Overactive Immune System in Lupus Linked to Specific Triggers

April 27, 2016

The little-understood antibody immunoglobulin E (IgE) plays a previously unknown role in systemic lupus erythematosus, study in Nature Immunology finds.

The little-understood antibody immunoglobulin E (IgE) plays a previously unknown role in systemic lupus erythematosus, new research finds.

IgE is known to protect against parasitic worms and can also trigger intense allergic reactions. Now, a new study in Nature Immunology reveals a link between the antibody and the release of interferon-a, which in turn causes tissue damage in lupus.  

"This research has led to a groundbreaking discovery that IgE leads a double life as a trigger of allergy symptoms and a self-destructive agent in SLE. These findings could have tremendous implications for the lupus community," study senior author Miguel Sanjuan, a senior scientist at MedImmune, said in a statement. "In addition to the potential of targeting IgE in lupus patients, these findings show the scientific research community that there is a new realm of previously unknown activity of IgE that unleashes its pathogenic potential beyond orchestrating allergy symptoms, which may also be responsible for other autoimmune conditions."   

In a systemic lupus erythematosus cohort of 180 patients, 54.4 percent had double-strand DNA-specific IgE, compared to zero percent in healthy controls or patients with atopic dermatitis. Of patients with lupus nephritis, 70 percent exhibited dsDNA-specific IgE, a number that rose to 82 percent in those with the most-severe lupus nephritis class IV.  [[{"type":"media","view_mode":"media_crop","fid":"48065","attributes":{"alt":"©Aysezgicmeli/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_8319846975264","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5718","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"©Aysezgicmeli/Shutterstock.com","typeof":"foaf:Image"}}]]

Circulating dsDNA-specific IgE levels were correlated with the marker of disease activity C3, and patients with greater disease activity had higher levels of dsDNA-specific IgE, Sanjuan and his collagues found. A multivariate analysis using SLEDAI to measure disease activity found the following effects for dsDNA-specific IgE an IgG as risk factors, with a confidence interval of 95 percent:

·         Anti-dsDNA IgG: 0.00426 (0.000453-0.00807), p=0.029

·         Anti-dsDNA IgE: 0.157 (0.0583-0.256) p=0.0020

·         Anti-dsDNA IgG x anti-dsDNA IgE: -0.000232 (-0.000681-0.000218) p=0.31

To uncover the mechanisms behind the IgE link, the researchers exposed peripheral blood mononuclear cells to dsDNA-IgE-positive serum from lupus patients while blocking IgE from binding to its receptor. To their surprise, this blockade reduced the production of IFN-a, suggesting that IgE itself plays a role in abnormal interferon-a secretion in systemic lupus erythematosus. Further experimentation revealed the immunocomplexes of DNA and IgE induced IFN-a secretion, as complexes of DNA and IgG were previously known to do - and at similar levels.

The dsDNA-IgE immunocomplexes are recognized at the cell surface by FcεRI receptors, which deliver them into intracellular compartments to be recognized by the toll-like receptor TLR9. TLR9, in turn, triggers the production of IFN-a and other proinflammatory cytokines, the researchers wrote. The dsDNA-IgE immunocomplexes were also found to induce plasmacytoid dendritic cell-dependent B cell responses, the researchers wrote, and to prompt B cells to differentiate into plasma cells.

No patient was found to have IgE alone without IgG, the researchers found, likely because exposed DNA is snapped up by both immunoglobulins to form the disastrous immunocomplexes that trigger the autoimmune response. In combination, the two immunoglobulins elicited larger amounts of IFN-a secretion than either alone. This increased secretion resulted from more cells responding rather than the same amount of cells excreting more of the interferon, the researchers found, suggesting that IgE lowers the cellular threshold for response.

In the healthy immune system, IgE may work with IgG to improve the sensing of viruses, Sanjuan and his colleagues wrote. In that sense, the study helps illuminate the a wider role for this immunoglobulin than parasite defense. In the context of autoimmune disease, IgE's newly discovered role may make it particularly harmful - but also a potentially promising target for treatment.

"The previously unrecognized link between IgE and the interferon pathway that we have reported here provides additional insight into the pathological mechanisms underlying autoimmunity and might be useful in the rational design of therapies for the treatment of diseases such as SLE," Sanjuan and his colleagues wrote.

 

References:

Henault J, Riggs JM, Karnell JL, et al. Self-reactive IgE exacerbates interferon responses associated with autoimmunityNature Immunology Nat Immunol 2015;17(2):196–203. doi:10.1038/ni.3326.