Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice.

Mice selected for the maximum acute inflammatory reaction (AIRmax) are highly susceptible to pristane-induced arthritis (PIA), whereas mice selected for the minimum response (AIRmin) are resistant. These lines show distinct patterns of leukocyte infiltration and R and S allele frequency disequilibrium of the solute carrier family 11a member 1 (Slc11a1) gene. In order to study the interactions of the Slc11a1 R and S alleles with the inflammation modulating Quantitative Trait Loci (QTL) during PIA development, homozygous AIRmax(RR), AIRmax(SS), AIRmin(RR) and AIRmin(SS) lines were produced by genotype-assisted breedings. These mice received two intraperitoneal injections of 0.5 ml pristane at 60-day intervals, and the subsequent development of arthritis was assessed for 210 days. Cytokine-secreting cell profiles were investigated using enzyme-linked immunospot. Arthritis incidence in AIRmax(RR) mice reached 29%, whereas PIA incidence in AIRmax(SS) mice was 70% by day 180. AIRmin(RR) mice were resistant, whereas 13.3% of AIRmin(SS) mice became arthritic. The presence of the defective S allele also increased arthritis severity, although acute inflammation was higher in mice bearing the R allele. A predominant Th0/Th2-type response in Slc11a1(SS) mice was observed. These results indicate that Slc11a1 is a strong candidate for the QTL modulating acute inflammation and for PIA.

Involvement of antibody production quantitative trait loci in the susceptibility to pristane-induced arthritis in the mouse.

Mice obtained by bidirectional selective breeding for high (HIII) or low (LIII) antibody (Ab) production are resistant or extremely susceptible to pristane-induced arthritis (PIA), respectively. Several quantitative trait loci regulating Ab production (Ab QTL) have been mapped in these lines, which were used to investigate the influence of these Ab QTL in PIA. Parental HIII and LIII mice and their F1 and F2 intercrosses were injected twice with pristane, and arthritis was observed for 200 days. In LIII mice PIA was more severe and incidence was 100% at day 105, while F1 and F2 mice showed intermediate values. HIII mice were totally resistant. Microsatellite polymorphisms of Ab QTL were analysed and D3Mit100 alleles cosegregated significantly with PIA incidence, severity and onset in F2 intercross mice, while the other four markers showed suggestive values. Results indicate colocalization of QTL for Ab production and PIA susceptibility. Moreover, the different cytokine and IgG isotype profiles observed in HIII and LIII lines after PIA induction are useful to candidate genes endowed with the regulation of the Ab production and arthritis phenotypes.

Innate resistance to infection by intracellular bacterial pathogens differs in mice selected for maximal or minimal acute inflammatory response

The intensity of nonspecific immune reaction and the host resistance to facultative intracellular pathogens are found to be associated in lines of mice selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory reactivity. AIRmax are more resistant than AIRmin mice to Salmonella typhimurium and Listeria monocytogenes infection, the differences between lines in LD50 being > 1000 and 100 times, respectively. This difference was shown to be related to the initial bacterial containment at the infectious focus, and to the control of bacterial multiplication in the spleen during the 1st week after s. c. inoculation of the bacteria. Specific immune responses were not deeply affected by the selective process: antibody production and delayed-type hypersensitivity were both of similar intensity in AIRmax and AIRmin mice. The differential susceptibility to infection seems independent of the Nramp-1 locus polymorphism; therefore, these two lines represent a powerful model for investigating the role of other genetic loci regulating the nonspecific immunity effectors in the course of infectious diseases.

Reduced humoral immunity in uremic mice genetically selected for high antibody response

Biozzi's Selection IV-A mice, genetically selected for 25 generations for high and low antibody response to sheep red blood cells (SRBC), 2-3 months old, were made uremic by subtotal nephrectomy and characterized for antibody production against the selection antigen. T cell activity was evaluated in vitro by lymphocyte proliferation and interleukin 2 (IL 2) production in response to the superantigen staphylococcal enterotoxin B (SEB). Total and IgM antibody titers (log2) were similar in uremic and non-uremic low responder mice (total antobody: 4.0 +/- 0.6 vs 3.6 +/- 0.6; IgG: 3.0 +/- 0.7 vs 2.4 +/- 0,4), while uremic high responders presented a blunted humoral immune response to SRBC when compared with non-uremic animals (total antibody: 10.8 +/- 1.6 vs 13.0 +/- 0.2; IgG: 10.3 +/- 1.5 vs 11.7 +/- 0.3). T cell proliferation and IL 2 production were similar in uremic and ...