is an NZM2410/NZW–derived locus on proximal chromosome 7 that facilitates spontaneous T cell hyperactivity and low-grade serological autoreactivity, when introgressed onto the normal B6 genetic background (22
). The present report adds to the earlier findings in several respects. Firstly, whereas the earlier report had detailed the phenotypic properties of a 40-cM interval on proximal chromosome 7 encompassing Sle3
, the present report focuses on mice that bear a 24-cM interval on mid–chromosome 7, encompassing Sle3
but not Sle5
(Table and Figure ). Secondly, the T cell repertoire is greatly simplified in the current study, owing to the use of an OVA-specific TCR Tg. Finally, and most importantly, the present study directs attention to the potential importance of aberrant myeloid-lineage cells in contributing to the immunological phenotypes associated with this congenic interval. Importantly, the adoptive transfer experiments indicate that the genetic makeup of the APC has the potential to influence the degree of T cell hyperactivity as well as serological autoreactivity, in lupus pathogenesis.
The current findings fortify the conclusions of several previous reports implicating the potential role of enhanced and/or hyperactive APCs in driving autoimmunity. Although the most cited example of elevated monocytosis in murine lupus is the BXSB model (30
), increased macrophages have also been documented in BWF1 and MRL/lpr
lupus mice (33
), with attendant anomalies in cytokine profiles (35
). Likewise, aberrant DC function has also been reported in murine lupus (36
), as well as the NOD model of diabetes (39
). Additionally, forward genetic studies have generated several “engineered” models of disease where systemic autoimmunity and myeloid hyperactivity both co-dominate the clinical phenotype. Thus, for example, Shp-1
, lyn CD200/OX2
, and Nfkb2
mice all have the potential to influence both autoimmunity and the myeloid cell compartment (43
). Although Sle3
-bearing APCs resemble APCs from mouse strains exhibiting aberrant expression of the above molecules, Sle3
does not represent an allelic variant of any of the above genes, as they are located on different chromosomes.
The notion that aberrant APCs can breach T cell tolerance is well accepted (48
). The underlying mechanism(s) that may explain why Sle3
-bearing APCs may be more potent at stimulating T cells in vitro, or in breaching tolerance in vivo, is an important issue to investigate. On the one hand, Sle3
-bearing DCs (and other APCs) may be more “costimulatory,” because of their increased surface expression of CD80/B7-1, I-Ab
, CD40, etc. The observation that blockade of B7:CD28 and CD40:CD40L interactions has the potential to ameliorate murine lupus lends support to this thesis (49
). In addition, their heightened secretion of proinflammatory cytokines may further augment the costimulatory potential of Sle3
APCs. The notion that a proinflammatory milieu could promote the rapid maturation of DCs and impair their T cell–tolerizing potential is well documented (52
). Clearly, both of the above mechanisms (i.e., increased costimulation and proinflammatory properties) may be synergistic in breaching T cell tolerance, as has been expounded by others (55
). Although one might have anticipated a phenotypic difference when Sle3
-bearing DCs were adoptively transferred into a B6 host, even without LPS coadministration, this was not the case. Apparently, the coadministration of LPS was essential to uncover the autoimmune potential of B6.Sle3
DCs. It is conceivable that LPS stimulation of the transferred B6.Sle3
DCs may be required for maximally modulating their activation status, cytokine profile, or survival advantage in vivo, drawing from the in vitro observations presented in Figures –.
Based on the in vitro studies in Figure , we postulate that the more mature and proinflammatory nature of B6.Sle3
DCs may have conferred a stronger proliferative edge and a better survival advantage to potentially autoreactive CD4 T cells. This could also account for the increased CD4/CD8 ratios noted in unmanipulated B6.Sle3
), and in the adoptive transfer experiments (Figure ). Autoreactive members among the expanded pool of CD4 T cells may in turn have been responsible for the increased serum ANAs observed, both in unmanipulated B6.Sle3
) and in the adoptive transfer studies (Figure ), through T-dependent B cell help. However, a direct impact of Sle3
-bearing myeloid cells on B cell function cannot yet be excluded. In addition to their potential impact on systemic T and B cells, it is conceivable that the hyperactive B6.Sle3
myeloid cells may also be responsible for the enhanced susceptibility to renal disease seen in B6.Sle3
congenics (Y. Fu and C. Mohan, unpublished observations). The notion that neutrophils and macrophages play an essential role in immune-mediated renal disease is well accepted (57
), and these cells do appear to play a more prominent role in the renal disease seen in B6.Sle3
mice (Y. Fu and C. Mohan, unpublished observations).
Collectively, it appears likely that the hyperactivated myeloid compartment in B6.Sle3 mice may be contributing to lupus through multiple mechanisms, both systemically and locally in the end organs. Although the expression of Sle3 within the myeloid cell compartment of these congenics appears to be sufficient to elicit the previously described Sle3-associated phenotypes, one cannot exclude the possibility that Sle3 may also be impacting additional cell types, and these additional cellular mechanisms may also be contributing to lupus pathogenesis. Specifically, one cannot exclude the possibility that T cell–intrinsic expression of Sle3 may be contributing at least in part to the “T cell hyperresponsiveness” noted in these mice. Although the T:DC coculture studies portrayed in Figure E might support this thesis, it is clearly possible that T cells isolated from B6.Sle3 congenics may appear to be hyperresponsive simply because they might have already been “primed” by Sle3-bearing APCs in vivo.
The chromosome 7 interval encompassing Sle3
has also been implicated in genetic analyses of other lupus models (18
). Presently, it is not clear whether the different loci uncovered in the different mouse models represent allelic variants of the same culprit gene(s). Given the repeated mapping of this chromosomal interval in several independent murine lupus studies and models, and the intriguing phenotypes associated with this locus, elucidating the candidate genes within this locus is of paramount importance. Since the phenotypes exhibited by the B6.Sle3
-derived macrophages, DCs, neutrophils, and T cells are fundamentally similar (i.e., reduced apoptosis with a concomitant increase in activation status), we hypothesize that a single genetic defect may be responsible for all of these cellular phenotypes. On the other hand, since the studied congenic interval is fairly large, it is certainly possible that 2 or more genes within the disease interval may be contributing to the observed cellular phenotypes. Among the 560 genes/open reading frames located within the Sle3
congenic interval, 1 gene that had potential significance to APC biology was FL
). However, sequencing and expression studies of the FL
gene in B6 and B6.Sle3
mice have failed to substantiate FL
as the culprit gene for Sle3
. Progressive narrowing of the recombinant congenic interval and additional candidate gene testing are in progress.
Given that Sle3
is a major disease susceptibility locus in the NZM2410 lupus model, one may infer that the “T cell hyperactivity” in NZM2410 lupus mice may be contingent upon intrinsic APC anomalies, to a significant degree. Lupus T cells have also been phenotyped as being hyperactive in other murine models, as reviewed (1
). Based on the present findings, it becomes important to evaluate the extent to which more exuberant APC function may also underlie the T cell hyperactivity noted in other lupus models. Finally, T cell hyperactivity, including several biochemical abnormalities that correlate with T cell hyperresponsiveness, and aberrant DC function have also been documented in human lupus (1
). The current findings raise the possibility that the T cell phenotypes noted in human SLE may also be influenced by intrinsic differences in DC/myeloid cell function, in addition to possible T cell–intrinsic anomalies (65
). Focusing future research efforts on the myeloid compartment may not only shed light on the pathogenic origins of lupus; it may also pave the way for novel therapeutic approaches.