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Brian L Kotzin

Publications and source records attributed to Brian L Kotzin.

At least 19 recordsLinked to original sources
PubMed2006

Increased expression of Ifi202, an IFN-activatable gene, in B6.Nba2 lupus susceptible mice inhibits p53-mediated apoptosis.

Increased expression of p202 protein (encoded by the Ifi202 gene) in splenocytes derived from B6.Nba2 mice (congenic for the Nba2 interval derived from the New Zealand Black mice) was correlated with defects in apoptosis of splenic B cells and increased susceptibility to develop systemic lupus erythematosus. We have now investigated the molecular mechanisms by which increased expression of p202 in B6.Nba2 cells contributes to defects in apoptosis. In this study, we report that increased expression of p202 in the B6.Nba2 splenocytes, as compared with cells derived from the parental C57BL/6 (B6) mice, was correlated with increased levels of p53 protein and inhibition of p53-mediated transcription of target genes that encode proapoptotic proteins. Conversely, knockdown of p202 expression in B6.Nba2 cells resulted in stimulation of p53-mediated transcription. We found that p202 bound to p53 in the N-terminal region (aa 44-83) comprising the proline-rich region that is important for p53-mediated apoptosis. Consistent with the binding of p202 to p53, increased expression of p202 in B6.Nba2 mouse embryonic fibroblasts inhibited UV-induced apoptosis. Taken together, our observations support the idea that increased expression of p202 in B6.Nba2 mice increases the susceptibility to develop lupus, in part, by inhibiting p53-mediated apoptosis.

Animals↗
PubMed2006

Contribution of NZB autoimmunity 2 to Y-linked autoimmune acceleration-induced monocytosis in association with murine systemic lupus.

The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of the Y-linked autoimmune acceleration (Yaa) mutation, which induces an age-dependent monocytosis. Using a cohort of C57BL/6 (B6) x (NZB x B6)F1 backcross male mice bearing the Yaa mutation, we defined the pathogenic role and genetic basis for Yaa-associated monocytosis. We observed a remarkable correlation of monocytosis with autoantibody production and subsequent development of lethal lupus nephritis, indicating that monocytosis is an additional useful indicator for severe SLE. In addition, we identified an NZB-derived locus on chromosome 1 predisposing to the development of monocytosis, which peaked at Fcgr2b encoding FcgammaRIIB and directly overlapped with the previously identified NZB autoimmunity 2 (Nba2) locus. The contribution of Nba2 to monocytosis was confirmed by the analysis of Yaa-bearing B6 mice congenic for the NZB-Nba2 locus. Finally, we observed a very low-level expression of FcgammaRIIB on macrophages bearing the NZB-type Fcgr2b allele, compared with those bearing the B6-type allele, and the development of monocytosis in FcgammaRIIB haploinsufficient B6 mice carrying the Yaa mutation. These data suggest that the Nba2 locus may play a supplementary role in the pathogenesis of SLE by promoting the development of monocytosis and the activation of effector cells bearing stimulatory FcgammaR, in addition to its implication in the dysregulated activation of autoreactive B cells.

Alleles↗
PubMed2005

Beryllium presentation to CD4+ T cells is dependent on a single amino acid residue of the MHC class II beta-chain.

Chronic beryllium disease (CBD) is characterized by a CD4+ T cell alveolitis and granulomatous inflammation in the lung. Genetic susceptibility to this disease has been linked with HLA-DP alleles, particularly those possessing a glutamic acid at position 69 (Glu69) of the beta-chain. However, 15% of CBD patients do not possess a Glu69-containing HLA-DP allele, suggesting that other MHC class II alleles may be involved in disease susceptibility. In CBD patients without a Glu69-containing HLA-DP allele, an increased frequency of HLA-DR13 alleles has been described, and these alleles possess a glutamic acid at position 71 of the beta-chain (which corresponds to position 69 of HLA-DP). Thus, we hypothesized that beryllium presentation to CD4+ T cells was dependent on a glutamic acid residue at the identical position of both HLA-DP and -DR. The results show that HLA-DP Glu69- and HLA-DR Glu71-expressing molecules are capable of inducing beryllium-specific proliferation and IFN-gamma expression by lung CD4+ T cells. Using fibroblasts expressing mutated HLA-DP2 and -DR13 molecules, beryllium recognition was dependent on the glutamic acid at position 69 of HLA-DP and 71 of HLA-DR, suggesting a critical role for this amino acid in beryllium presentation to Ag-specific CD4+ T cells. Thus, these results demonstrate that a single amino acid residue of the MHC class II beta-chain dictates beryllium presentation and potentially, disease susceptibility.

