Blood 94/10

IMPORTANT INSIGHTS into a number of biological processes have come from studies of rare inherited diseases. Goethe’s declaration is best exhibited by the leukocyte adhesion deficiency (LAD) syndromes, in which one of several molecules in the adhesion cascade is defective. Much has been learned from the study of LAD, yet the puzzle is far from being solved. Animal models have also been pivotal in understanding of biological events, and immunology has benefited tremendously from the investigation of various aspects of the immune response in mice. One of the most powerful techniques has been targeted gene deletion by homologous recombination.1 This approach allows comparison of animals of similar genetic backgrounds that differ only in the absence of a single gene. Phenotypic differences between the knockout and wild-type littermates are presumed then to be due to the targeted gene deletion. Furthermore, various knockout mice can be interbred to produce deletions of several genes, providing animal models for more complex genetic defects. Although gene targeting has many advantages, it is important to acknowledge that there are important differences in biology between the mice and humans. Indeed, comparisons between rare human disease and mice with deletion of the same gene have shown important differences as well as similarities. For example, the defect in Bruton’s tyrosine kinase (BTK) in humans leads to severe hypogammaglobulinemia with almost no B cells. In contrast, mice with targeted deletion of the BTK gene produce some antibodies with up to 30% of normal B-cell number.2 It is also important to recognize that comparisons may be confounded by the recruitment of alternative pathways in the human or mouse genetic deficiencies. In this regard, mice deficient in aV-integrins exhibited no deficit in angiogenesis or vasculogenesis,3 whereas aVb3-integrin antagonists inhibit angiogenic responses in wild-type animals.4 Whether such differences result from alternative pathways in the deficient animals or unexplained effects of the antagonists remains to be resolved. In this brief review, we will compare 2 human LAD syndromes (Table 1) with gene-targeted mice with various adhesion molecule-deficiencies (Table 2), highlighting both disparities and similarities (Tables 3 and 4).