Eur. J. Immunol. 1992. 22: 2555-2563 Genetics of acute inflammatory response 2555 zy Olga M. Ibanezoa, Claude Stiffel., Orlando G. Ribeiro., Wafa K. Cabreraoo, Solange Massaoo, Marcelo de Franco., Osvaldo A . Sant’Annaon, Claude Decreusefond., Denise Mouton., Maria Siqueiraoa and Guido Biozzi. Laboratorio de Immunogenetica, Instituto Butantan., Sao Paulo and Service d’lmmunoghktique, CNRS URA 1413, lnstitut Curie, Section de Biologie., Paris Genetics of nonspecific immunity: I. Bidirectional selective breeding of lines of mice endowed with maximal or minimal inflammatory responsiveness* The genetic regulation of acute inflammatory reaction (AIR) was studied by the method of bidirectional selective breeding, used to produce a line of mice giving the maximal and a line of mice giving the minimal inflammatory reaction (AIR max and AIR min, respectively). The AIR was triggered by subcutaneous injection of a neutral substrate (suspension of polyacrylamide microbeads), and measured by the leukocyte and serum protein accumulation in the exudate. The two parameters are positively correlated and present a normal frequency distribution. The highly genetically heterogeneous foundation population was produced by the equipoised intercrossing of eight inbred strains of mice, and selective breeding carried out by assortative matings of extreme phenotypes. The response to selection in 11 consecutive generations was highly asymmetrical: a marked AIR increase in the AIR max and no change in the AIR min line occurred.The mean value of realized heritability in the AIR max line was 0.26 and 0.18 for cell and protein concentrations, respectively. The response to selection must have resulted from the interaction of seven to nine independent gene loci endowed with additive effects. The lack of response to selection of the AIR min line is discussed. The large inter-line difference opens new possibilities for studying the biochemistry and molecular genetics of inflammation, and also for investigating the beneficial or detrimental effect of inflammatory responses. 1 Introduction Inflammation is primarily a beneficial reaction of vascular- ized tissues to physical, chemical or biological aggressions (infections). It is a phylogenetic, primitive, nonspecific phenomenon followed, later in the evolutionary process, by immunological responses endowed with specificity and memory [ l , 21. However, inflammation is a “double-edged sword”: an inadequate inflammatory reaction can lead to a compromised host, while an excessive one can predispose to inflammatory diseases [3, 41. Extensive investigation has been dedicated to the humoral, cellular and molecular aspects of inflammation [5-81, but astonishingly, little is known about the genetic regulation of the intensity of inflammatory reactions. Our information in this field is restricted to the differences observed in a few inbred strains of rodents in response to various types of stimulation [9-161. [I 105271 zyxwvu * This work was partly supported by grant 86-2211-0 from FAPESl? Supported by a fellowship of FAPESF! to Cientifico zyxwvutsrqpo e Tecnologico. zyxwvuts a Supported in part by the Conselho Nacional de Desenvolvimen- The inflammatory process is both varied and extremely complex, nevertheless its initial phase, the acute inflamma- tory reaction (AIR), is quite uniform. It is characterized by a local increase in blood flow, exudation of plasma proteins and migration and activation of leukocytes, accompanied by general effects [ 17-20]. A quantitative method for measuring the intensity of AIR based on the determination of leukocyte and protein concentration in the local exudate was described by Fauve et al. [21, 221. The local AIR is induced by subcutaneous injection of a suspension of polyacrylamide microbeads, which is an entirely insoluble, chemically inert, non- antigenic substrate, acting as a neutral foreign material. As a consequence, the intensity of locally produced AIR is solely regulated by endogenous factors, and does not depend on the nature of the inflammatory stimulus. Using this method, we measured the degree of AIR in several inbred strains of mice and in lines of mice selected for high or low antibody (Ab) responsiveness [23]. A large and continuous range of AIR intensity was observed in these genetically distinct mouse populations, suggesting a poly- genic regulation of this character [3,24]. No correlation was demonstrated between Ab responsiveness and AIR, indi- cating that the specific and nonspecific defense mechanisms were controlled by independent polygenic regulations z r-l 131 ’ T~ investigate the polygenic regulation of AIR, we prod- uced by bidirectional selective breeding a line of mice Hcritability realized during the selective breeding a line Of mice giving the minima1 inflammatory response to selection S: Sclection differential Fo: Foundation popula- (AIR min) to subcutaneously injected polyacrylamide tion microbead suspension. Correspondence: Guido Biozzi, Service d’ImmunogtnCtique, Institut Curie, Section de Biologie, 26, rue d’Ulm, F-75231 Paris Ccdex 05, France Abbreviations: AIR: Acute inflammatory responsiveness hZ: giving the response max) and z R: Response zyxwv 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1992 0014-2980/92/1010-2555$3.50 + .25/0