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M Siqueira

Publications and source records attributed to M Siqueira.

At least 19 recordsLinked to original sources
PubMed1992

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.

Acute Disease↗
PubMed1992

T-helper functions in lines of mice selected for high or low antibody production (Selection III): modulation by anti-CD4+ monoclonal antibody.

T-helper function was evaluated in mice genetically selected for high (H) or low (L) antibody (Ab) responsiveness to Salmonella flagellar antigen (Ag) (Selection III). In this Selection as opposed to what was demonstrated in Selections I, II and IVA, the interline difference was not proven to be based upon the modification of Ag processing and presentation at macrophage level. CD4+/CD8+ lymph node ratio is similar in HIII and LIII mice, both lines being equally susceptible to in vivo depletion of CD4+ T cells by GK 1-5 monoclonal antibody (mAb) treatment. Nevertheless, the Ab responsiveness of the two lines was differently modulated by GK 1-5 mAb: the inhibition of Ab responses to various Ag required lower mAb doses and was long lasting in LIII as compared to the transient effect of higher mAb doses observed in HIII. LIII mice were also refractory to Salmonella-induced reversion of GK 1-5 mAb inhibition. Moreover, in vitro specific I proliferation was constantly lower in LIII, though its IL-2 production was unexpectedly similar to that of HIII T cells. Results of in vivo and in vitro experiments are thus consistent with a defective response of T-helper cells to immunogenic challenge in LIII mice.

Animals↗
PubMed1990

Genetics of acute inflammation: inflammatory reactions in inbred lines of mice and in their interline crosses.

Acute inflammation is induced by the subcutaneous injection of swollen polyacrylamide microbeads, its intensity measured by the cell and protein concentration of the local exudates. A large and continuous range of responses is obtained in different inbred strains of mice, which suggests a polygenic control of the inflammatory response. The variable levels of the global dominance observed in F1 hybrids issued from several parental combinations indicated that the pattern of alleles controlling high or low response was different in each parental strain. Balanced intercrossing of the 8 inbred strains studied has provided a genetically heterogeneous F3 population, presenting a high variability of responses. The value of the genetic part of F3 phenotypic variance, the spread of the interstrain differences, as well as the polygenic nature of the regulation of inflammatory responses pointed out the possibility to perform a bidirectional genetic selection by using the F3 mice as the foundation population, and response to microbeads as the selective phenotypic character.

Acrylic Resins↗
PubMed1989

Salmonella typhimurium infection in high and low antibody responder mice: inverse correlation between antibody responsiveness and resistance to infection.

Susceptibility to Salmonella typhimurium infection was compared in H (high Ab responder) and L (low Ab responder) mice obtained by several selective breeding experiments (Selections I, II, III, IV and IV A). H mice were always much more susceptible to infection than their L mice counterparts within a continuous LD 50 variation range. In three of the selections (I, II and IV A) the low responsiveness character is known to result mainly from rapid Ag degradation in L mice macrophages. It was hypothesized that resistance to multiplication of intracellular pathogens could be related to an increased catabolic activity towards Ag. This was actually demonstrated, in F2 segregant hybrids of selection IV A, by the significant inverse correlation between capacity for Ab production and resistance to infection.

Animals↗
PubMed1988

Genetic regulation of multispecific antibody responsiveness: improvement of "high" and "low" characters.

The five selections carried out in the mouse for high or low antibody responsiveness to various multideterminant immunogens were successful. In all cases the large interline difference was shown to result from the additive effects of several independently segregating loci (polygenic regulation). However, important peculiarities were demonstrated in these original selections concerning either the cellular mechanisms operating or the effect of the selected genes on antibody responses to antigens unrelated with those used for the selection (multi-specific effect). In an attempt to improve and generalize the effect of selection, the 5 high and the 5 low lines were inter-crossed to obtain populations with a balanced proportion of the 5 genomes. These two populations were then submitted to selective breedings in which the phenotypic character was the weighted responses to pluri-antigen immunization. The data obtained in 16 consecutive generations of two selective breedings (general-primary, GP and general-secondary, GS, responses) carried out from these populations are reported. The genetic parameters of the response to GP and GS selections are compared with those obtained in the original selections. The final result of both GP and GS selections demonstrate a marked improvement of the high and low antibody production traits, both quantitatively (interline divergence) and qualitatively (multi-specific effect). The success of GP and GS selections agrees with the concept that distinct groups of genes are preferentially affected by selection according to the nature of the selection antigen and the immunization procedure.

