Jean-Claude Mevel

Basal immunoglobulin serum concentration and isotype distribution in relation to the polygenic control of antibody responsiveness in mice

Serum Ig concentration and isotype distribution were determined in the high (H) and low (L) responder lines selected for antibody response to complex immunogens. Data were recorded in normal and postimmunization sera from the H and L lines produced by five independent selective breedings (selections I, 11, III, IV, and V). Ig levels were much higher in H than in L mice of all the selections. In four selections this interline difference increased further after immunization with the selection antigens. This is in agreement with the general effect of the polygenic control of antibody responses operating in H and L lines. The Ig isotype profiles of normal sera were different in each line; however, similitudes were noticed between H and L lines in selections I and If. In contrast, in selections III, IV, and V a similar interline difference was observed: the lack of IgG2a isotype in L lines only. After immunization there were minor alterations of the isotype profiles except in the H lines of selections III and IV, in which a clear inverse modification of IgG1 and IgG2a proportions occurred. The characteristic pattern of each selection may be partially dependent on isotype-restricted regulatory effects in relation to the immunization procedure used for selective breeding.

Polymorphism of Tcrb and Tcrg genes in Biozzi mice : segregation analysis of a new Tcrg haplotype with antibody responsiveness

Tcrb andTcrg gene polymorphism was investigated in high (H) and low (L) responder Biozzi mice from selection I, II, and GS by Southern blot analysis with appropriateV andC probes. No polymorphism of theTcrb haplotype was detected between H and L mice in all selections which were all found to be of the BALB/c type. The H-I and H-II g genotype was of BALB/c and DBA/2 type, respectively. In contrast, a newTcrg haplotype shared by L-I and L-II mice was identified and characterized by Cγ1, 2, 3, Cγ4, Vγ1, 2, 3, Vγ5, and Vγ6 restriction fragment length polymorphisms (RFLPs).Tcrg genotypes were not fixed in the GS selection and two additional new haplotypes were identified in two L-GS mice. An attempt was made to correlate the L-Ig genotype with the low responder status by analyzingg haplotypes among highest and lowest responder (H-1 x L-I)F2 hybrids immunized with sheep red blood cells (SRBC). No correlation was found in this segregation study, whereas a highly significant one was established with theH-2 haplotype, a locus already known to participate in the genetic control of H-I/L-I difference. The lack of correlation between SRBC response and theTcrg genotype was consistent with the heterogenousg haplotypes found in mice of the GS selection. Together, the present results suggest that H and L mice have the sameTcrab potential repertoire and that T-cell receptor (Tcr) genes cannot be considered as immune response genes in this model. Our results also indicate that the F2 segregation analysis, given a polymorphic gene, is suitable for an investigation of its immune response functions.

Dose-dependent efficacy of vaccination against K. pneumoniae in high and low antibody responder lines of mice

Innate and acquired resistance to Klebsiella pneumoniae infection were investigated in high (HI) and low (LI) antibody responder lines of mice. The two lines were very susceptible to infection since even small inoculum doses of a virulent strain provoked a 100% mortality within a few days. However the mean survival time was significantly longer in LI than in HI. (HI X LI) F1 hybrids were more resistant than both parental lines. Immunization with heat killed K. pneumoniae was able to confer full protection on the mice in the two lines. However there was a large difference in the number of killed bacteria required to induce the protective effect in HI and in LI mice. The dose-effect relationship for protection correlated with that of antibody production. The protective role of antibodies was confirmed by the survival of HI and LI mice, when antibodies were passively given prior to lethal challenge. The results are in agreement with the fact already demonstrated, that the defect of LI mice in antibody responsiveness is a quantitative one. Therefore a satisfactory immune protection against K. pneumoniae could be obtained in LI mice by adapting the vaccination procedure.

INTERACTIONS BETWEEN H-2 AND BACKGROUND GENES MODULATE COLLAGEN INDUCED ARTHRITIS IN HIGH (HI) AND LOW (LI) ANTIBODY PRODUCER BIOZZI MICE

The experimental arthritis (collagen induced arthritis, CIA) induced in mice by heterologous collagen of type II is mainly restricted to the H-2q or H-2r haplotypes. However, data including ours, strongly suggest that CIA is also under non MHC polygenic control. This point has been studied in new sub-strains of high (HI) and low (LI) Biozzi mice made congenic for H-2q and H-2s: the original Biozzi lines HI/H-2q and LI/H-2s and the new HI/H-2s, LI/H-2q congenic mice. 80% of the HI/H-2q mice develop severe chronic inflammatory symptoms with joint deformation and swelling soon after induction of the disease, while 60% of LI/H-2q counterpart develop at a later stage, deformation of joints with no or mild swelling. In the H-2s haplotype, considered to be non or weakly permissive to CIA, 40% of HI/H-2s have strong CIA symptoms; the LI/H-2s being totally refractory. Thus, if MHC products play a crucial role in selecting the arthritogenic epitope of CII; non H-2 genes strongly modulate the severity of experimental arthritis.

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.