Alleles↗
PubMed2005

Effects of MHC and gender on lupus-like autoimmunity in Nba2 congenic mice.

The lupus-like disease that develops in hybrids of NZB and NZW mice is genetically complex, involving both MHC- and non-MHC-encoded genes. Studies in this model have indicated that the H2d/z MHC type, compared with H2d/d or H2z/z, is critical for disease development. C57BL/6 (B6) mice (H2b/b) congenic for NZB autoimmunity 2 (Nba2), a NZB-derived susceptibility locus on distal chromosome 1, produce autoantibodies to nuclear Ags, but do not develop kidney disease. Crossing B6.Nba2 to NZW results in H2b/z F1 offspring that develop severe lupus nephritis. Despite the importance of H2z in past studies, we found no enhancement of autoantibody production or nephritis in H2b/z vs H2b/b B6.Nba2 mice, and inheritance of H2z/z markedly suppressed autoantibody production. (B6.Nba2 x NZW)F1 mice, compared with MHC-matched B6.Nba2 mice, produced higher levels of IgG autoantibodies to chromatin, but not to dsDNA. Although progressive renal damage with proteinuria only occurred in F1 mice, kidneys of some B6.Nba2 mice showed similar extensive IgG and C3 deposition. We also studied male and female B6.Nba2 and F1 mice with different MHC combinations to determine whether increased susceptibility to lupus among females was also expressed within the context of the Nba2 locus. Regardless of MHC or the presence of NZW genes, females produced higher levels of antinuclear autoantibodies, and female F1 mice developed severe proteinuria with higher frequencies. Together, these studies help to clarify particular genetic and sex-specific influences on the pathogenesis of lupus nephritis.

Animals↗
PubMed2005

Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response.

Beryllium exposure can lead to the development of beryllium-specific CD4+ T cells and chronic beryllium disease (CBD), which is characterized by the presence of lung granulomas and a CD4+ T cell alveolitis. Studies have documented the presence of proliferating and cytokine-secreting CD4+ T cells in blood of CBD patients after beryllium stimulation. However, some patients were noted to have cytokine-secreting CD4 T cells in blood in the absence of beryllium-induced proliferation, and overall, the correlation between the 2 types of responses was poor. We hypothesized that the relative proportion of memory T cell subsets determined antigen-specific proliferation. In most CBD patients, the majority of beryllium-specific CD4+ T cells in blood expressed an effector memory T cell maturation phenotype. However, the ability of blood cells to proliferate in the presence of beryllium strongly correlated with the fraction expressing a central memory T cell phenotype. In addition, we found a direct correlation between the percentage of beryllium-specific CD4+ T(EM) cells in blood and T cell lymphocytosis in the lung. Together, these findings indicate that the functional capability of antigen-specific CD4+ T cells is determined by the relative proportion of memory T cell subsets, which may reflect internal organ involvement.

Aged↗
PubMed2005

Oligoclonal CD4+ T cells in the lungs of patients with severe emphysema.

RATIONALE: Within the lungs of patients with severe emphysema, inflammation continues despite smoking cessation. Foci of T lymphocytes in the small airways of patients with emphysema have been associated with disease severity. Whether these T cells play an important role in this continued inflammatory response is unknown. OBJECTIVE: The aim of this study was to determine if T cells recruited to the lungs of subjects with severe emphysema contain oligoclonal T-cell populations, suggesting their accumulation in response to antigenic stimuli. METHODS: Lung T-cell receptor (TCR) Vbeta repertoire from eight patients with severe emphysema and six control subjects was evaluated at the time of tissue procurement (ex vivo) and after 2 weeks of culture with interleukin 2 (in vitro). Junctional region nucleotide sequencing of expanded TCR-Vbeta subsets was performed. RESULTS: No significantly expanded TCR-Vbeta subsets were identified in ex vivo samples. However, T cells grew from all emphysema (n = 8) but from only one of the control lung samples (n = 6) when exposed to interleukin 2 (p = 0.0013). Within the cultured cells, seven major CD4-expressing TCR-Vbeta subset expansions were identified from five of the patients with emphysema. These expansions were composed of oligoclonal populations of T cells that had already been expanded in vivo. CONCLUSION: Severe emphysema is associated with inflammation involving T lymphocytes that are composed of oligoclonal CD4+ T cells. These T cells are accumulating in the lung secondary to conventional antigenic stimulation and are likely involved in the persistent pulmonary inflammation characteristic of severe emphysema.

