Nephritogenicity of anti-proteoglycan antibodies in experimental murine lupus nephritis.

BACKGROUND: Cross-reactivity between anti-DNA antibodies and heparan sulfate (HS)/heparan sulfate-proteoglycan (HS-PG) of glomerular basement membrane has been previously reported. Conceivably, this determines the final outcome of glomerular injury in lupus nephritis. EXPERIMENTAL DESIGN: We investigated the status of glomerular injury in NZB/NZW F1 mice after the administration of rabbit anti-HS-PG antibody (experiment group). The controls received normal rabbit IgG only. RESULTS: All experimental animals became proteinuric 2 weeks after the administration of anti-HS-PG. The animals of the older age group (16 weeks) had significant hematuria as well. Their glomeruli exhibited hypercellularity with a heavy influx of polymorphonuclear leukocytes and monocytes into their capillaries, and some of them exhibited crescentic changes. Electron-dense deposits were present in subepithelial, subendothelial, and mesangial regions of the glomeruli. The control group had normocellular glomeruli with a few mesangial deposits. Mouse IgG and C3 displayed a granular pattern of immunofluorescence in the experimental group. Anti-rabbit IgG titers in the serum were higher in the control group, which lower in the renal glomerular eluates. No significant differences were observed in the concentrations of anti-dsDNA and -ssDNA either in the sera or in the eluates. There was also no difference between the control and experimental group in terms of antibody synthesis by the splenic lymphocytes and their proliferation subsequent to antigenic challenge. CONCLUSIONS: Data suggest that administration of anti-HS-PG accentuates the glomerular injury during the natural course of lupus nephritis in (NZB/NZW F1 mice; seemingly these two antibodies (anti-HS-PG and -DNA) do not competitively inhibit the binding of the other to the same anionic sites of glomerular basement membrane enriched with heparan sulfate in vivo.

Effects of long-term treatment of mice with anti-I-J monoclonal antibody and dialyzable leukocyte extract on immune function and lifespan.

In 1969 Walford hypothesized that age-related dysfunctions of the immune system may be involved in the pathogenesis of the lesions and disease of aging. Studies were initiated to test whether immunologic interventions intended to maintain the integrity of the immune system would delay the onset of diseases of aging and prolong lifespan. Adult BC3F1 mice were treated with anti-I-J monoclonal antibody, with human dialyzable leukocyte extract, or with saline once a week for one year. Spleen cells from the mice were then assayed for suppressor, T-helper and B-cell activity. Treatment with dialyzable leukocyte extract decreased the elevated nonspecific suppressor activity. Mice treated with anti-I-J antibody had elevated T-helper cell activity. In another experiment, mice were treated weekly with anti-I-J antibody, dialyzable leukocyte extract, or saline from 18 months of age until natural death. The mice were immunized with avian gammaglobulin at 27 and again at 29 months of age. Both types of immunologic intervention resulted in a greater secondary antibody response than that of the saline-treated control mice. Mice treated with anti-I-J antibody survived longer than did mice of the other two groups. There was a correlation between the magnitude of the secondary response of individual mice and their lifespan. The results provide support for the immunologic theory of aging.

The role of I-J and Igh determinants on F1-derived suppressor factor in controlling restriction specificity.

In the 4-hydroxy-3-nitrophenyl acetyl (NP) contact sensitivity system, the activity of third-order suppressor cells and their factors is restricted by H-2(I-J) and Igh linked genes. The present report analyzes the specificity of NP-specific Ts3 cells and factors derived from H-2 and Igh heterozygous (B6 X C3H)F1 mice. Two approaches were used. First, heterogeneous populations of F1 Ts3 cells were activated in vitro and then assayed in Ts3-depleted recipients which carried different combinations of H-2 and Igh alleles. The second approach was to hybridize the Ts3 cells and analyze the specificity of the F1-derived TsF3. The combined data demonstrated four functionally distinct populations of Ts3 cells. The activity of each population was restricted by a particular combination of H-2 and Igh haplotypes. Thus, Ts3 cells derived from F1 donors can demonstrate an apparent scrambling of H-2 and Igh restriction specificities. There was functional allelic exclusion of the H-2(I-J) and Igh determinants expressed on (B6 X C3H)F1 hybridoma-derived TsF3. Thus, TsF3 from each cloned hybridoma line expressed only one set of I-J and Igh determinants. Furthermore, there was a complete correlation between the I-J and Igh linked determinants expressed on TsF3 and the restriction specificity. In view of the recent findings on the molecular biology of the I-J region, an alternative interpretation of the role of I-J determinants on suppressor cells and factors is offered.

Evidence for two suppressor factors secreted by a single cell suggests a solution to the J-locus paradox.

The hybridoma produced by the fusion of lactate dehydrogenase-B (LDH-B)-primed B10.A(2R) mouse suppressor T (Ts) cells with the BW5147 thymoma secretes two kinds of T suppressor factors (TsF), TsF-A and TsF-E. The TsF-A suppresses A beta-restricted and the TsF-E, E beta-restricted helper T (Th) cells. Each of the two factors consists of two polypeptide chains, an antigen-binding chain (ABC) and a major histocompatibility complex (MHC) chain. The ABC binds LDH-B, which is then recognized by one of the two receptors of the Th cell and an antigen bridge is formed between the factor and the Th cell. This chain is presumably identical in both factors. The MHC chain of the TsF-A carries antigenic determinants recognized by three sets of monoclonal antibodies: antibodies specific for the A beta chain, antibodies specific for class II determinants expressed in T cells and controlled by the A beta-E beta chromosomal segment, and antibodies crossreacting with J determinants. The MHC chain of the TsF-E carries determinants recognized by E beta-specific and by J-specific antibodies. Only some of these serologically detectable determinants reside in the region of the TsF molecule recognized by Th cells. These findings suggest that the J determinants are carried by the modified E beta and also by the modified A beta chains.

Antibody production in organ culture by bursae of mature chickens and the development of immunological compentence.

Antibody responsiveness of bursal lymphocytes was studied in vitro. Organ culture of bursal tissue in the presence of antigen, either sheep erythrocytes or bovine serum albumin, results in significant numbers of plaque-forming cells (PFC) compared to controls. The response in organ culture is age-dependent in that only bursae from chickens at least three weeks of age contained significantly increased numbers of secreting cells. Prolonged culture of normally unresponsive bursae from newly hatched birds results in a PFC response to antigen, suggesting that in vitro maturation occurs.