Levels Of IgG Autoantibodies Research Articles

Serologic follow-up of children born to mothers with Ro/SSA autoantibodies

Neonatal lupus erythematosus (NLE) develops in foetuses of mothers with Ro/SSA and La/SSB antibodies and may include foetal atrioventricular block and dermatologic manifestations. In this study, we investigated postnatal Ro and La IgG, IgA and IgM antibody levels up to 1 year of age in 32 children born to Ro/SSA positive mothers. Antibody levels were correlated with NLE manifestations, and the role of breast feeding in transfer of autoantibodies from mother to child was evaluated. Ro52, Ro60 and La IgG antibodies all transferred from the mothers to their foetus in utero and were present in the infant at birth as detected by enzyme-linked immunosorbent assay using recombinant antigens and a synthetic peptide. A significant decrease in Ro52, Ro60 and La IgG autoantibody levels of the infants was observed from birth to 4-5 weeks of age (P < 0.05, P < 0.05 and P < 0.01). Ro- and La-specific IgA and IgM antibodies were detected in the serum from a subset of mothers. However, Ro- and La-specific IgA and IgM antibody levels were low or non-detectable in children raised both with and without breastfeeding. Furthermore, NLE skin lesions developed independently of breastfeeding. Our findings support a role for placental materno-foetal transfer of IgG autoantibodies in the pathogenesis of NLE and indicate that refraining from breastfeeding does not protect from NLE skin involvement.

Prospective Study on Autoantibodies Against Apolipoprotein H (β2GPI) in Several Clinical Parameters From Patients With Terminal Renal Failure and Functioning Renal Transplants

Renal transplantation is the best therapeutic option for patients with end-stage renal disease. However, long-term results have not been very encouraging because of patient deaths due to cardiovascular disease and chronic transplant nephropathy (CTN), which includes vascular damage similar to arteriosclerosis injury. Several autoantibodies have been related to vasculopathy in the transplant such as anti-beta2GPI IgA, IgG, and IgM autoantibodies. We analyzed the levels of these autoantibodies among a cohort of 176 transplant recipients and a control group of 80 healthy subjects using enzyme-linked immunosorbent assay (ELISA). We collected data concerning the cardiovascular status of the patients, such as age, sex, diabetes mellitus, biopsy-confirmed CTN, schemic cardiopathy, cholesterol, triglycerides, and renal status by Modification of Diet in Renal Disease (MDRD) clearance and proteinuria. We also selected other characteristics, including hepatitis C virus infection and systolic/diastolic arterial pressures. The proportion of patients with high levels of IgG and IgM anti-beta2GPI autoantibodies did not differ from that observed in the control group, whereas the difference became significant in the case of anti-beta2GPI IgA autoantibodies (19.88% vs 1%). These results for the presence of anti-beta2GPI IgA autoantibodies were related to clinical data through a multivariate analysis, where the only parameter influenced by the presence of these autoantibodies seemed to be proteinuria, which in most cases was due to CTN.

Autoantibody profile against retinal proteins in patients with age-related macular degeneration and possible role in neovascularization (137.13)

Abstract Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the United States and in other developed countries. Recent findings indicate that circulating autoantibodies specific for retinal proteins and macular deposits, drusen, are associated with AMD pathogenesis, yet only a few antibodies have been identified in sera from patients with AMD. In order to reveal an autoantibody profile for AMD, we performed an antigen microarray with constituents of drusen and liquid chromatography and tandem mass spectrometry analysis following two-dimensional immunoblot analysis with retinal proteins using serum samples from patients with AMD and healthy controls. Sera from the AMD group contained high levels of IgG autoantibodies against numerous ocular antigens including lipoproteins and collagen when compared to the normal group. Moreover, IgGs purified from sera of AMD patients induced more tube formation on choroidal-retinal endothelial cells and increased VEGF production on monocytes compared to those of healthy donors. Our data suggest that these IgG autoantibodies may be used as biomarkers for AMD and contribute to progression of this disease.