Analysis of Variance↗
PubMed1988

Polygenic control of quantitative antibody responsiveness: restrictions of the multispecific effect related to the selection antigen.

Among the differences observed between the various high (H) and low (L) antibody responder lines of mice resulting from distinct bidirectional selective breedings, one of the most puzzling is the variation in the "multispecific effect," i.e., in the modification of antibody responses to antigens unrelated to those used during the selection. The best examples are the H and L lines of selection IV, selected on the basis of responses to somatic antigen of Salmonella which do not differ in their antibody responses to sheep erythrocytes (SE). However, a wide range of variability is observed in the responses of (HIV X LIV)F2 hybrids to this antigen, and it was therefore hypothesized that distinct groups of genes might regulate antibody responses to SE and the somatic antigen. Indeed, a new selection (IV-A) for anti-SE responsiveness started from these (HIV X LIV)F2 successfully produced a high and a low anti-SE responder line. The results of selection IV-A and the variance analysis of (HIV-A X LIV-A)F2 hybrids are reported. They are roughly similar to those in selection I, also carried out for anti-SE responsiveness. In vivo attempts to identify the major regulatory mechanism which contributes to the interline difference indicate that the efficiency of macrophage accessory function has been modified in selection IV-A, as was observed in selection I, whereas this function did not differ in HIV and LIV lines. Probably in relation to the involvement of macrophage function there is a notable increase of the multispecific effect in selection IV-A when compared with selection IV. The results of selection IV-A demonstrate that responsiveness to heterologous erythrocytes and to somatic antigen of Salmonella are under separate polygenic control operating through distinct regulatory mechanisms. The choice of the selection antigen and immunization procedure is of major importance for defining the gene interaction operating in each selective breeding experiment and the extent of its multispecific effect.

Animals↗
PubMed1987

Genetic regulation of the specific and non-specific component of immunity.

Bi-directional selective breeding for antibody (Ab) responsiveness to heterologous erythrocytes (Selection I) produced a high (H) and a low (L) responder line of mice which were also remarkably separated for Ab responses to many unrelated natural antigens (Ags) such as heterologous proteins, viruses, bacteria, parasites and haptens carried by these immunogens. The character "quantitative Ab responsiveness" is controlled by several independently segregating loci (polygenic regulation). The major genetic modification is produced at the level of macrophage activities. The Ag is slowly catabolized and persists for a long time on the macrophage membrane of the H line, whereas it is rapidly destroyed in L line macrophages. The bactericidal and bacteriostatic activity of the macrophage is also strong in the L line and weak in the H line. The opposite genetic regulation of Ab responsiveness and macrophage activity is a fundamental phenomenon for understanding natural and vaccination-induced anti-infectious immunity. The L line is more resistant than the H line against the infections due to intracellular microorganisms (Salmonellae, Yersinia, Mycobacteria, Brucellae, Leishmania) where the macrophage plays the dominant defensive barrier. The H line is more resistant than the L line to the extracellular microorganisms which are efficiently counteracted by a strong antibody response (Pneumococcus, Klebsiella, Plasmodia, Trypanosoma). The intensity of T cell-mediated immunity as measured by delayed type hypersensitivity, which is independent of the genetic regulation of antibody responsiveness, is correlated with the degree of nonspecific inflammation produced at the site of the reaction by the Ag injection in non-sensitized mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Potentiation of immune complex injury in rats by pretreatment with subnephrotoxic doses of guinea pig anti-glomerular basement membrane IgG1.