Adult↗
PubMed2005

Identification of 2 major loci linked to autoimmune hemolytic anemia in NZB mice.

Using a cohort of C57BL/6 (B6) x (NZB x B6)F1 backcross male mice bearing the Yaa (Y-linked autoimmune acceleration) mutation, we mapped and characterized the NZB-derived susceptibility loci predisposing to the development of autoimmune hemolytic anemia (AHA). Our analysis identified 2 major loci on NZB chromosome 7 and chromosome 1 linked with Coombs antierythrocyte autoantibody production, and their contributions were confirmed by the analysis of B6.Yaa mice (B6 mice bearing the Yaa mutation) congenic for each NZB-derived susceptibility interval. A newly identified Aia3 (autoimmune anemia 3) locus present on NZB chromosome 7 selectively regulated Coombs antibody responses, while the second locus, directly overlapping with Nba2 (NZB autoimmunity 2) on chromosome 1, promoted the development of AHA, likely as part of its effect on overall production of lupus autoantibodies. A higher incidence of Coombs antibody production in B6.Aia3 congenic mice (B6 mice bearing the NZB-Aia3 locus) than B6.Nba2 mice (B6 mice bearing the NZB-Nba2 locus) indicated a major role for Aia3 in AHA. Notably, lack of expansion of B1 cells in B6.Aia3 congenic mice argued against the involvement of this subset in AHA. Finally, our analysis of BC mice also demonstrated the presence of a B6-derived H2-linked locus on chromosome 17 that apparently regulated the production of Coombs antibodies as a result of its overall autoimmune promoting effect.

Anemia, Hemolytic, Autoimmune↗
PubMed2005

Activation pathways implicate anti-HLA-DP and anti-LFA-1 antibodies as lead candidates for intervention in chronic berylliosis.

CD4(+) T cells play a key role in granulomatous inflammation in the lung of patients with chronic beryllium disease. The goal of this study was to characterize activation pathways of beryllium-responsive bronchoalveolar lavage (BAL) CD4(+) T cells from chronic beryllium disease patients to identify possible therapeutic interventional strategies. Our results demonstrate that in the presence of APCs, beryllium induced strong proliferation responses of BAL CD4(+) T cells, production of superoptimal concentrations of secreted proinflammatory cytokines, IFN-gamma, TNF-alpha,and IL-2, and up-regulation of numerous T cell surface markers that would promote T-T Ag presentation. Ab blocking experiments revealed that anti-HLA-DP or anti-LFA-1 Ab strongly reduced proliferation responses and cytokine secretion by BAL CD4(+) T cells. In contrast, anti-HLA-DR or anti-OX40 ligand Ab mainly affected beryllium-induced proliferation responses with little impact on cytokines other than IL-2, thus implying that nonproliferating BAL CD4(+) T cells may still contribute to inflammation. Blockade with CTLA4-Ig had a minimal effect on proliferation and cytokine responses, confirming that activation was independent of B7/CD28 costimulation. These results indicate a prominent role for HLA-DP and LFA-1 in BAL CD4(+) T cell activation and further suggest that specific Abs to these molecules could serve as a possible therapy for chronic beryllium disease.

Antibodies, Monoclonal↗
PubMed2005

Differential role of three major New Zealand Black-derived loci linked with Yaa-induced murine lupus nephritis.

