene at a measurable rate. Cytogenetic investigations among albinos and normals did not reveal any difference as regards frequency of aneuploidy, association of acrocentrics and chromatid gaps. The role of random processes in evolution is mentioned and the possibility that they may be more important than it is sometimes assumed is stressed.