The development of systemic autoimmunity in diseases like systemic lupus erythematosus (SLE)*
require the interaction of multiple genetic loci with environmental factors to result in the loss of tolerance, the development of an autoreactive repertoire, and the amplification of autoreactive cells to produce pathogenic autoantibodies (1
). The deposition of these autoantibodies as immune complexes and the activation of effector mechanisms to trigger tissue pathology require still additional genetic interactions to result in the systemic pathology typical of these diseases. Recent studies in both rodents and humans have begun to clarify some of the genetic interactions that underlie autoimmune disease susceptibility and progression (for a review, see reference 5
). Two types of studies have been undertaken to identify these genetic components – classic linkage analysis in multiplex SLE families and lupus-prone inbred mouse strains; and candidate gene analysis in human patient populations and animal models via genomic manipulation.
Genetic studies in susceptible human or murine populations have demonstrated that disease susceptibility is multifactorial, involving complex interactions among several genes together with poorly defined environmental factors (4
). While the contribution of the MHC to lupus susceptibility has been well documented by numerous studies (6
), the importance of non-MHC loci that either increase or suppress susceptibility to lupus has recently been appreciated. A total of 31 susceptibility loci have thus been defined, distributed among 21 nonoverlapping genomic intervals, further indicating the genetic complexity involved in autoimmune diseases like lupus (4
). Syntenic loci have been identified in the mouse and human for lupus susceptibility on mouse chromosomes 1, 5, 6, 7, and 18. The distal region of chromosome 1 is perhaps the best characterized with the identification of a cluster of loci including Sle1
, and Lbw7
involved in antinuclear antibody production (8
, for example, was derived from the autoimmune strain NZM 2410 as a 37 cM region of chromosome 1 from NZW (11
). C57BL/6 mice congenic for Sle1
develop antichromatin autoantibodies and will progress to autoimmune disease when combined with other NZM-derived loci. Sle1
has been further subdivided into four distinct, although functionally related regions, designated Sle1a
, and d
). Although each of these genes will express an autoimmune phenotype when isolated from the others, their autoimmune phenotype is strongly enhanced when they are expressed in combination, suggesting that they may impact a common pathway leading to the loss of tolerance to nuclear antigens (13
In a second type of study, candidate genes have been modified in unaffected mouse strains to determine their contribution to disease susceptibility. A common theme has emerged from these studies highlighting the central role of inhibitory molecules in maintaining tolerance to nuclear antigens. For example, deletion of the inhibitory surface molecules CD22, cytotoxic T lymphocyte antigen 4, PD-1, or FcγRIIB result in animals with autoimmune phenotypes of differing degrees of severity; references 14
). Similarly, deletion of the inhibitory signaling molecules src homology 1, cbl-b, or lyn also results in autoimmunity and disease (18
). These studies further support the threshold nature of autoimmunity and emphasize the importance of preventing inappropriate lymphocyte stimulation at subthreshold levels of antigen.
The central role of autoantibodies and immune complexes in the pathophysiology of autoimmune diseases like lupus has focused attention on the role of cellular receptors for these pathogenic ligands. The Fc receptors for IgG, FcγRs, by transducing signals from the IgG immune complex to APCs, B cells, and effector cells, are responsible for much of the immune responses triggered by these ligands (22
). Activation FcγRs, like FcγRIII, are responsible for triggering effector cell responses to cytotoxic IgGs or immune complexes; deletion of this receptor protects mice from autoimmune disease initiated by cytotoxic IgG antibodies or immune complex deposition (23
). Conversely, the inhibitory FcγR, FcγRIIB, prevents inappropriate activation of effector responses; its deletion renders animals hyperresponsive to sub-threshold levels of cytotoxic antibodies and immune complexes (24
). Expression of FcγRIIB on B cells and APCs plays a critical role in the maintenance of peripheral tolerance. Deletion of FcγRIIB results in autoantibody production in animals presented with potentially cross reactive antigens, like collagens type II or IV or when modified by specific genetic backgrounds, like C57BL/6 (17
). This epistatic property of the FcγRIIB deficiency model of SLE mimics the multigenic nature of human SLE.
To investigate the mechanisms that contribute to the loss of tolerance and disease progression by FcγRIIB deficiency, we have pursued genetic studies aimed at dissecting the interactions that are responsible for these phenotypes. In this study, we have constructed hybrids between B6.RIIB−/− and the Sle1 susceptibility locus or the SLE modifiers yaa and lpr and analyzed autoantibody production and disease progression. Sle1 and B6.RIIB−/− lie on a common genetic pathway that results in the loss of tolerance to nuclear antigens. The pathogenicity of these autoantibodies leading to disease progression is determined by loci such as yaa and lpr, independent of autoantibody titer. Yaa enhances disease by changing the specificity of the autoantibodies generated, while lpr uncouples autoantibody production from autoimmune disease thus preventing disease progression. The importance of epistasis is further emphasized by the identification of two novel, recessive loci on B6 that are required for antinuclear antibody production by FcγRIIB. These studies demonstrate the relevance of the B6.RIIB−/− model to the genetics of human SLE and reveal some of the mechanisms required for the manifestation of SLE.