Aberrant Adaptive Immunity in Lupus

Vertebrates acquire adaptive immunity after birth, which is a response to specific antigens that involves B and T cells of the immune system and frequently leads to a state of immune memory (Iwasaki and Medzhitov 2004). The adaptive immune system produces antibodies and T cells that are highly specific for a particular pathogen (or antigen). The relative specificity of SLE sera to a selected subset of nuclear antigens (as opposed to reacting to the whole universe of antigens) suggests that lupus genes must be impacting adaptive immunity at some level. Our recent genetic dissection studies have indicated that Sle1z may be one such locus/gene (Figure. 1).

The Sle1z interval, located on distal chromosome 1, is perhaps one of the most extensively studied chromosomal intervals in murine lupus, since it confers disease susceptibility in multiple spontaneous lupus models including the BWF1, SNF1, BXSB, and NZM2410 mice (Morel and Wakeland 2000). The Sle1z interval is home to three

Genetic dissection of lupus

Genetic dissection of lupus

Generalized B cell hyperactivity Expanded B1 cells Polyreactive IgM No renal disease 1997 JI 159:454

Activated T cells Impaired AICD Increased CD4:CD8 Modest ANAs Moderate GN 1999 JI 162:6492

Anti-chromatin ANAs Activated B an d T cells Intrinsic to B/T cells Modest anti-dsDNA Minimal renal disease 1998 JCI 101:1362

Anti-chromatin ANAs Activated B an d T cells Intrinsic to B/T cells Modest anti-dsDNA Minimal renal disease 1998 JCI 101:1362

Generalized B cell hyperactivity Expanded B1 cells Polyreactive IgM No renal disease 1997 JI 159:454

Activated T cells Impaired AICD Increased CD4:CD8 Modest ANAs Moderate GN 1999 JI 162:6492

B6. Sle1.Yaa B6. Sle1.Lpr B6. Sle1 .Sle3 B6.Sle2.Sle3 PNAS 97:6670 JEM 196:281 JCI 103:1685 PNAS 97:6670

B6.Sle 1.Sle2.Sle3 PNAS 97:6670

B6. Sle1.Yaa B6. Sle1.Lpr B6. Sle1 .Sle3 B6.Sle2.Sle3 PNAS 97:6670 JEM 196:281 JCI 103:1685 PNAS 97:6670

B6.Sle 1.Sle2.Sle3 PNAS 97:6670

Genetic reconstitution of lupus

Figure 1. Genetic dissection and genetic reconstitution of murine lupus using congenic strains.

Note: The strains exhibit varying degrees IgG anti-dsDNA Abs, renal disease, and Lymphoproliferation. The most severely affected strains are B6Slel.lpr and B6.Slel.Sle2.Sle3

sub-loci: Sle1az, Sle1bz, and Sle1cz. Among these, the NZM2410/NZW-derived "z" allele of Sle1bz leads to the highest levels and penetrance of antinuclear autoanti bodies (ANAs) (Morel et al. 2001). We found that Sle1z could breach tolerance among B cells with low-avidity but not high-avidity reactivity to self-antigens (Kumar et al. 2006). To understand how Sle1z breached B cell tolerance, we examined the immature and mature B cells in these nice further. Sle1z did not impact the activation or apoptosis of mature splenic B cells, but caused a significant expansion of transitional immature T1 B cells (B220+AA4.1+CD21-CD23-), alluding to a relative block in the transition from T1 to mature B cells in the presence of Sle1z. IL-7-driven immature B cells from the Sle1z-and Sle1bz--bearing bone marrow (BM) also exhibited a profound reduction in calcium flux and cell death following B-cell receptor (BCR) cross-linking, revealing that the Sle1bz lupus susceptibility locus significantly dampens BCR signaling within immature B cells. This observation that is consistent with literature reports that the degree of BCR signaling can dictate B cell tolerance outcomes.

Through a meticulous positional cloning approach, Wakeland and colleagues demonstrated the SLAM family of co-stimulatory molecules to be the candidate genes for Sle1bz. These molecules, Ly9, CD84, CD244 (2B4), SLAM (CD150),

Ly108, and CS1 are expressed in B cells (Wandstrat et al. 2004). Among these genes, Ly108 has a profound impact on early B cell tolerance (Kumar et al. 2006). The normal "b" allele of Ly108 encodes predominantly the Ly108.2 isoform (bearing three intracellular ITSM signaling motifs); in contrast, the lupus-associated "z" allele of Ly108 encodes predominantly the Ly108.1 isoform (bearing two intracellular ITSM motifs) due to a splice-site mutation. Immature B cells represent a critical stage in B cell development, at which point self-reactive B cells are censored by deletion or receptor editing. Importantly, immature B cells transfected with the lupus-associated Ly108.1 isoform showed impaired calcium flux, apoptotic cell loss, and BCR editing compared to transfectants bearing the normal Ly108.2 isoform. Thus, the presence of the normal Ly108.2 isoform may render immature B cells sensitive to BCR cross-linking, effectively facilitating the operation of several tolerance mechanisms including receptor editing and deletion, whereas the lupus-associated isoform, Ly108.1, appears to thwart these processes (Kumar et al. 2006).

Collectively, the above studies reveal that a mutant form of the SLAM gamily gene, Ly108, can profoundly impact key checkpoints in early B cell tolerance, hence leading to the emergence of self-reactive antibodies. Since a similar locus (Tsao et al. 1999) and gene(s) (unpublished observations) are also at play in human SLE, dys-regulation of the adaptive immune system, early during B cell development, may constitute a central mechanism leading to lupus, both in mice and in patients.

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