1. Female Wistar rats received a single subnephrotoxic dose of guinea pig anti-glomerular basement membrane (GBM) IgG1, 2.5 mg, followed by infusion of preformed immune complexes (BSA, 5.0 mg/rabbit anti-BSA, 6 mg), 10 X antigen excess. Control groups received guinea-pig IgG1 anti-GBM, or preformed immune complexes alone, or isotonic saline. Systemic reactions were observed clinically during the first 24 h, and 24 h urine was collected for the measurement of proteinuria and hematuria. 2. Blood was collected before and 2 h after the above treatment for the determination of complement (50% hemolytic assay), kininogen (isolated guinea pig assay of released bradykinin-like spasmogenic activity) and activated partial thromboplastin time (APTT). Kidney and lung tissue was examined by light microscopy, immunofluorescence and electron microscopy. 3. Rats treated with guinea pig anti-GBM IgG1 followed by BSA immune complex presented a severe systemic picture, with macroscopic hematuria (9/14), several deaths (8/14), slight proteinuria (24.6 +/- 5.2 mg/day), marked complement consumption (delta = 49.4 +/- 2.4 UCH50/ml), intravascular coagulation and severe diffuse interstitial pneumonia, obliteration of glomerular capillary walls by edema of endothelial cells, without deposition of immune complexes in kidneys or lungs. The control groups showed no signs of systemic reaction (isotonic saline alone) or slight dyspnea (guinea pig anti-GBM IgG1 or immune complexes alone), without proteinuria or macroscopic hematuria, and with foci of interstitial pneumonia. 4. Complement consumption was significant in rats receiving immune complexes alone (delta = 31.1 +/- 1.3 UCH50/ml) and even higher when associated with infusion of guinea pig anti-GBM IgG1 (delta = 49.3 +/- 2.4 UCH50/ml). APTT was significantly lengthened only for the group treated with guinea pig anti-GBM IgG1 plus immune complexes (delta = 18.5 +/- 1.9 s), with no alterations in the other groups. Kininogen consumption was demonstrable for all groups except the saline control and was more extensive in rats which received immune complexes alone or preceded by guinea pig IgG1. 5. These data show that previous infusion of a subnephrotoxic dose of guinea pig IgG1 anti-GBM aggravated the pathological effects of preformed immune complexes by promoting marked complement consumption and activation of the coagulation system, rather than by enhancing tissue deposition.

Animals↗
PubMed1986

Genetics of antibody responsiveness to bovine serum albumin and rabbit gamma-globulin. I. Genetic analysis of high and low responder lines of mice produced by selective breeding.

The selective breeding for antibody production against bovine serum albumin (BSA) and rabbit gamma-globulin (RGG) induced a large modification in responsiveness in the high (Hv) and low (Lv) responder lines at selection limit. The total response to selection (RT) was 9.0 log2 for BSA and 8.4 log2 for RGG. This gives an interline difference of 500-fold and 337-fold respectively in terms of passive agglutinin titres. For BSA responsiveness, there is, in F1 interline hybrids, an incomplete dominance effect of the low character (-0.41) and a marked maternal effect. Complete dominance effect of high character (1.08) without any maternal effect is observed for responses to RGG. The phenotypical variability of BSA responses in F2 segregants is due 60% to genetic factors and 40% to environmental effects. Such a distribution cannot be achieved for RGG responsiveness. Both responses to BSA and RGG are controlled by the additive effect of several independent loci (polygenic regulation). One of these genes is linked with the H-2 locus. The H-2 linked gene accounts for 29% of the total interline difference for response to BSA and only 11% for response to RGG. Experiments carried out to measure the reciprocal nonspecific effect of BSA and RGG responses failed to give clear-cut results. This important phenomenon will be the subject of the companion article.

Animals↗
PubMed1986

Genetics of antibody responsiveness to bovine serum albumin and rabbit gamma-globulin. II. Evidence for a partially common genetic regulation of response to bovine serum albumin and rabbit gamma-globulin.