By assessing the development of Y-linked autoimmune acceleration (Yaa) gene-induced systemic lupus erythematosus in C57BL/6 (B6) x (New Zealand Black (NZB) x B6.Yaa)F(1) backcross male mice, we mapped three major susceptibility loci derived from the NZB strain. These three quantitative trait loci (QTL) on NZB chromosomes 1, 7, and 13 differentially regulated three different autoimmune traits: anti-nuclear autoantibody production, gp70-anti-gp70 immune complex (gp70 IC) formation, and glomerulonephritis. Contributions to the disease traits were further confirmed by generating and analyzing three different B6.Yaa congenic mice, each carrying one individual NZB QTL. The chromosome 1 locus that overlapped with the previously identified Nba2 (NZB autoimmunity 2) locus regulated all three traits. A newly identified chromosome 7 locus, designated Nba5, selectively promoted anti-gp70 autoantibody production, hence the formation of gp70 IC and glomerulonephritis. B6.Yaa mice bearing the NZB chromosome 13 locus displayed increased serum gp70 production, but not gp70 IC formation and glomerulonephritis. This locus, called Sgp3 (serum gp70 production 3), selectively regulated the production of serum gp70, thereby contributing to the formation of nephritogenic gp70 IC and glomerulonephritis, in combination with Nba2 and Nba5 in NZB mice. Among these three loci, a major role of Nba2 was demonstrated, because B6.Yaa Nba2 congenic male mice developed the most severe disease. Finally, our analysis revealed the presence in B6 mice of an H2-linked QTL, which regulated autoantibody production. This locus had no apparent individual effect, but most likely modulated disease severity through interaction with NZB-derived susceptibility loci.

Animals↗
PubMed2005

Class II major histocompatibility complex-peptide tetramer staining in relation to functional avidity and T cell receptor diversity in the mouse CD4(+) T cell response to a rheumatoid arthritis-associated antigen.

OBJECTIVE: Although studies have suggested that human cartilage (HC) gp-39 may be an antigen recognized by autoreactive CD4(+) T cells in rheumatoid arthritis, we previously failed to identify specific CD4(+) T cells in patients' synovial fluid or blood using a class II major histocompatibility complex-peptide tetramer composed of the immunodominant HC gp-39(263-275) epitope covalently linked to DR4. We undertook this study to better understand the parameters for specific binding of this tetramer. METHODS: DR4-transgenic mice were immunized with the HC gp-39 peptide, and a set of peptide-responsive hybridomas was derived. Hybridomas were stained with the DR4-gp-39 tetramer and cultured with increasing amounts of peptide in the presence of DR4-expressing antigen-presenting cells to determine functional avidity. RESULTS: Great variability was apparent in the ability of the tetramer to stain the hybridomas, and there was a strong correlation between the intensity of tetramer staining and functional avidity. Importantly, nearly 30% of the hybridomas did not stain with tetramer, and these cells exhibited relatively low functional avidity. Although the addition of an anti-T cell receptor (anti-TCR) monoclonal antibody during the staining procedure enhanced binding of the tetramer to a number of the hybridomas, a significant percentage remained unstainable. Analysis of TCR expression showed that >90% of the hybridomas expressed the same TCR beta-chain variable region (V(beta)10), and sequencing of the TCR junctional regions showed diversity in the third complementarity-determining region. CONCLUSION: These results suggest that immune responses dominated by relatively low-affinity TCR interactions, such as those that may occur in autoimmune disease, will be difficult to detect using standard tetramer techniques.

Animals↗
PubMed2005

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus.

OBJECTIVE: To determine whether overexpression of BAFF can accelerate the development of systemic lupus erythematosus-associated end-organ disease in hosts with an underlying autoimmune diathesis. METHODS: We introduced a BAFF transgene (Tg) into autoimmune-prone B6.Sle1 and B6.Nba2 mice and evaluated these mice for serologic autoimmunity and renal pathology. RESULTS: B6.Sle1.BAFF and B6.Nba2.BAFF mice, but not non-Tg littermates, frequently developed severe glomerular pathology by 3 months of age. Age-matched B6.BAFF mice, despite renal Ig deposits and increases in B cells and Ig production similar to those in B6.Sle1.BAFF and B6.Nba2.BAFF mice, did not develop glomerular pathology. In B6.Sle1.BAFF and B6.Nba2.BAFF mice, severity of glomerular disease did not obligately correlate with circulating levels of IgG anti-chromatin and/or anti-double-stranded DNA antibodies or with amounts of these autoantibodies deposited in the kidneys. Even in mice with severe glomerular disease, renal tubulointerstitial infiltrates were very limited, and increased proteinuria was not detected. CONCLUSION: BAFF-driven effects on glomerular pathology may be mediated, at least in part, by autoantibodies with specificities other than chromatin and/or by autoantibody-independent means. There is an uncoupling of BAFF-driven precocious glomerular pathology from concomitant development of clinically apparent renal disease, strongly suggesting that BAFF overexpression works in concert with other factors to promote overt renal disease.

