New genetic mechanism of immune deficiency discovered

April 20, 2012

Researchers at National Jewish Health have discovered a novel genetic mechanism of immune deficiency. Magdalena M. Gorska, MD, PhD, and Rafeul Alam, MD, PhD, identified a mutation in Unc119 that causes immunodeficiency known as idiopathic CD4 lymphopenia. Unc119 is a signaling protein that activates and induces T cell proliferation.

The mutation impairs Unc119 ability to activate . Dr. Gorska, will present her findings April 20 at Translational Science 2012, an NIH-funded conference in Washington D.C.

"A better understanding of the molecular mechanisms associated with this mutation will improve diagnosis and pave the way for development of new therapies," said Dr. Gorska.

Drs. Gorska and Alam previously published their findings in the journal Blood and Dr. Gorska delivered a Presidential Plenary on the topic at the annual meeting of the American Academy of Allergy & Immunology.

Nearly a decade ago Drs. Alam and Gorska identified Unc119 as a novel activator of SRC-type tyrosine kinases, important regulators of cellular function. Since then, they have published numerous papers where they characterized the function of this protein in various aspects of the immune system. Idiopathic CD4 lymphopenia is a rare and heterogeneous syndrome defined by low levels of CD4 T cells in the absence of HIV infection, which predisposes patients to infections and malignancies. Recent research by others had linked the syndrome to reduced activation of the SRC-type kinase known as Lck. The latter kinase is involved in T cell development, activation and proliferation.

So, Drs. Alam and Gorska thought Unc119, an activator of Lck, might be involved. They kept an eye out for patients with CD4 lymphopenia coming to National Jewish Health, which specializes in immune-related disorders as well as respiratory and cardiac diseases. They identified three patients with CD4 lymphopenia, then sequenced their Unc119 gene as well as the Unc119 gene in several patients who suffered low CD4 T cell counts as a result of other conditions.

One of the three patients, a 32-year-old woman with a history of recurrent infections, had a missense mutation in her Unc119 gene. The same mutation was not present in other lymphopenia patients nor in any genetic database.

The researchers then performed several studies with the woman's blood cells, to understand the mutation's effect. They introduced the mutated gene into normal T cells and examined the outcome. The mutation prevents Lck activation and its downstream signaling. It also reduces the amount of Lck found near the plasma membrane, where it plays a major role in propagating signals from the T-cell receptor. Proliferation of T cells, which normally occurs on stimulation of T-cell receptors, was profoundly reduced in cells from the patient.

"Since we originally published our findings earlier this year, we have received inquiries from many physicians with lymphopenia subjects," said Dr. Alam. "Working with them, we expect to find several more patients with this novel mutation, which should help us better understand its effect, improve diagnosis and possibly find therapies."

At this point there is no treatment for caused by this mutation other than close monitoring of the patient and treatment of resulting infections and malignancies.

Explore further: New memory for HIV patients

Related Stories

New memory for HIV patients

March 26, 2012

The hallmark loss of helper CD4+ T cells during human immunodeficiency virus (HIV) infection may be a red herring for therapeutics, according to a study published on March 26th in the Journal of Experimental Medicine.

Recommended for you

Research could lead to better vaccines and new antivirals

February 27, 2017

Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new regulator of the innate immune response—the immediate, natural immune response to foreign invaders. The study, published recently ...

Nature study suggests new therapy for Gaucher disease

February 22, 2017

Scientists propose in Nature blocking a molecule that drives inflammation and organ damage in Gaucher and maybe other lysosomal storage diseases as a possible treatment with fewer risks and lower costs than current therapies.

T cells support long-lived antibody-producing cells

February 21, 2017

If you've ever wondered how a vaccine given decades ago can still protect against infection, you have your plasma cells to thank. Plasma cells are long-lived B cells that reside in the bone marrow and churn out antibodies ...

Understanding how HIV evades the immune system

February 21, 2017

Monash University (Australia) and Cardiff University (UK) researchers have come a step further in understanding how the human immunodeficiency virus (HIV) evades the immune system.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.