Findings shed light on autoimmune disorders, produce vital research tools.
New research into the causes of the excessive inflammation that drives multiple sclerosis has identified a faulty “brake” within immune cells, a brake that should be controlling the inflammation. This points to a potential target for developing new therapies to treat multiple sclerosis and could have important implications for other autoimmune diseases, such as the colon disease colitis and the chronic skin condition atopic dermatitis.
Further, the work has produced new research models of multiple sclerosis symptoms such as movement disorders and balance control problems that have, until now, resisted efforts to mimic them effectively in the lab. These models represent important new tools in the efforts to better understand – and eventually cure – MS and other autoimmune conditions.
The researchers determined that a mutation in the gene Nlrp12 was causing immune cells known as T cells to go haywire. Normally, the researchers determined, the protein the gene produces acts as a brake within T cells to control the inflammatory response. But a mutation in that gene disrupts the natural process and provokes severe inflammation – with effects the researchers found most intriguing.
To the researchers’ surprise, the resulting inflammation did not produce the paralysis often associated with multiple sclerosis. It did, however, produce other MS symptoms — such as movement disorders and problems with balance control — which scientists have struggled to replicate in experimental lab settings.
“It’s important to note that MS is a spectrum disorder – some patients present with paralyzing conditions and some patients don’t,” said researcher John Lukens, PhD, of the University of Virginia School of Medicine Department of Neuroscience and its Center for Brain Immunology and Glia. “Not everybody’s symptoms are the same, so this might give us a glimpse into the etiology or pathogenesis of that family of MS.”
By blocking the inflammatory response, doctors may one day be able to control the symptoms it causes, both in MS and in other diseases driven by hyperinflammation.
About this neurology research
The article was authored by Lukens, of UVA and formerly of St. Jude Children’s Research Hospital; Prajwal Gurung, of St. Jude; Patrick J. Shaw, of St. Jude; Maggie J. Barr, of St. Jude; Md. Hasan Zaki, of the University of Texas Southwestern Medical Center; Scott A. Brown, of St. Jude; Peter Vogel, of St. Jude; Hongbo Chi, of St. Jude; and Thirumala-Devi Kanneganti, of St. Jude.
Source: Josh Barney – University of Virginia Health System Image Credit: The image credite to NIAID/NIH and is in the public domain Original Research:Abstract for “The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells” by John R. Lukens, Prajwal Gurung, Patrick J. Shaw, Maggie J. Barr, Md. Hasan Zaki, Scott A. Brown, Peter Vogel, Hongbo Chi, and Thirumala-Devi Kanneganti in Immunity. Published online April 14 2015 doi:10.1016/j.immuni.2015.03.006
The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells
Highlights •Deficiency in NLRP12 promotes the generation of hyperinflammatory T cell responses •Induction of EAE in Nlrp12−/− mice results in atypical neuroinflammatory disease •NLRP12 is an intrinsic regulator of T cells •Dysregulated IL-4 production causes T-cell-induced inflammation in Nlrp12−/− mice
Summary Missense mutations in the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing family of gene 12 (Nlrp12) are associated with periodic fever syndromes and atopic dermatitis in humans. Here, we have demonstrated a crucial role for NLRP12 in negatively regulating pathogenic T cell responses. Nlrp12−/− mice responded to antigen immunization with hyperinflammatory T cell responses. Furthermore, transfer of CD4+CD45RBhi Nlrp12−/− T cells into immunodeficient mice led to more severe colitis and atopic dermatitis. NLRP12 deficiency did not, however, cause exacerbated ascending paralysis during experimental autoimmune encephalomyelitis (EAE); instead, Nlrp12−/− mice developed atypical neuroinflammatory symptoms that were characterized by ataxia and loss of balance. Enhanced T-cell-mediated interleukin-4 (IL-4) production promotes the development of atypical EAE disease in Nlrp12−/− mice. These results define an unexpected role for NLRP12 as an intrinsic negative regulator of T-cell-mediated immunity and identify altered NF-κB regulation and IL-4 production as key mediators of NLRP12-associated disease.
“The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells” by John R. Lukens, Prajwal Gurung, Patrick J. Shaw, Maggie J. Barr, Md. Hasan Zaki, Scott A. Brown, Peter Vogel, Hongbo Chi, and Thirumala-Devi Kanneganti in Immunity. Published online April 14 2015 doi:10.1016/j.immuni.2015.03.006