Allelic variants of Fc ␥ R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc ␥ RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc ␥ RIIa-H131 is the only human Fc ␥ R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc ␥ RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc ␥ RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc ␥ RIIA alleles, with only 9% of SLE patients homozygous for Fc ␥ RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P ϭ 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc ␥ RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc ␥ RIIA-H131 as the likelihood for lupus nephritis increased ( P ϭ 0.0004) consistent with a protective effect of the Fc ␥ RIIA-H131 gene. The skewing in the distribution of Fc ␥ RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans. ( J.

Dscam is an immunoglobulin (Ig) superfamily protein required for the formation of neuronal connections in Drosophila. Through alternative splicing, Dscam potentially gives rise to 19,008 different extracellular domains linked to one of two alternative transmembrane segments, resulting in 38,016 isoforms. All isoforms share the same domain structure but contain variable amino acid sequences within three Ig domains in the extracellular region. We demonstrate that different isoforms exhibit different binding specificity. Each isoform binds to itself but does not bind or binds poorly to other isoforms. The amino acid sequences of all three variable Ig domains determine binding specificity. Even closely related isoforms sharing nearly identical amino acid sequences exhibit isoform-specific binding. We propose that this preferential homophilic binding specificity regulates interactions between cells and contributes to the formation of complex patterns of neuronal connections.

Sensory processing centres in both the vertebrate and the invertebrate brain are often organized into reiterated columns, thus facilitating an internal topographic representation of the external world. Cells within each column are arranged in a stereotyped fashion and form precise patterns of synaptic connections within discrete layers. These connections are largely confined to a single column, thereby preserving the spatial information from the periphery. Other neurons integrate this information by connecting to multiple columns. Restricting axons to columns is conceptually similar to tiling. Axons and dendrites of neighbouring neurons of the same class use tiling to form complete, yet non-overlapping, receptive fields1-3. It is thought that, at the molecular level, cellsurface proteins mediate tiling through contact-dependent repulsive interactions1,2,4,5, but proteins serving this function have not yet been identified. Here we show that the immunoglobulin superfamily member Dscam2 restricts the connections formed by L1 lamina neurons to columns in the Drosophila visual system. Our data support a model in which Dscam2 homophilic interactions mediate repulsion between neurites of L1 cells in neighbouring columns. We propose that Dscam2 is a tiling receptor for L1 neurons.The Drosophila visual system is a modular structure6,7. The retina contains 750 simple eyes, each containing eight photoreceptor neurons or R cells (R1-R8). R cells project into the brain, where they make connections within two neuropils, the lamina and medulla. R1-R6 neurons target to the lamina, where they form synapses with lamina neurons (L1-L5). R7, R8 and L1-L5 form connections in single columns within layers in the medulla, and each column contains one axon of each of these cell types. As a consequence of this wiring pattern, each column processes motion (lamina neurons) and colour (R7 and R8) from a single point in space6. Although some progress has been made in understanding how neurons select different layers within each of the 750 columns6, the molecular mechanisms that restrict synaptic connections to a single column are not known.Dscam2 belongs to a conserved family of cell-surface proteins expressed in the nervous systems of many different organisms8-10. Down syndrome cell adhesion molecule (DSCAM) was originally identified as an open reading frame in a region of human chromosome 21 critical for Down's syndrome11. There are four Dscam genes in the fly genome (Dscam,. They encode type I transmembrane proteins that share about 30% sequence identity and have a common extracellular domain comprising ten ©2007 Nature Publishing GroupCorrespondence and requests for materials should be addressed to S.L.Z. (lzipursky@mednet.ucla.edu).. Full Methods and any associated references are available in the online version of the paper at www.nature.com/nature.Supplementary Information is linked to the online version of the paper at www.nature.com/nature.Reprints and permissions information is available at www.nature.com/reprints. The Dscam...