1. Genetics and Genomics

Autoimmune Disorders: Thinking differently about lupus

https://doi.org/10.7554/eLife.15352
  • Download
  • Cite
  • CommentOpen annotations (there are currently 0 annotations on this page).
Share this article
Cite this article
  1. Arthur Wuster
  2. Timothy W Behrens
(2016)
Autoimmune Disorders: Thinking differently about lupus
eLife 5:e15352.
https://doi.org/10.7554/eLife.15352
  2. Download BibTeX
  3. Download .RIS
  1. Arthur Wuster
  2. Timothy W Behrens  Is a corresponding author
  1. 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

Article and author information

Author details

  1. Arthur Wuster

    Genentech Inc., South San Francisco, United States
    Competing interests
    AW, TWB are full-time employees of Genentech, Inc.

  2. Timothy W Behrens

    Genentech Inc., South San Francisco, United States
    For correspondence
    behrens.tim@gene.com
    Competing interests
    AW, TWB are full-time employees of Genentech, Inc.

Publication history

  1. Version of Record published:

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.

Download links

Categories and tags

Research organism

    1. Related to

    Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

    Prithvi Raj, Ekta Rai ... Edward K Wakeland
  2. Further reading

Further reading

    1. Genetics and Genomics

    Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

    Prithvi Raj, Ekta Rai ... Edward K Wakeland
    Research Article Updated

    Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.

    1. Genetics and Genomics
    2. Microbiology and Infectious Disease

    Control of pili synthesis and putrescine homeostasis in Escherichia coli

    Iti Mehta, Jacob B Hogins ... Larry Reitzer
    Research Article

    Polyamines are biologically ubiquitous cations that bind to nucleic acids, ribosomes, and phospholipids and, thereby, modulate numerous processes, including surface motility in Escherichia coli. We characterized the metabolic pathways that contribute to polyamine-dependent control of surface motility in the commonly used strain W3110 and the transcriptome of a mutant lacking a putrescine synthetic pathway that was required for surface motility. Genetic analysis showed that surface motility required type 1 pili, the simultaneous presence of two independent putrescine anabolic pathways, and modulation by putrescine transport and catabolism. An immunological assay for FimA—the major pili subunit, reverse transcription quantitative PCR of fimA, and transmission electron microscopy confirmed that pili synthesis required putrescine. Comparative RNAseq analysis of a wild type and ΔspeB mutant which exhibits impaired pili synthesis showed that the latter had fewer transcripts for pili structural genes and for fimB which codes for the phase variation recombinase that orients the fim operon promoter in the ON phase, although loss of speB did not affect the promoter orientation. Results from the RNAseq analysis also suggested (a) changes in transcripts for several transcription factor genes that affect fim operon expression, (b) compensatory mechanisms for low putrescine which implies a putrescine homeostatic network, and (c) decreased transcripts of genes for oxidative energy metabolism and iron transport which a previous genetic analysis suggests may be sufficient to account for the pili defect in putrescine synthesis mutants. We conclude that pili synthesis requires putrescine and putrescine concentration is controlled by a complex homeostatic network that includes the genes of oxidative energy metabolism.

    1. Genetics and Genomics

    UBR-1 deficiency leads to ivermectin resistance in Caenorhabditis elegans

    Yi Li, Long Gong ... Shangbang Gao
    Research Article

    Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.