Circulating levels of autoantibodies to oxidized low-density lipoprotein and C-reactive protein levels correlate with endothelial function in resistance arteries in men with coronary heart disease

The association between C-reactive protein (CRP) and future cardiovascular risk has been of particular interest during recent years. Oxidized low-density lipoprotein (ox-LDL) is another marker linking the immune system with the atherogenic process. The aim of this study was to examine whether ox-LDL and CRP were associated with endothelial function in peripheral resistance arteries. Twenty-five men with a previous hospital-diagnosed myocardial infarction were enrolled in the study. The exclusion criterion was a history of diabetes mellitus. IgG and IgM autoantibodies to malonyldialdehyde low-density lipoprotein (MDA-LDL) and high-sensitivity CRP (hs-CRP) were measured. Flow-mediated dilatation was measured in isolated resistance arteries from subcutaneous fat biopsies. Endothelial function test reflecting the maximum vessel dilatation in male subjects was inversely related to MDA-LDL IgG autoantibody levels (r = -0.6 and P = 0.003). Comparison of hs-CRP levels and of maximum vessel dilatation in males revealed also an inverse relation (r= -0.4 and P = 0.04). In conclusion, a clear correlation exists between flow-mediated dilatation in subcutaneous resistance arteries and plasma levels of MDA-LDL IgG autoantibody and CRP in male patients with coronary heart disease.

Humoral Autoimmune Responses to the Squamous Cell Carcinoma Antigen Protein Family in Psoriasis

Substantial evidence indicates that psoriasis is a T-lymphocyte-mediated autoimmune disease. However, longstanding data also indicate IgG and complement deposition in upper epidermis of psoriasis plaques. This led us to propose that autoantigen-autoantibody interactions in the skin may also be of pathogenic importance. Here, we have confirmed the presence of IgG in upper lesional epidermis and used high-resolution two-dimensional immunoblotting of extracts from this tissue, and laser desorption mass spectrometry of tryptic peptides, to define a series of epidermal proteins that bind IgG from psoriatic serum. The most prominent of these autoantigens are homologues of the serpin, squamous cell carcinoma antigen (SCCA), the other autoantigens identified including arginase 1, enolase 1, and keratin 10. Blood levels of IgG autoantibodies that bind to SCCA proteins were significantly higher in psoriasis than healthy controls (P=0.005), but were not detectable in sera from patients with active atopic dermatitis. To our knowledge, SCCA proteins have not previously been described as autoantigenic in animals or humans and form complexes with IgG that are associated with complement deposition. These findings expose potentially pathogenic humoral immunologic events and thus possible therapeutic targets in psoriasis.

Evidence for Genes in Addition to Tlr7 in the Yaa Translocation Linked with Acceleration of Systemic Lupus Erythematosus

The accelerated development of systemic lupus erythematosus (SLE) in male BXSB mice is associated with the genetic abnormality in its Y chromosome, designated Yaa (Y-linked autoimmune acceleration). Recently, the Yaa mutation was identified to be a translocation from the telomeric end of the X chromosome (containing the gene encoding TLR7) onto the Y chromosome. In the present study, we determined whether the Tlr7 gene duplication is indeed responsible for the Yaa-mediated acceleration of SLE. Analysis of C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus (B6.Nba2) bearing the Yaa mutation revealed that introduction of the Tlr7 null mutation on the X chromosome significantly reduced serum levels of IgG autoantibodies against DNA and ribonucleoproteins, as well as the incidence of lupus nephritis. However, the protection was not complete, because these mice still developed high titers of anti-chromatin autoantibodies and retroviral gp70-anti-gp70 immune complexes, and severe lupus nephritis, which was not the case in male B6.Nba2 mice lacking the Yaa mutation. Moreover, we found that the Tlr7 gene duplication contributed to the development of monocytosis, but not to the reduction of marginal zone B cells, which both are cellular abnormalities causally linked to the Yaa mutation. Our results indicate that the Yaa-mediated acceleration of SLE as well as various Yaa-linked cellular traits cannot be explained by the Tlr7 gene duplication alone, and suggest additional contributions from other duplicated genes in the translocated X chromosome.

