Genetic mutation leads to cold allergy, immune deficiency and autoimmunity

January 11, 2012

Investigators at the National Institutes of Health have identified a genetic mutation in three unrelated families that causes a rare immune disorder characterized by excessive and impaired immune function. Symptoms of this condition include immune deficiency, autoimmunity, inflammatory skin disorders and cold-induced hives, a condition known as cold urticaria.

The study was led by Joshua Milner, M.D., in the Laboratory of at the National Institute of Allergy and Infectious Diseases (NIAID), and Daniel Kastner, M.D., Ph.D., scientific director at the National Institute (NHGRI). It will appear in the online edition of the on Jan. 11, 2012.

The mutation discovered occurs in a gene for phospholipase C-gamma2 (PLCG2), an enzyme involved in the activation of cells. The investigators have named the condition PLCG2-associated antibody deficiency and immune dysregulation, or PLAID.

"Investigating gives researchers more clues about how the healthy immune system functions," says NIAID Director Anthony S. Fauci, M.D. "More importantly, identifying the genetic cause of these disorders opens up possibilities for better disease management and potentially a cure for people who may have spent their entire lives debilitated by severe and unexplained symptoms."

The NIH study involved 27 people from three separate families who all suffered from an inherited form of cold urticaria, an allergic disease characterized by the formation of itchy, sometimes painful hives, episodes of fainting and, in certain cases, life-threatening reactions in response to cold temperatures.

Blood sample analysis revealed that many patients produced antibodies to their own cells and tissues (autoantibodies), making them more susceptible to developing autoimmune disease. More than half had a history of recurrent infections, and laboratory tests revealed that most had low levels of infection-fighting antibodies and low numbers and reduced activity of circulating immune B cells—all symptoms of immune deficiency disease. In three cases, patients had common variable immunodeficiency, a disease that requires frequent intravenous infusions of immune globulin to prevent severe infections. Seven patients suffered from granulomas, inflamed masses of tissue, which formed on their fingers, ears, nose and other parts of their skin.

"This is one of few examples in which the allergy symptom directed us to a genetic syndrome," says Dr. Milner. "In trying to understand the link between this group of conditions—autoimmunity, chronic infections and cold urticaria—we not only identified a disease-causing mutation but uncovered a unique and fascinating genetic mechanism at the crux of allergy, immune defense and self-tolerance."

"This study illustrates the power of multidisciplinary teamwork involving clinicians, geneticists and basic immunologists to get to the heart of seemingly insoluble medical mysteries," says Dr. Kastner. "Our team and colleagues working in the field now have much better odds of improving health outcomes for people with PLAID and for understanding this gene's role in other disorders."

The NIAID investigators teamed up with gene hunting experts in Dr. Kastner's laboratory and found the PLCG2 mutation after performing gene analysis and DNA sequencing studies. The mutation caused the PLCG2 enzyme to function without shutting off. Despite the fact that the enzyme was constantly turned on, immune cells ignored its signaling and did not activate normally.

Investigators performed a series of laboratory experiments to understand how the PLCG2 mutation affects B cells and mast cells, immune cells that contain histamine and other chemicals that are released during an allergic response. Patients' B cells containing the mutated gene fail to turn on normally, leading to their inability to produce antibody, but also an inability to sense when they are producing autoantibodies. Laboratory-developed mast cells containing the mutated gene released chemicals on exposure to cool temperatures, which could explain why the patients developed cold-induced hives.

According to the investigators, their findings suggest that inhibiting PLCG2 activity could be a therapeutic strategy to treat cold-induced hives, autoimmunity and immune deficiency in people with PLAID, but more studies are needed. The study findings also suggest that people previously diagnosed with common variable immunodeficiency disease or with granulomatous diseases could have a PLCG2 gene mutation. Further study is needed to understand PLAID and how mutations in PLCG2 could contribute to other allergic and immunologic disorders.

"These findings are gratifying both for researchers and for people with this disorder," says NHGRI Director Eric Green, M.D., Ph.D. "Furthermore, this study illustrates how genome-analysis methods can empower efforts to unravel the molecular basis of rare genetic diseases."

Explore further: To treat rare disease, NIH scientists repurpose FDA-approved drug

More information: Ombrello MJ et al. Cold urticaria, immune deficiency and autoimmunity due to PLCG2 deletions. New England Journal of Medicine. DOI:10.1056/NEJMoa1102140 (2012).

Related Stories

To treat rare disease, NIH scientists repurpose FDA-approved drug

September 2, 2011
A new study reports that a drug already approved by the Food and Drug Administration for use in patients undergoing a bone marrow transplant may also have promise for treating people who have a rare immune deficiency known ...

Recommended for you

Exosomes are the missing link to insulin resistance in diabetes

September 21, 2017
Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked, until now.

Thousands of new microbial communities identified in human body

September 20, 2017
A new study of the human microbiome—the trillions of microbial organisms that live on and within our bodies—has analyzed thousands of new measurements of microbial communities from the gut, skin, mouth, and vaginal microbiome, ...

Study finds immune system is critical to regeneration

September 20, 2017
The answer to regenerative medicine's most compelling question—why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot—may lie with the body's innate immune system, ...

Immune cells produce wound healing factor, could lead to new IBD treatment

September 20, 2017
Specific immune cells have the ability to produce a healing factor that can promote wound repair in the intestine, a finding that could lead to new, potential therapeutic treatments for inflammatory bowel disease (IBD), according ...

As men's weight rises, sperm health may fall

September 20, 2017
(HealthDay)—A widening waistline may make for shrinking numbers of sperm, new research suggests.

New model may help science overcome the brain's fortress-like barrier

September 19, 2017
Scientists have helped provide a way to better understand how to enable drugs to enter the brain and how cancer cells make it past the blood brain barrier.

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.