Marko A. Radic, PhD

University of Tennessee, Memphis, TN

2009 B Cells
2005 Environmental Triggers

Defects in the body’s removal of dead cells stimulate the production of damaging autoantibodies in lupus

With LRI funding, Dr. Radic and his team will examine interactions between “apoptotic bodies,” which are generated when cells break down, and the B cells that produce autoantibodies in lupus. He will isolate the apoptotic bodies, characterize the DNA found at their surface—and then construct “artificial” apoptotic bodies.

By mixing artificial apoptotic bodies and self-reactive B cells, Dr. Radic will take what is considered the first step in designing a “Poison Pill” therapeutic approach to switching off precisely those B cells that are responsible for pumping out lupus antibodies and causing so much destruction to otherwise healthy organs and tissues.

With LRI funding in 2005, Dr. Radic pursued a high-risk but potentially high-yield idea that common germs may sometimes trigger lupus, documenting that a bacterial or viral infection can indeed trigger chemical modifications to proteins on immune system cells that end up generating autoimmune assaults.

Published in February's 2008’s Journal of Immunology, his discovery could explain why autoimmune diseases often first appear following an infection.

The discovery

The human immune system is programmed to ignore the proteins that make up our own cells. But this state of tolerance can break down, causing the immune system to launch a devastating attack on the body itself.

What causes tolerance to break down? One theory is that proteins are chemically modified in such a way that the immune system no longer recognizes them as ‘self’ and so attacks them as if they were invading viruses or bacteria.

Researchers are especially interested in how tolerance to DNA packaging proteins, known as histones, is broken as these proteins are a focus of immune attack in lupus.

Dr. Radic and his team at the University of Tennessee Health Sciences Center in Memphis suspected that a particular modification of proteins known as citrullination could break tolerance to histones as patients with the related autoimmune disease rheumatoid arthritis have antibodies directed at citrullinated proteins. They wanted to know what causes histones to become citrullinated.

Dr. Radic knew that white blood cells known as neutrophils were the most adept at citrullination. And he expected that citrullination would happen in dying cells. But he quickly discovered that this was not the case; neutrophils only citrullinated histones when they were activated to respond to infection (and were very much alive).

Moreover, Dr. Radic found that activated neutrophils expel citrullinated histones as part of a sticky rope-like structure, which they throw out in order to trap and kill bacteria. This explains how a modified protein normally found inside cells might be ‘seen’ by the immune system—and trigger an autoimmune attack.

This new theory to explain the triggering of autoimmunity is supported by observations in people. For example, patients with autoimmune diseases often have an infection (and therefore lots of neutrophil activity) just before their symptoms flare up.

Select publications:

Histone deimination as a response to inflammatory stimuli in neutrophils. Neeli I, Khan SN, Radic M. J Immunol. 2008 Feb 1;180(3):1895-902.

Regulation of Extracellular Chromatin Release from Neutrophils. Journal of Innate Immunity. I Neeli, N Dwivedi, S Khan, M Radic. J Innate Immunol. 2009 1(3):194-201.

Intra-Golgi Formation of IgM-Glycosaminoglycan Complexes Promotes Ig Deposition. Khan SN, Cox JV, Nishimoto SK, Chen C, Fritzler MJ, Hendershot LM, Weigert M, Radic M. J Immunol. 2011 Sep 15;187(6):3198-207. Epub 2011 Aug 12.

Ongoing funding:

Dr. Radic won a $600,000 grant from the Dana Foundation, along with LRI researchers Dr. Zhang and Dr. Weigert, to continue working on an aspect of his lupus research.

Rev. September 2011

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