NG contributed to developing the defective 3 heavy chain allele, conceived and designed the studies, interpreted the data, and wrote the manuscript

NG contributed to developing the defective 3 heavy chain allele, conceived and designed the studies, interpreted the data, and wrote the manuscript. those of age-matched gamma3 -/- mice after ~21 weeks of age. Histopathological examination of kidneys from mice sacrificed at pre-determined ages also revealed more extensive glomerulosclerosis in gamma3 +/+ or +/- mice than in -/- mice beginning at 21 weeks of age. Survival analysis for IgG3-deficient and IgG3-producing MRL/lprmice revealed that gamma3 -/- mice lived significantly longer (p = 0.0006) than either gamma3 +/- or +/+ mice. Spontaneous death appeared to be due to irreversible renal failure, because > 85% of glomeruli in kidneys from mice that died spontaneously were obliterated by glomerulosclerosis. == Conclusions == The available evidence suggests that IgG3 deficiency partially protects MRL/lprmice against glomerulonephritis-associated morbidity and mortality by slowing or arresting the Rabbit Polyclonal to Mevalonate Kinase progression to glomerulosclerosis. == Reviewers == This article was reviewed by Pushpa Pandiyan, Irun Cohen, and Etienne Joly. == Background == Mice of the MRL/MpJ-Tnfrsf6lpr(MRL/lpr) inbred strain are genetically predisposed to a spontaneous autoimmune syndrome that resembles K 858 human systemic lupus erythematosus (SLE or lupus) in several key features. As in lupus patients, a major cause of morbidity K 858 and mortality in both male and female MRL/lprmice is progressive glomerulonephritis [1-3]. The pathogenic cascade that culminates in renal damage in human and mouse has been correlated with the renal deposition of auto-antibodies, many of which exhibit specificity for antigens that derive from cell nuclei [4]. Analysis of antibodies specific for auto-antigens or those deposited in the affected kidneys has revealed that IgG antibodies are the dominant isotype [5]. In terms of IgG subclasses, there is evidence implicating both IgG2a and IgG3 antibodies in the pathogenesis of renal disease in MRL/lprmice [6]. Several distinct experimental manipulations that decreased IgG3 production have been associated with less severe renal disease in mice of the MRL/lpror other inbred strains prone to autoimmune disease [7-9]. Conversely, increased production of IgG3 antibodies associated with expression of the Yaa gene on the MRL background has been correlated with more severe renal disease [7]. Similarly, genetic elimination of IgM secretion in the MRL/lprbackground was associated with increased titers of serum auto-antibodies of the IgG3 (as well as the IgG1 and IgG2a subclasses) specific for dsDNA and more severe glomerulonephritis and earlier mortality [10]. In all cases, these perturbations likely generated potentially relevant physiologic effects other than altered concentration of IgG3 antibodies in serum. Although passive transfer of substantial amounts of IgG3 monoclonal antibodies with rheumatoid factor activity can elicit renal pathology analogous to the damage that develops spontaneously in MRL/lprmice [11-14], the serum levels of such antibodies required for these effects may surpass those that are physiologically relevant in the spontaneous disease. In the course of characterizing the J606 myeloma protein, the first identified murine IgG3 antibody, the investigators noted that the J606 Fc regions tended to self-associate at concentrations in the mg/ml range [15]. Subsequent reports revealed that a notable characteristic of many IgG3 antibodies is to self-associate in antigen-independent [16-20] or antigen-dependent [21-24] contexts, the latter at much lower antibody concentrations. We hypothesized that Fc-Fc interaction between IgG3 molecules confers a greater effective valence, and thereby greater functional affinity, permitting antibodies with relatively modest intrinsic (i.e., per site) affinities to bind effectively to highly multivalent antigens [21]. This physical-chemical phenotype, unique among the mouse IgG subclasses, has been rationalized [25] with reference to the remarkable association between IgG3 production and immunization with polysaccharide (or, less commonly, protein) antigens bearing multiple copies of the same epitope [26]. Previous studies with IgG3-deficient mice of the BALB/c background demonstrated that such mice were more K 858 susceptible to mortality following pneumococcal infection than wild-type BALB/c mice [27]. These mice were also less effectively protected by a vaccine consisting only.