Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.     

The double nature of Maxwell's physical analogies

Building upon work by Mary Hesse (1974), this paper aims to show that a single method of investigation lies behind Maxwell's use of physical analogies in his major scientific works before the Treatise on Electricity and Magnetism. Key to understanding the operation of this method is to recognize that Maxwell's physical analogies are intended to possess an ‘inductive’ function in addition to an ‘illustrative’ one. That is to say, they not only serve to clarify the equations proposed for an unfamiliar domain with a working interpretation drawn from a more familiar science, but can also be sources of defeasible yet relatively strong arguments from features of the more familiar domain to features of the less. Compared with the reconstructions by Achinstein (1991), Siegel (1991), Harman (1998) and others, which postulate a discontinuity in Maxwell's approach to physical analogy, the account defended in this paper i) makes sense of the continuity in Maxwell's remarks on scientific methodology, ii) explains his quest for a “mathematical classification of physical quantities” and iii) offers a new and more plausible interpretation of the debated episode of the introduction of the displacement current in Maxwell's “On Physical Lines of Forces”.