Human leukocyte antigen-B27 has led to a three-decade quest

Fort Lauderdale, FL-James T. Rosenbaum, MD, has dedicated his career to ferreting out the secrets surrounding human leukocyte antigen B27 (HLA-B27) and its association with ankylosing spondylitis. He reviewed the relevant scientific discoveries and recounted his laboratory's contributions to the body of knowledge on the topic at the annual meeting of the Association for Research in Vision and Ophthalmology, where he delivered the Friedenwald Lecture.

Later, Hugh McDevitt, MD, Dr. Rosenbaum's mentor, discovered that the immune response is genetically controlled and that the major histocompatibility complex (MHC) dictated whether an antigen was recognized. The major MHC in humans is HLA. Dr. McDevitt predicted that this type of genetic control in specific immune responses may play an important role in the susceptibility to a variety of diseases in humans and other animals, Dr. Rosenbaum explained.

"This means that HLA-B27 increases the risk of developing ankylosing spondylitis about 100 times," said Dr. Rosenbaum, head of the Uveitis Clinic, director of Inflammatory Research, division chief of Arthritis and Rheumatic Diseases, and the Edward E. Rosenbaum Professor of Inflammatory Diseases, Casey Eye Institute, Oregon Health and Science University, Portland. "However, we still don't know why."

Wherever there is HLA-B27, there is ankylosing spondylitis, which in turn leads to acute anterior uveitis. Eight percent of the U.S. population has been estimated to be HLA-B27-positive, 14% of Finns, and as many as 50% of Haida Native Americans from British Columbia, according to Dr. Rosenbaum.

Three theories exist as to why HLA-B27 predisposes to inflammation. The first is that B27 directly affects the immune response leading to disease; however, no antigen has been uncovered that recognizes B27 uniquely. The second theory is that B27 dimerizes on cell surfaces and activates natural killer cells; and the third is that B27 stimulates the unfolded protein response.

"As good as these theories are, none is adequate," Dr. Rosenbaum said.

Reactive arthritis

When Dr. Rosenbaum started his fellowship in Dr. McDevitt's laboratory, he wanted to understand the association that Dr. McDevitt described previously.

Reactive arthritis, he pointed out, has a distinct relationship to infections, in that the disease occurs after infections caused by various pathogens, such as Salmonella, Shigella, Campylobacter, and Chlamydia. After injecting Lewis rats with these bacteria, he found that the rats did not develop arthritis, but they did get anterior uveitis. This model of endotoxin-induced uveitis provided lessons about cytokine synthesis in the eye, leukocyte migration into the eye, adhesion molecules, complement, and cell types and pathways that contribute to inflammation in the eye.

The model limitations are that it is independent of MHC, it induces transient bilateral inflammation as opposed to unilateral inflammation in humans, chronic inflammation was not possible, and it involved the innate (nonspecific) and not the adaptive (targeted) immune system. Until recently almost every immune-mediated disease was attributed to adaptive immune response.

B27-associated uveitis

Uveitis is a unilaterally occurring, acute, anterior disease. It also can be an intermediate or posterior disease, but in almost all cases it occurs in the anterior segment.

"Uveitis is a public health problem because children with juvenile rheumatoid arthritis and individuals in the prime of life get uveitis," Dr. Rosenbaum said. "The disease is tied with age-related macular degeneration and diabetic retinopathy when the number of years of vision loss is considered."

In addition to the ocular locations, uveitis also can be characterized by etiology-specifically, infection, immune-mediated syndromes localized to the eye, systemic immune-mediated syndromes, and masquerade syndromes such as lymphoma. Of the 20 or so systemic immune-mediated syndromes, 16 involve the eye and the joint.