In order to measure the reciprocal nonspecific effect of the genetic regulation of antibody responsiveness to bovine serum albumin (BSA) and rabbit gamma-globulin (RGG), two independent bidirectional selective breedings for responses to these two antigens were carried out: selection V/BSA and selection V/RGG respectively. The total interline separation at selection limit (RT) was 5.3 log2 for selection V/BSA and 2.6 log2 for selection V/RGG. The sum of these two values (7.9 log2) is similar to the RT in selection V carried out by alternating these two antigens in consecutive generations. In selection V/BSA, the nonspecific effect for responsiveness to RGG was 72%. In selection V/RGG, the nonspecific effect for BSA responsiveness was 135%. The F1 hybrids between homologous lines of selection V/BSA and selection V/RGG presented a larger difference in antibody response to both antigens than their parental lines. This demonstrates an additive effect of the loci controlling the two responses.

Animals↗
PubMed1985

Non-specific regulation of immune responsiveness to a thymus-independent antigen, TNP-LPS, in high and low responder lines of mice.

Responsiveness to a thymus-independent (TI-1) antigen, TNP-LPS, was investigated in the high and low responder lines of mice resulting from four independent selective breedings carried out for antibody production to various complex natural immunogens (selections I, III, IV and V). The superiority of the high responder vs. the low responder line was generally observed, confirming that the genes accumulated through selective breeding can modify the responsiveness to unrelated antigens including TI antigens. Two special features were observed in selection III: (1) A secondary response to TNP-LPS: higher peak values and IgG isotype antibody production were obtained in the H line. (2) Pretreatment with LPS modified the responses to TNP in the L line only.

Animals↗
PubMed1985

Effect of genetic modification of antibody responsiveness on resistance to Toxoplasma gondii infection.

Resistance to Toxoplasma gondii infection was studied in the high (H/f) and low (L/f) antibody responder lines of mice that were selected on the basis of quantitative antibody responsiveness to the flagellar antigen of Salmonella (selection III). No interline difference was observed in resistance to a highly virulent strain of T. gondii. In contrast, H/f mice were much more resistant than L/f mice to a moderately virulent strain of T. gondii: a 5000-fold difference in terms of the 50% lethal dose was found. The degree of resistance in (H/f X L/f)F1 hybrids was intermediate compared with that in parental lines for both mortality and survival time. The antibody titers to Toxoplasma antigens measured during the course of the infection were significantly higher in H/f than in L/f mice. This interline difference was underestimated because parasite multiplication occurs faster in L/f mice, which increases antigenic stimulation. The stronger resistance of H/f mice is probably due to their higher capacity of antibody production in the course of infection.

Animals↗
PubMed1985

Potentialities of immunocompetent cells in high and low antibody-producing lines of mice obtained by selective breedings for responsiveness to flagellar or somatic antigens of Salmonellae.

The genetic modifications of immunocompetent cell functions were investigated in high (H) and low (L) antibody responder lines of mice obtained by selective breeding for responsiveness to flagellar and somatic antigens of Salmonellae (Selection III and Selection IV, respectively). Several lines of evidence converge to demonstrate that the differences in antibody responses between the H and L lines of the two selections are not due to the modification of antigen handling by macrophages. This contrasts with previous observations that macrophages play a major role in interline differences in Selections I and II. The choice of antibody titres after secondary challenge as the phenotypic character in Selections III and IV may explain why the regulatory role of macrophages was minimized, compared with Selections I and II which were carried out for primary responses to heterologous erythrocytes. In Selections III and IV, H mouse lymphocytes were more efficient than L mouse lymphocytes in restoring immunoresponsiveness to irradiated hosts. In contrast, allogeneic skin grafts were rejected at a similar rate in L as well as in H mice of the two Selections and in vitro lymphoproliferative responses to T cell mitogens were also equivalent in the four lines.

Animals↗
PubMed1985

Independent polygenic regulation of quantitative antibody responsiveness and expression of delayed-type hypersensitivity (DTH).

