Understanding autoimmune diseases is one of the great challenges facing immunologists and is linked to the fundamental question: How is self - nonself discrimination achieved? Even if this discrimination is not absolute, and autoimmunity can be demonstrated in many, why does it produce disease in so few? It has been appreciated for quite some time that these diseases are influenced by both environmental and genetic factors, and study of animal models has contributed immensely to our current understanding. Study of genetics has been especially accelerated recently through the advent of the mouse and human genome projects, and promises great discoveries, especially since one of the ways to tackle the complex mechanisms leading to autoimmune disease is to define the genetic components and allelic variations which lead to disease.
The usefulness of understanding genetics in the development of autoimmune disease is amply demonstrated by recent discoveries by Wakeland et al. who have been studying a murine model of Systemic Lupus Erythematosus (SLE). The NZM2410 mouse is a recombinant inbred mouse derived from the lupus prone NZM and NZB lineages, and demonstrates early expression of anti-nuclear autoantibodies and severe glomerulonephritis which are features of human SLE. Over the past ten years, classic genetic analysis of this mouse has demonstrated three major loci, Sle1, Sle2, and Sle3, which are essential for the inheritance of this disease. In earlier work, Wakeland et al have demonstrated that disease can be reconstituted in the ordinarily healthy C57Bl6 mouse through the introduction of these three loci from the NZM2410 background, fulfilling the genetic equivalent of Koch's postulates for transmission of a disease. Furthermore, introduction of certain pairs of loci, such as Sle1 and Sle2, or Sle1 and Sle3, but not Sle2 and Sle3 into the C57Bl6 background can recapitulate some, albeit milder forms of the disease. Interestingly, although expression of Sle1, Sle2 or Sle3 individually in the C57Bl6 background results in no apparent disease, there are noticeable immunologic abnormalities. For example, B6 mice with Sle1 alone produce antinuclear autoantibodies, and mice with Sle2 alone have hyperreactive B Cells and similarly, mice with Sle3 alone demonstrate T cell hyperreactivity.
More thorough analysis of the Sle1 locus has demonstrated that it actually contains three closely linked loci, which are now referred to as Sle1a, Sle1b and Sle1c. In recently published work, Wakeland et al. have further scrutinized the Sle1c locus and have come up with an interesting polymorphism, one found in the complement receptor (CR2), which may explain why NZM2410 mice break tolerance to nuclear antigens. The NZM2410 allele of CR2 has a single nucleotide difference compared to most strains of mice, which introduces a novel N-linked glycosylation site (residue D53). Indeed, Wakeland et al. show that the NZM2410 allele is glycoslyated at this site and results in a heavier protein. Most interestingly however, they discover that this new allele of CR2 binds its ligand, C3d more weakly and consequently induces more modest calcium influxes in B cells upon receptor engagement compared to control studies performed on C57Bl6 mice. Taking note of the recently solved crystal structure of human CR2/CR1 which functions as a dimer, Wakeland et al show that the allelic variation in CR2 happens to fall right in the middle of the dimerization domain, and addition of sugar moieties could be postulated to disrupt dimerization, and lead to the observed differences in ligand binding and signaling in NZM2410 B cells.
Historically, complement and complement receptors have been described as the scavengers of the immune system, passively labeling antigens and organisms for clearance, however recently, their role in actively shaping adaptive immunity is becoming more and more clear. Most significantly, it has been discovered that signals emanating from complement receptors are integrated into the antigen specific surface immunoglobulin receptors on B cells, potentially influencing the character of the response. Wakeland et al suggest that since stimulation of immature B cells through their surface immunoglobulin and complement receptors by self antigens can lead to clonal deletion, inheritance of a complement receptor that is not as efficient in transmitting signals as in the case of the NZM2410 allele, may lead to the escape of self-reactive B cell clones and breach of tolerance.
Firm establishment of the CR2 polymorphism as the responsible gene in the Sle1c locus leading to production of anti-nuclear autoantibodies will have to wait for more direct knock-in or transgenic studies, however, these current discoveries demonstrate the value of genetic analysis of complex disease states like autoimmune diseases.
Commentary prepared by Mehmet Guler