Animals↗
PubMed2005

Selective expansion of a monocyte subset expressing the CD11c dendritic cell marker in the Yaa model of systemic lupus erythematosus.

OBJECTIVE: Monocytosis is a unique cellular abnormality associated with the Yaa (Y-linked autoimmune acceleration) mutation. The present study was designed to define the cellular mechanism responsible for the development of monocytosis and to characterize the effect of the Yaa mutation on the development of monocyte subsets. METHODS: We produced bone marrow chimeras reconstituted with a mixture of Yaa and non-Yaa bone marrow cells bearing distinct Ly-17 alloantigens, and determined whether monocytes of Yaa origin became dominant. Moreover, we defined the 2 major inflammatory (Gr-1+,CD62 ligand [CD62L]+) and resident (Gr-1-,CD62L-) subsets of blood monocytes in aged BXSB Yaa male mice, as compared with BXSB male mice lacking the Yaa mutation. RESULTS: Analysis of the Ly17 allotype of blood monocytes in chimeric mice revealed that monocytes of both Yaa and non-Yaa origin were similarly involved in monocytosis. Significantly, the development of monocytosis paralleled a selective expansion of the resident monocyte subset compared with the inflammatory subset, and the former expressed CD11c, a marker of dendritic cells. Neither monocytosis nor the change in monocyte subpopulations, including CD11c expression, was observed in Yaa-bearing C57BL/6 mice, in which systemic lupus erythematosus (SLE) fails to develop. CONCLUSION: Our results suggest that Yaa-associated monocytosis is not attributable to an intrinsic abnormality in the growth potential of monocyte lineage cells bearing the Yaa mutation and that the Yaa mutation could lead to the expansion of dendritic cells, thereby contributing to the accelerated development of SLE.

Animals↗
PubMed2005

Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia.

Biliary atresia (BA) is an inflammatory cholangiopathy of infancy. A proposed mechanism regarding the pathogenesis of BA is that of a virus-induced, immune-mediated injury to bile ducts. The rotavirus (RRV)-induced murine model of BA was utilized to determine the hepatic inflammatory response related to ductal obstruction and if the immune response recapitulated human BA. One week after infection, there was a significant increase in liver CD4(+) T cells producing IFN-gamma and in macrophages producing TNF-alpha. The intrahepatic pattern of inflammation evolved rapidly from an initial predominant CD4(+) Th1 cellular response to a subsequent influx of activated macrophages producing TNF-alpha and iNOS. This immune response persisted despite viral clearance and was representative of the hepatic immune profile present in human BA. Utilization of the murine model of BA yielded mechanistic data that can provide much needed insight into the role played by different arms of the immune system related to the pathogenesis of human BA.

Animals↗
PubMed2005

Frequency of beryllium-specific, TH1-type cytokine-expressing CD4+ T cells in patients with beryllium-induced disease.

BACKGROUND: Beryllium sensitization is caused by exposure to beryllium in the workplace. A subset of beryllium-sensitized (BeS) subjects progress to chronic beryllium disease (CBD), a disorder characterized by a CD4+ T-cell alveolitis and granulomatous inflammation. Whether biomarkers are present in blood that would allow separation of CBD from beryllium sensitization without invasive pulmonary procedures is unknown. OBJECTIVE: The aim of this study was to determine whether the quantity of beryllium-specific T cells in blood of patients with CBD differs from that found in BeS subjects. METHODS: Beryllium-induced T-cell proliferation and T H 1-type cytokine secretion were determined in blood cells from 33 patients with CBD and 18 BeS subjects. RESULTS: We demonstrate here that patients with CBD have a significantly elevated number of IFN-gamma-producing and IL-2-producing beryllium-specific CD4+ T cells in blood compared with both BeS and normal control subjects. In contrast, no difference in beryllium-induced proliferation of blood T cells was seen between BeS patients and patients with CBD. Compared with the blood beryllium lymphocyte proliferation test, which detected beryllium-induced proliferation in 65% of BeS patients and patients with CBD, ELISPOT analysis detected IFN-gamma secretion in 80% of these subjects. Higher numbers of beryllium-specific cells in blood were also associated with the extent of alveolar inflammation, as measured by both bronchoalveolar lavage white blood cell and lymphocyte counts. CONCLUSION: The frequency of beryllium-specific T cells in the blood of beryllium-exposed subjects may be a useful biomarker that helps discriminate between beryllium sensitization and progression to CBD.