The intensity of delayed-type hypersensitivity (DTH) expression measured by footpad swelling was established in high and low antibody responder lines of mice produced by bidirectional selective breeding for antibody responsiveness to different antigens. These lines of mice presented a very large difference in antibody response to the antigens used in each selective breeding (selection Ags) and to several other unrelated Ags (nonspecific effect). The intensity of DTH reactivity to selection Ags and to unrelated Ags differed in the various lines investigated, but the intensity of DTH reactions was not correlated with antibody responsiveness. The results of the present article demonstrated that the expression of DTH reactivity and antibody responsiveness to the same antigens are polygenic characters subject to independent quantitative regulation.

Animals↗
PubMed1979

Rabies virus immunity in genetically selected high- and low-responder lines of mice.

The antibody responsiveness to and the specific vaccination effect of rabies virus infection were investigated in high- and low-responder lines of mice produced by two-way selective breedings for quantitative production of antibodies to flagellar (H/f and L/f lines) or somatic (H/s and L/s lines) antigens of salmonellae. After specific immunization, both high lines were more resistant to rabies virus infection than were the low lines, and the protector effect was related to the level of antibody produced, as demonstrated by neutralizing serum activity. The present findings confirm the nonspecific genetic modification of the general antibody responsiveness induced in high- and low-responder lines selected for quantitative antibody production.

Animals↗
PubMed1979

Differences in the genetic control of primary and secondary antibody responses.

Primary and secondary antibody responses to f and s antigens of Salmonella typhimurium have been studied in H and L lines of mice genetically selected for primary reponse to sheep erythrocytes (SE) (Selection I). The range of interline separation obtained (non-specific effect of Selection I) was as large as for the selection antigen in the primary response to f antigen and slightly smaller in the primary response to s antigen. For these two antigens the interline difference was reduced after booster. The kinetics of responses were compared with those obtained in H and L lines of Selections III and IV carried out for secondary responses to f and s antigens of S. typhimurium respectively (specific effect of Selection III and IV). The genetic analysis was made in Selection I from the variances of individual agglutinin titres obtained in large groups of interline hybrids immunized with S. typhimurium. These calculations gave a reliable estimate of the effective number of independent loci regulating primary and secondary responses. The results demonstrated a major difference in the genetic control: a single locus regulated the secondary response to f antigen while six loci were involved in the control of the primary response. A similar difference was evident for s antigen. The primary response was likely to be under polygenic regulation although the effective number of loci could not be calculated, while the secondary response was under monogenic control.

Agglutinins↗
PubMed1977

Nonspecific genetic regulation of antibody responsiveness in the mouse.

Four lines of mice were produced by selective breeding for quantitative agglutinin responsiveness to flagellar (f) or somatic (s) antigens (Ags) of Salmonellae: high (H) or low (L) responder lines to fAg and H and L responder lines to sAg. The Salmonellae contained both f and sAgs, the Ag used to perform the selection was the Selection Ag and the other was the Associated Ag. The selective breeding produced a progressive interline separation with an equivalent effect for both Ags. After 15 generations (F15) the level of agglutinin response was about 60 times higher in H than in L responders. About 50% of the phenotypic variation of the character investigated is determined by a group of immune response genes, the rest is due to environmental factors. The nonspecific effect of this group of immune response genes was investigated by measuring the responses to three independent antigens: Sheep erythrocytes (SE), dinitrophenyl-conjugated human IgG (DNP-HGG) and bovine IgG (BGG). The selection for fAg response produced an equivalent modification in the respnsiveness to the Associated Ag (97%) and to BGG (130%). This nonspecific effect was smaller for responsiveness to SE and DNP-HGG, 58% and 41% of the Selection Ag response, respectively. The selection for sAg response produced a nonspecific modification of responsiveness of 94% for the Associated Ag of 74% for BGG and 63% for DNP-HGG. An important exception concerned SE to which an equal antibody response is produced in high and low lines of sAg selection.

Animals↗