Autoimmune Disease

Autoimmune Disease

The National Institutes of Health estimate that more than 23 million Americans suffer from autoimmune disease, making it one of the most prevalent categories of disease, ahead of both disease and cancer.

Overview

The immune system is a finely engineered defense system designed to shield our body from harmful pathogens and cancer cells. But sometimes the battle gets out of hand and the immune system turns on the very “self” it is meant to protect. What results are chronic autoimmune and inflammatory conditions that, over time, lead to tissue damage.

Investigators have catalogued over 80 such conditions: prominent among them are type 1 diabetes, in which immune cells destroy insulin-producing pancreatic cells, rheumatoid arthritis (RA), which attacks the lining of joints, and multiple sclerosis (MS), which irreparably damages the myelin sheath that covers nerve fibers. Related conditions include pathologies that don’t seem intuitively “autoimmune,” such as heart disease or Alzheimer’s, both of which have an inflammatory component.

Autoimmune Disease on the Rise

For reasons not yet understood, the incidence of autoimmune diseases is increasing in developed countries. Some attribute this surge to environmental toxins that incite an immune attack, and others to the obesity pandemic, as adipose tissue generates inflammatory factors. Others say it stems from exposure to bacterial or viral pathogens that induce a “mimicry response”, in which the body mistakes its own healthy cells for infected ones.

Whatever the cause, inappropriate mobilization of T cells against a person’s own tissues occurs in almost all autoimmunity. The good news is that a familiar cast of immune cell players often drives or repels the attack, meaning that drugs aimed at the pro-inflammatory contingent can sometimes be effective against multiple conditions. Among the most familiar are corticosteroids, wonder drugs first used 50 years ago to treat rheumatoid arthritis (RA) and now found in ointment form in most medicine cabinets.

Steroids have brought relief to sufferers of autoimmune conditions (and also saved lives of transplant patients) but their side effects limit long-term use. For patients with life-long autoimmune disease, non-steroidal treatments are now an option, thanks in part to what we’ve learned after almost three decades of research, some conducted at LJI, about signaling factors known as tumor necrosis factor (TNF) proteins.

New TNF blockers
TNF proteins, or “pro-inflammatory cytokines”, foment beneficial and harmful immune attacks by summoning lymphocytes to an inflammatory site and activating inflammation-related gene expression. Drugs blocking those signals, called TNF inhibitors, are now routinely used to treat RA and inflammatory bowel disease (IBD), but not all patients respond to them. For those individuals, LJI scientists are researching new ways to target TNF and even devising next-generation drugs to disrupt parallel anti-inflammatory pathways. Among the former, potential therapies emerging at LJI include novel anti-TNF drugs to treat two prominent IBDs: Crohn’s disease and ulcerative colitis, and the skin disease psoriasis, all of which are in clinical trials.

Among alternate strategies, LJI investigators are creating reagents to block activity of protein kinase C theta (PKCθ), an enzyme first discovered by LJI scientist, Amnon Altman, Ph.D., in the mid-90’s. PKCθ activates T cells, prompting drug companies to develop pharmaceuticals to block its catalytic activity to treat autoimmune conditions. However, given that PKCθ also has anti-infection activity, LJI scientists are taking a different tack by exploring ways to disrupt PKCθ interaction with a receptor expressed on T-cells. That strategy could block a destructive autoimmune response without compromising the body’s ability to fight infections.

LJI biologists also study structural proteins called septins, which form a molecular scaffold or cage around calcium channels that stud the surface of T cells. Opening of those channels is necessary to activate T cells, and LJI investigators have evidence that septins coordinate that activity. If so, that suggests that septins themselves could be targeted to dampen T cell activity when the immune system becomes overactive.

FACULTY MEMBERS

altman
Amnon Altman, Ph.D.
Dr.HildeCheroutre
Hilde Cheroutre, Ph.D.
Dr.MickCroft2
Michael Croft, Ph.D.
LynnH
Catherine “Lynn” Hedrick, Ph.D.
von-herrath
Matthias von Herrath, M.D.
Hogan1
Patrick Hogan, Ph.D.
kawakami
Toshiaki Kawakami, M.D., Ph.D.
kronenberg
Mitchell Kronenberg, Ph.D.
Klaus Ley
Klaus Ley, M.D.
liu
Yun-Cai Liu, Ph.D.
rao
Anjana Rao, Ph.D.
Zajonc,Dirk
Dirk Zajonc, Ph.D.

From The Lab

Mar 27, 2017

Scientists make advance against Type 2 diabetes

Mar 6, 2017 // San Diego Union Tribune

Engineered red blood cells can relieve autoimmune diseases, study finds

Dec 7, 2016

TET proteins drive early neurogenesis

Nov 13, 2016 // The San Diego Union Tribune

Our perpetually vigilant internal guardian

Nov 1, 2016

LJI scientists flip molecular switches to distinguish closely related immune cell populations