Genetics of nonspecific immunity: I. Bidirectional selective breeding of lines of mice endowed with maximal or minimal inflammatory responsiveness

Abstract

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.

Aryl hydrocarbon receptor polymorphism modulates DMBA‐induced inflammation and carcinogenesis in phenotypically selected mice

“…The functional A375V polymorphism of Ahr was automatically genotyped by pyrosequencing. 1 Fisher's exact test.…”

“…Two nonisogenic mouse lines derived by bidirectional selection based on the intensity of local acute inflammatory reactions (AIR) to polyacrylamide beads (Biogel) 1 have shown striking differences in resistance/susceptibility to chemical-induced carcinogenesis. Mice with the maximum acute inflammatory reaction (AIRmax) are significantly more resistant than minimum responders (AIRmin) to two-stage skin tumorigenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) followed by repeated doses of the promoter agent 12-O-tetradecanoyl-phorbol-13-acetate (TPA), 2 and also to lung carcinogenesis induced by urethane, 3 suggesting that a subset of loci affecting the inflammatory response also act as cancer modifier loci.…”

Avaliação dos efeitos da inflamação na infecção respiratória por<i> Streptococcus</i> <i>pneumoniae</i> em camundongos.

“…As linhagens de camundongos AIRmin e AIRmax foram selecionadas geneticamente para resposta inflamatória aguda mínima e máxima, respectivamente, e representam um interessante modelo para o estudo da infecção respiratória por pneumococo (Ibanez et al, 1992 . É importante ressaltar, no entanto, que nos animais vacinados, níveis altos de anticorpos anti-PspA são encontrados nos pulmões e participam no controle da infecção (Lima et al, 2012;Oliveira et al, 2010 Os macrófagos possuem duas vias de diferenciação, macrófagos ativados pela via clássica (denominados M1) e macrófagos ativados pela via alternativa (M2).…”

“…Embora o processo inflamatório possa ser multifacetado, características iniciais da reação inflamatória aguda são únicas. Inicia-se com o aumento da vascularização local, com o extravasamento de fluido rico em proteínas (exsudato) e consequente migração e ativação de leucócitos (Schreiber et al, 1989 (Ibanez et al, 1992;Stiffel et al, 1987). (Ibanez et al, 1992).…”

“…A partir daí foram realizadas as seleções mediante de cruzamento bidirecional, considerando as respostas individuais altas e baixas com relação à concentração de proteínas e células infiltradas no exsudato local (Ibanez et al, 1992). As linhagens AIRmin e AIRmax foram estabelecidas e bem caracterizadas pelo grupo do laboratório de imunogenética e desde então têm contribuído para a compreensão da regulação genética da resposta inflamatória aguda.…”