Novel recombinant congenic mouse strain developing arthritis with enthesopathy

Based on the hypothesis that the complex pathological and immunological manifestations of rheumatoid arthritis (RA) and the related diseases are under the control of multiple gene loci with allelic polymorphism, a recombinant congenic mouse strain was prepared between an MRL/Mp-lpr/lpr (MRL/lpr) strain, which develops arthritis resembling RA, and a non-arthritic strain C3H/HeJ-lpr/lpr (C3H/lpr). In MRL/lpr x (MRL/lpr x C3H/lpr) F1 mice, the mice developing severe arthritis were selected based on joint swelling to further continue intercrosses, and then an McH-lpr/lpr-RA1 (McH/lpr-RA1) strain was established and its histopathological phenotypes of joints and autoimmune traits were analyzed. Arthritis in McH/lpr-RA1 mice developed at a higher incidence by 20 weeks of age, compared with that in the MRL/lpr mice, who had severe synovitis (ankle, 60.3%; knee, 65.1%), and also fibrous and fibrocartilaginous lesions of articular ligamenta resembling enthesopathy (ankle, 79.4%; knee, 38.1%), resulting in ankylosis. The lymphoproliferative disorder was less, and serum levels of IgG and IgG autoantibodies including anti-dsDNA and rheumatoid factor were lower than those of both MRL/lpr and C3H/lpr strains. McH/lpr-RA1 mice may provide a new insight into the study of RA regarding the common genomic spectrum of seronegative RA and enthesopathy.

Global T Cell Dysregulation in Non-Autoimmune-Prone Mice Promotes Rapid Development of BAFF-Independent, Systemic Lupus Erythematosus-Like Autoimmunity

In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.

Serum autoantibody profile of patients with age‐related macular degeneration

Age‐related macular degeneration (AMD) is the leading cause of irreversible blindness in industrial countries. Recent findings indicate that both genetic and immunological factors are involved in the pathogenesis of AMD. Autoantibodies in particular have been implicated in AMD pathogenesis, yet only a few antibodies have been identified in sera from patients with AMD. In order to reveal an autoantibody profile for AMD and identify biomarkers for progression of this disease, we incubated an antigen microarray with serum samples from patients with AMD and healthy controls. Sera from the AMD group contained high levels of IgG autoantibodies to some antigens including cyclic nucleotide phosphodiesterase and proliferating cell nuclear antigen, when compared to the normal group. Moreover, the IgG/IgM ratio for antibodies to some systemic antigens correlated with the stage of AMD. Our data suggest that these IgG autoantibodies and the ratio may be used as biomarkers for AMD. Further studies are needed to clarify whether the autoantibodies directly cause AMD or are secondary products in the progression of AMD. This work is supported by the Dobbs Foundation, Special Trustees of Moorfields Eye Hospital and the NIH.

Induction of Experimental Arthritis in Balb/C Mice by Inclusion of a Foreign Protein in the Collagen Inoculum

The susceptibility of mice to collagen-induced arthritis (CIA) has, among other things, been linked to the major histocompatibility complex class II genes as well as other genes. This study was designed to examine the possibilities to establish CIA in low susceptible I-Ad (Balb/C) mice. Balb/C mice were immunized twice with bovine type II collagen (BCII) in complete Freund's adjuvant (CFA) containing the amount of Mycobacterium tuberculosis needed to induce CIA in low susceptible I-Ab (C57BL/6) mice. Some mice received the conceivable arthritogenic inoculum mixed with ovalbumin (OVA). Clinical arthritis was monitored. Antibody activity and T-cell reactivity to BCII were determined. Unexpectedly, only mice that were immunized with the BCII-OVA mixture developed arthritis. Combining BCII with another foreign protein, keyhole limpet hemocyanin, but not the self-protein mouse serum albumin, also triggered arthritis. Prior to the appearance of arthritis the serum levels of IgG autoantibodies to BCII were higher in the coimmunized mice than in the mice that were immunized with BCII alone. Yet, splenocytes stimulated in vitro with BCII did not proliferate or produce interferon-gamma. Immunization of Balb/c mice with an emulsion-containing CFA and BCII mixed with a foreign body, but not a self-protein, elevates the level of circulating autoantibodies to CII and subsequently induces arthritis.