Adult↗
PubMed2005

The role of B cells in the pathogenesis of rheumatoid arthritis.

The classical paradigm for rheumatoid arthritis (RA) pathogenesis holds that CD4+ T cells mediate joint damage both directly and by driving non-T effector cells to release inflammatory cytokines. By contrast, the new paradigm that is developing centers on an interaction of CD4+ T cells with B cells. Evidence reviewed in this article shows that autoreactive B cells can be driven by the T cells to produce IgG autoantibodies that may be directly involved in joint damage, and B cells are known to be critical in activating CD4+ T cells. As the B cell appears to play an important role in the RA process, it is appropriate to consider how B cell-mediated effects might be reduced or prevented in patients with this disease. As the targeted depletion of B cells with a monoclonal antibody such as rituximab appears to be clinically effective in RA patients, this approach shows great therapeutic potential.

Animals↗
PubMed2004

Biliary atresia is associated with CD4+ Th1 cell-mediated portal tract inflammation.

A proposed mechanism in the pathogenesis of biliary atresia involves an initial virus-induced, progressive T cell-mediated inflammatory obliteration of bile ducts. The aim of this study was to characterize the inflammatory environment present within the liver of infants with biliary atresia to gain insight into the role of a primary immune-mediated process versus a nonspecific secondary response to biliary obstruction. Frozen liver tissue obtained from patients with biliary atresia, neonatal giant cell hepatitis, total parenteral nutrition (TPN)-related cholestasis, choledochal cysts, and normal control subjects was used for fluorescent immunohistochemistry studies of cellular infiltrates, cytokine mRNA expression, and in situ hybridization for localization of cytokine-producing cells. Immunohistochemistry revealed increases in CD8(+) and CD4(+) T cells and Kupffer cells (CD68(+)) in the portal tracts of biliary atresia. Reverse transcription-PCR analysis of biliary atresia tissue showed a Th1-type cytokine profile with expression of IL-2, interferon-gamma, tumor necrosis factor-alpha, and IL-12. This profile was not seen in normal, neonatal hepatitis or choledochal cyst livers but was present in TPN-related cholestasis. In situ hybridization revealed that the Th1 cytokine-producing cells were located in the portal tracts in biliary atresia and in the parenchyma of TPN-related cholestasis. A distinctive portal tract inflammatory environment is present in biliary atresia, involving CD4(+) Th1 cell-mediated immunity. The absence of similar inflammation in other pediatric cholestatic conditions suggests that the portal tract inflammation in biliary atresia is not a secondary response to cholestasis but rather indicates a specific immune response involved in the pathogenesis of biliary atresia.

Bile Ducts, Extrahepatic↗
PubMed2004

A novel locus regulates both retroviral glycoprotein 70 and anti-glycoprotein 70 antibody production in New Zealand mice when crossed with BALB/c.

Lupus-prone New Zealand Black and New Zealand White mice produce high serum levels of the endogenous retroviral envelope protein gp70 and develop an Ab response to this autoantigen as part of their autoimmune disease. Linkage analysis of two crosses involving New Zealand and BALB/c mice mapped these traits to a group of overlapping loci, including a novel locus on proximal chromosome 12. This locus was linked with serum gp70 and the autoimmune response against it. The linkage of serum gp70 levels to a previously described locus on distal chromosome 4 was also confirmed. Sequence analysis of a candidate gene on distal chromosome 4, Fv1, provided support that this gene may be associated with the control of serum gp70 levels in both New Zealand Black and New Zealand White mice. Linkage data and statistical analysis confirmed a close correlation between gp70 Ag and anti-gp70 Ab levels, and together gave support to the concept that a threshold level of gp70 is required for the production of anti-gp70 Abs. Serum levels of anti-gp70 Abs were closely correlated with the presence of renal disease, more so than anti-dsDNA Abs. Understanding the genetic basis of this complex autoantigen-autoantibody system will provide insight into the pathogenesis of lupus in mice, which may have implications for human disease.

Animals↗