Autoimmune Disorders: Thinking differently about lupus
- Genentech Inc., United States
It is always exciting when a new study opens up a whole new way of thinking about a scientific problem. This is especially true if the problem is a health condition that is both poorly understood and incurable. Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system attacks healthy tissue – including the skin, joints and many internal organs – by mistake. Moreover, the underlying causes of the disease are not fully understood, so available treatments only tackle its symptoms. Now, in eLife, Patrick Gaffney, Edward Wakeland and colleagues – who include Prithvi Raj and Ekta Rai as joint first authors – report an extensive sequencing study of over 1,000 people with SLE that provides many new insights into the genetics of lupus (Raj et al., 2016).
The researchers – who are based at the University of Texas Southwestern Medical Center, the Oklahoma Medical Research Foundation and other centers in the United States, Belgium and India – focused on 16 regions of the human genome that are known to influence a person’s risk of SLE. Their findings highlight the complexity of the changes in the genome that can predispose someone to develop SLE. Amongst the treasure-trove of data is one gold nugget that stands apart: the discovery that the expression level of the so-called Human Leukocyte Antigen (HLA) class II genes contributes to risk of the disease. This is an entirely new twist on an old story.
The HLA genes are found in a long stretch of DNA on chromosome 6 that contains more than 140 protein-coding genes, many of which are important for immune responses (MHC Sequencing Consortium, 1999; de Bakker et al., 2006). The class I genes encode proteins that are found on the outer membrane of all cells, whereas the class II genes encode proteins found only on specialized immune cells called antigen-presenting cells. In both cases, these proteins bind to small fragments of other proteins and then display them to the immune system. Class I proteins display fragments from within our own cells and protect us from cancer, viral infections and certain bacteria that can live within our cells. Class II proteins, on the other hand, display fragments from foreign invaders and are important for instructing the immune system to mount neutralizing responses to parasites and bacteria that live outside of cells.
The HLA class I and II genes are amongst the most variable DNA sequences in the human genome. There are more than 8,000 different variants, or alleles, of class I genes and more than 2,500 class II alleles (Robinson et al., 2015). These alleles encode slightly different proteins, each with the potential to bind to, and display, different protein fragments.
Hundreds of studies have previously linked class I and II variants with the risk of specific diseases and, without exception, these studies have emphasized the sequence diversity of class I and II genes as the important factor (Welter et al., 2014. For example, individuals who carry the class I allele known as B27 are strongly predisposed to developing a type of arthritis called ankylosing spondylitis, whereas people without the B27 allele appear to be protected against the disease (Caffrey and James, 1973).
The new findings show that the HLA class II alleles conferring risk for SLE encode proteins that are found in greater numbers on the surface of antigen-presenting cells than those encoded by alleles that do not increase the risk (Raj et al., 2016). These data suggest, for the first time, that the abundance of class II proteins on antigen-presenting cells could strongly influence risk of certain diseases.
It remains to be determined how differences in the abundance of class II molecules translate to increased disease risk. Higher levels of class II molecules on antigen-presenting cells could increase the chances that circulating immune cells bind to these molecules, and lead to more efficient immune and autoimmune responses. Another possibility is that the extra class II proteins on antigen-presenting cells could adversely affect a developmental process that would normally eliminate those immune cells that have the potential to cause autoimmune disorders.
Further studies now need to extend the analysis of Raj, Rai et al. to the other major class II alleles that are associated with disease in humans. It will also be important to see if this paradigm extends to the class I alleles. These studies will improve our understanding of the earliest events in autoimmunity and hopefully lead to new treatment options for autoimmune disorders.
References
-
The IPD and IMGT/HLA database: allele variant databasesNucleic Acids Research 43:D423–431.https://doi.org/10.1093/nar/gku1161
-
The NHGRI GWAS Catalog, a curated resource of SNP-trait associationsNucleic Acids Research 42:D1001–D1006.https://doi.org/10.1093/nar/gkt1229
Article and author information
Author details
Publication history
Copyright
© 2016, Wuster et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,213
- views
-
- 164
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Autoimmune Disorders: Thinking differently about lupus
eLife 5:e15352.
https://doi.org/10.7554/eLife.15352
Further reading
-
- Developmental Biology
- Genetics and Genomics
Repurposing of pleiotropic factors during execution of diverse cellular processes has emerged as a regulatory paradigm. Embryonic development in metazoans is controlled by maternal factors deposited in the egg during oogenesis. Here, we explore maternal role(s) of Caspar (Casp), the Drosophila orthologue of human Fas-associated factor-1 (FAF1) originally implicated in host-defense as a negative regulator of NF-κB signaling. Maternal loss of either Casp or it’s protein partner, transitional endoplasmic reticulum 94 (TER94) leads to partial embryonic lethality correlated with aberrant centrosome behavior, cytoskeletal abnormalities, and defective gastrulation. Although ubiquitously distributed, both proteins are enriched in the primordial germ cells (PGCs), and in keeping with the centrosome problems, mutant embryos display a significant reduction in the PGC count. Moreover, the total number of pole buds is directly proportional to the level of Casp. Consistently, it’s ‘loss’ and ‘gain’ results in respective reduction and increase in the Oskar protein levels, the master determinant of PGC fate. To elucidate this regulatory loop, we analyzed several known components of mid-blastula transition and identify the translational repressor Smaug, a zygotic regulator of germ cell specification, as a potential critical target. We present a detailed structure-function analysis of Casp aimed at understanding its novel involvement during PGC development.
-
- Genetics and Genomics
Recent studies have revealed a role for zinc in insulin secretion and glucose homeostasis. Randomized placebo-controlled zinc supplementation trials have demonstrated improved glycemic traits in patients with type II diabetes (T2D). Moreover, rare loss-of-function variants in the zinc efflux transporter SLC30A8 reduce T2D risk. Despite this accumulated evidence, a mechanistic understanding of how zinc influences systemic glucose homeostasis and consequently T2D risk remains unclear. To further explore the relationship between zinc and metabolic traits, we searched the exome database of the Regeneron Genetics Center-Geisinger Health System DiscovEHR cohort for genes that regulate zinc levels and associate with changes in metabolic traits. We then explored our main finding using in vitro and in vivo models. We identified rare loss-of-function (LOF) variants (MAF <1%) in Solute Carrier Family 39, Member 5 (SLC39A5) associated with increased circulating zinc (p=4.9 × 10-4). Trans-ancestry meta-analysis across four studies exhibited a nominal association of SLC39A5 LOF variants with decreased T2D risk. To explore the mechanisms underlying these associations, we generated mice lacking Slc39a5. Slc39a5-/- mice display improved liver function and reduced hyperglycemia when challenged with congenital or diet-induced obesity. These improvements result from elevated hepatic zinc levels and concomitant activation of hepatic AMPK and AKT signaling, in part due to zinc-mediated inhibition of hepatic protein phosphatase activity. Furthermore, under conditions of diet-induced non-alcoholic steatohepatitis (NASH), Slc39a5-/- mice display significantly attenuated fibrosis and inflammation. Taken together, these results suggest SLC39A5 as a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD) due to metabolic derangements including T2D.