Serum levels of IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid

Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the hemidesmosomal proteins, BP180 and BP230. NC16A, a non-collagenous stretch of the BP180 ectodomain is the primary target of pathogenic IgG antibodies. Whereas IgG anti-BP180 autoantibodies play a primary role in the pathogenesis, there is a growing number of data regarding the potential pathogenic roles of IgE class autoantibodies in BP. To examine the levels of IgG and IgE autoantibodies against BP180 and BP230, and to investigate mutual association and clinical relevance. Sera obtained from 67BP patients and 36 healthy donors were subjected to ELISA assays to measure serum IgG and IgE levels of anti-BP180 and anti-BP230 antibodies. IgG anti-BP180 antibodies were positive in 63 (94%) of 67BP patients. IgG anti-BP230, IgE anti-BP180, and IgE anti-BP230 antibodies were found in 48 (72%), 20 (30%) and 45 (67%), respectively. IgG anti-BP180 levels were correlated with the affected areas. IgG anti-BP230 antibodies tended to increase in proportion to elongation of disease duration. IgE anti-BP230 levels showed a strong association with local eosinophil accumulation, while the levels were reversely related with the affected areas in BP. IgE autoantibodies to BP180 and BP230 are detected at high frequencies in BP. IgE anti-BP230 antibodies may have a role in attracting eosinophils to the skin lesions.

Sle3 and Sle5 can independently couple with Sle1 to mediate severe lupus nephritis

Genetic analyses of the lupus-prone NZM2410 mouse have identified multiple susceptibility loci on chromosome 7, termed Sle3 and Sle5. Both of these loci were contained within a large congenic interval, originally termed as Sle3 that strongly impacts a variety of myeloid and T-cell phenotypes and mediates fatal lupus nephritis when combined with Sle1. We have now produced two subcongenic strains, B6.Sle3 and B6.Sle5, carrying the Sle3 and Sle5 intervals separately and characterized their phenotypes as monocongenic strains and individually in combination with Sle1. Neither B6.Sle3 nor B6.Sle5 monocongenic strain develop severe autoimmunity; however, both of these intervals cause the development of severe glomerulonephritis when combined with Sle1. Thus, B6.Sle1Sle3 and B6.Sle1Sle5 exhibit splenomegaly, expansion of activated B and CD4+ T-cell populations and high levels of IgG and IgM autoantibodies targeting multiple nuclear antigens, intact glomeruli and various other autoantigens. In addition, B6.Sle1Sle3 mice also produced higher levels of IgA antinuclear autoantibodies, which were implicated in the development of IgA nephropathy. Our results indicate that Sle3 and Sle5 can independently complement with Sle1, through shared and unique mechanisms, to mediate the development of severe autoimmunity.

Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events

The relationship between autoantibodies to oxidized low density lipoprotein (OxLDL) and coronary artery disease (CAD) remains controversial. IgM and IgG OxLDL autoantibodies to malondialdehyde (MDA)-modified LDL, copper oxidized low density lipoprotein (CuOxLDL), and oxidized cholesterol linoleate (OxCL), as well as apolipoprotein B-100 immune complexes (apoB-ICs), were measured in 504 patients undergoing clinically indicated coronary angiography. Patients were followed for cardiovascular events for a median of 4 years. In univariate analysis, IgM OxLDL autoantibodies and IgM apoB-ICs were inversely associated with the presence of angiographically determined CAD, whereas IgG OxLDL autoantibodies and IgG apoB-ICs were positively associated. In logistic regression analysis, compared with the first quartile, patients in the fourth quartile of IgM OxLDL autoantibodies and apoB-ICs showed a lower probability of angiographically determined CAD (>50% diameter stenosis). Odds ratios and (95% confidence intervals) were as follows: MDA-LDL, 0.51 (0.32-0.82; P = 0.005); CuOxLDL, 0.63 (0.39-1.01; P = 0.05); OxCL, 0.63 (0.39-1.01; P = 0.05); and apoB-IC, 0.55 (0.34-0.88; P = 0.013). These relationships were accentuated in the setting of hypercholesterolemia, with the highest IgM levels showing the lowest risk of CAD for the same level of hypercholesterolemia. Multivariable analysis revealed that neither IgM or IgG OxLDL autoantibodies nor apoB-ICs were independently associated with angiographically determined CAD or cardiovascular events. In conclusion, IgG and IgM OxLDL biomarkers have divergent associations with CAD in univariate analysis but are not independent predictors of CAD or clinical events.

Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes

The objective of this study was to investigate the prevalence and clinical significance of a spectrum of autoantibodies in systemic lupus erythematosus and incomplete lupus syndromes using a proteome microarray bearing 70 autoantigens. Microarrays containing candidate autoantigens or control proteins were printed on 16-section slides. These arrays were used to profile 93 serum samples from patients with systemic lupus erythematosus (SLE (n = 33), incomplete LE (ILE; n = 23), first-degree relatives (FDRs) of SLE patients (n = 20) and non-autoimmune controls (NC; n = 17). Data were analysed using the significance analysis of microarray (SAM) and clustering algorithms. Correlations with disease features were determined. Serum from ILE and SLE patients contained high levels of IgG autoantibodies to 50 autoantigens and IgM autoantibodies to 12 autoantigens. Elevated levels of at least one IgG autoantibody were detected in 26% of SLE and 19% of ILE samples; elevated IgM autoantibodies were present in 13% of SLE and 17% of ILE samples. IgG autoantibodies segregated into seven clusters including two specific for DNA and RNA autoantigens that were correlated with the number of lupus criteria. Three IgG autoantibody clusters specific for collagens, DNA and histones, were correlated with renal involvement. Of the four IgM autoantibody clusters, two were correlated negatively with the number of lupus criteria; none were correlated with renal disease. The IgG : IgM autoantibody ratios generally showed a stepwise increase in the groups following disease burden from NC to SLE. Insights derived from the expanded autoantibody profiling made possible with the antigen array suggest differences in autoreactivity in ILE and SLE. Determining whether the IgM aurotreactivity that predominates in ILE represents an early stage prior to IgG switching or is persistent and relatively protective will require further longitudinal studies.

Ro52, Ro60 and La IgG autoantibody levels and Ro52 IgG subclass profiles longitudinally throughout pregnancy in congenital heart block risk pregnancies

Congenital heart block occurs in fetuses of Ro/SSA and La/SSB positive women. To investigate the stability of maternal autoantibody levels during pregnancy, we followed Ro52, Ro60 and La autoantibody IgG level variation and Ro52 subclass profiles longitudinally in selected congenital heart block risk pregnancies. Serum samples were obtained from 12 Ro/La positive women diagnosed with a systemic rheumatic disease and followed on average 60 months (range two to 84) which included 13 pregnancies. Seven children were affected by neonatal lupus, whereof four developed complete congenital heart block. Serum was also collected from the babies at birth. Ro52, Ro60 and La IgG as well as subclass antibodies were analysed by ELISA using recombinant antigens. Six Ro/La negative rheumatic patients were included as controls for antibody levels during pregnancy. Ro52, Ro60 and La IgG levels decreased progressively from early to late pregnancy, significantly for Ro52 and Ro60 (P < 0.01). No peaks or persistent elevation of antibody levels were noted in any of the CHB risk pregnancies. Ro52 IgG1 antibody levels were significantly higher than IgG2 (P < 0.01), IgG3 (P < 0.01) and IgG4 (P < 0.05) levels in the mothers during pregnancy. Ro52 IgG1 and IgG4 levels decreased significantly from early to late pregnancy (P = 0.02), while levels of IgG2 and IgG3 were low and the decrease was not significant. All IgG subclasses were transferred to the children. We conclude that maternal levels of Ro52, Ro60 and La autoantibodies tended rather to decrease than to increase during pregnancy.

Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations

AbstractChronic graft-vs-host disease (GVHD) is a major cause of morbidity and mortality of long-term survivors of allogeneic hemato-poietic cell transplantation (HCT). Chronic GVHD can have features of an autoimmune collagen vascular disease with clinical manifestations similar to autoimmune scleroderma and systemic lupus erythematosus (SLE). However, the pathogenesis of chronic GVHD is poorly understood. It is unclear how autoreactive T and B cells are generated in chronic GVHD recipients. We have recently developed a new chronic GVHD model by transplantation of donor DBA/2 (H-2d) spleen cells into major histocompatibility complex (MHC)-matched but minor antigen-mismatched sublethally irradiated BALB/c (H-2d) recipients as well as athymic BALB/cnu/nu and adult-thymectomized BALB/c recipients. Both euthymic and athymic BALB/c recipients developed high levels of serum IgG autoantibodies, sclerodermatous skin damage, and glomerulonephritis. Disease induction required both donor CD25-CD4+ T and B cells in transplants. In contrast, donor CD25+CD4+ T regulatory (Treg) cells prevented the disease induction. These results indicate that host thymus is not required for induction of chronic GVHD and that quiescent autoreactive T and B cells in transplants from nonautoimmune donors may be activated and expanded to cause chronic GVHD with autoimmune manifestations in allogeneic recipients, and donor Treg cells can suppress this process.

