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.

Functional differences in the specific B-cell compartment in high or low antibody responder mice.

The role of antigen-presenting cells (APC) in quantitative antibody synthesis regulation was studied in mice genetically selected for high (HI) or low (LI) antibody response. Irradiated spleen cells and enriched specific B cells from HI and LI mice co-isogenic at H-2s locus, were compared for their capacity to present chicken ovalbumin (OVA) to specific T-cell hybridomas. Minor differences were observed between HI and LI mice when three distinct hybridomas were stimulated in the presence of OVA and splenic macrophages APC. These differences were totally abolished when APC were pulsed with OVAxAb complexes. Looking at the B-cell compartment, hybridoma IL-2 responses were similar when TNP primed B cells were pulsed with OVA. However, when OVA was targeted on TNP-specific enriched B cells by pulsing with TNP-OVA, the IL-2 production by the T-cell hybridomas was stronger in the presence of HI B cells than in the presence of LI B cells. These results strongly suggest that an efficient Ag handling/processing by specific B cells is a major component of the high Ab responder status in Biozzi mice.

T helper subset involvement in two high antibody responder lines of mice (Biozzi mice): HI (susceptible) and HII (resistant) to collagen-induced arthritis.

CD4+ T helper cells play a critical role in the chronicity of collagen-induced arthritis (CIA) in mice. The present results focus on the involvement of Th1 and Th2 subsets at the initial stage of the experimental disease in two lines of mice selected for high antibody production: HI that is susceptible, and HII that is resistant to CIA. Both lines are known to be H-2q, display an identical full set of V-beta genes, and mount similar antibody responses to both heterologous and autologous CII. The kinetic analysis of local T cell and anti-bovine CII antibody responses was followed by Elispot assays, the production of interferon-gamma (IFN-gamma) and IgG2a being considered indicative of a Th1 profile, and interleukin-5 (IL-5) as well as IgG1-IgE, of a Th2 profile. The number of IL-5 Elispots is constantly higher in susceptible than in resistant mice. The IFN-gamma production is rather low in HI compared to HII, and besides, preferential help is observed for the Th2-dependent IgG1-IgE isotype-producing B cells in HI, while a switch-over toward IgG2a anti-CII isotype is found in HII. These results suggest that a Th1 preeminence at the onset of the anti-CII response is decisive in the resistance to CIA.