Autoantibodies to oxidized LDL and cardiovascular risk: The Framingham Offspring Study

Background The relation between measures of oxidation of lipid particles and cardiovascular disease has not been extensively investigated prospectively on a population basis. Methods A community cohort of 1192 men and 1427 women with measures of IgG antibodies to oxidized LDL were followed 8 years for the development of initial coronary heart disease (CHD) and cardiovascular disease (CVD) events. Results Levels of IgG autoantibodies to a form of oxidized LDL were significantly associated with age in both sexes, positively with fibrinogen in men and negatively with HDL cholesterol in women. In sex-specific models that adjusted for age alone or those that adjusted for age, cholesterol, HDL cholesterol, smoking, and diabetes mellitus, there was no relation between level of antibodies to oxidized LDL and the development of CHD or CVD. Conclusion Autoantibodies to oxidized LDL were strongly related to age and were not related to incident CHD or CVD over 8 years of follow up.

Association of Mixed Hematopoietic Chimerism with Elevated Circulating Autoantibodies and Chronic Graft-versus-Host Disease Occurrence

Use of a reduced-intensity conditioning regimen before an allogeneic hematopoietic cell transplantation is frequently associated with an early state of mixed hematopoietic chimerism. Such a coexistence of both host and donor hematopoietic cells may influence posttransplant alloreactivity and may affect the occurrence and severity of acute and chronic graft-versus-host disease (GVHD) as well as the intensity of the graft-versus-leukemia effect. Here we evaluated the relation between chimerism state after reduced-intensity conditioning transplantation (RICT), autoantibody production, and chronic GVHD (cGVHD)-related pathology. Chimerism state, circulating anticardiolipin, and antidouble stranded DNA autoantibody (Ab) titers as well as occurrence of cGVHD-like lesions were investigated in a murine RICT model. We observed a novel association between mixed chimerism state, high levels of pathogenic IgG autoantibodies, and subsequent development of cGVHD-like lesions. Furthermore, we found that the persistence of host B cells, but not dendritic cell origin or subset, was a factor associated with the appearance of cGVHD-like lesions. The implication of host B cells was confirmed by a host origin of autoantibodies. Recipient B cell persistence may contribute to the frequency and/or severity of cGVHD after RICT.

A Mimic of p21WAF1/CIP1 Ameliorates Murine Lupus

Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by the production of high levels of affinity-matured IgG autoantibodies to dsDNA and, possibly, visceral involvement. Pathogenic autoantibodies result from the activation and proliferation of autoreactive T and B lymphocytes stimulated by epitopes borne by nucleosomal histones. To inhibit the proliferation of autoreactive cells and abrogate the development of SLE, a novel tool, cell cycle inhibiting peptide therapy, was used. Thus, a peptidyl mimic of p21WAF1/CIP1 that inhibits the interaction between cyclin-dependent kinase 4 and type D cyclins abrogated the in vitro proliferative response of T cells to histones and T-independent and T-dependent proliferative responses of B cells. The WAF1/CIP1 mimic also abrogated the in vitro production of total and anti-dsDNA IgG Abs by B cells. Similarly, the p21WAF1/CIP1 construct inhibited the ex vivo T and B cell proliferative responses to histones and decreased the numbers of activated/memory B and T spleen cells. The alterations in the balance of spleen cell subsets resulted from proapoptotic effects of the p21WAF1/CIP1)construct on activated splenocytes. Finally, in vivo, four i.v. injections of the p21WAF1/CIP1 mimic were sufficient to inhibit the progression of the lupus-like syndrome in (NZB x NZW)F1 mice. The levels of anti-dsDNA IgG autoantibodies and the incidence and severity of renal involvement were lower in treated mice than in nontreated mice. Those observations open new avenues for the treatment of SLE and prompt us to evaluate the potential interest of peptidic therapy in human SLE.

Effects of MHC and Gender on Lupus-Like Autoimmunity inNba2Congenic 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.