RHEUMATOLOGY GRAND ROUNDS AT RUSH EDITORS:ROBERT S. KATZ, MD, AND JOEL A. BLOCK, MD HLA-B27 and Its Pathogenic Role Muhammad Asim Khan, MD, MACP, FRCP T he year 1973 is a very memorable year for me because it was the year that the remarkable association was first reported between HLA-B27 and ankylosing spondylitis (AS), as I had suffered since 1956 from this illness. Moreover, in 1973, I passed on my HLA-B27 gene to my first offspring, finished my fellowship training in rheumatology, and started my academic career. DISCOVERY OF HLA-B27 It was Erik Thorsby from Norway who first described HLA-B27, originally named TH-FJH. 1 It was detected by using an antibody that was produced by “planned immuni- zation,” a method that was being used by several investi- gators. He immunized a colleague, FJH, with a skin trans- plant and cells from a healthy donor who was HLA identical with the recipient because Eric assumed that the donor might possess a hitherto undetected HLA antigen. The recipient produced an antibody that detected a “new” antigen, which he named TH-FJH, and this antigen was later given the name HLA-B27. Erik told me that later when he tested his own family, he noticed that one family member who carried this new antigen had AS, whereas another had questionable AS (per- sonal communication). However, since most of his family members who carried the new antigen were completely healthy, he discarded this finding as being caused by chance. He has ever since regretted that he did not pursue this possible association by testing some other patients who suf- fered from AS. Had he done so he would have been the very first to detect an association between an HLA antigen and a disease! HLA-B27 PREVALENCE AND DISEASE ASSOCIATION The prevalence of HLA-B27 varies markedly in the various population groups worldwide (see Table 1). 2 Its association with AS is among the strongest of an MHC antigen and any disease. HLA-B27 also shows a strong association with the related spondyloarthropathies (SpA), although not as strong as with AS (Table 2). 2 Moreover, the strength of these disease associations also varies among the various ethnic and racial groups worldwide. 2–5 Speaking in general terms, the prevalence of AS roughly correlates with the prevalence of HLA-B27 but with certain glaring excep- tions. For example, HLA-B27 is present in West African countries, such as Senegal and Gambia, but it is very difficult to find any cases of AS in these countries. CLINICAL UTILITY OF HLA-B27 TEST AS AN AID TO DIAGNOSIS To use of B27 typing as an aid to diagnosis in clinical medicine, we must know how to use laboratory tests that are imperfect; i.e., they are neither 100% sensitive nor 100% specific and cannot be used as a diagnostic or screening test. The result of the test has to be interpreted in light of the a priori clinical likelihood that the person had that disease before the test was ordered. Those interested in this subject are referred to my prior publications on this subject. 3–6 HLA-B27 POSITIVE VERSUS HLA-B27 NEGATIVE DISEASE There are phenotypic differences between B27 positive and B27 negative patients with AS; for example the B27- positive patients are significantly more likely to get acute anterior uveitis and are more likely to have a family history of AS and related spondyloarthropathies than a B27 negative patient. 7 The disease can occur in the absence of B27 because there are additional yet undiscovered disease-predisposing genes in the rest of the genome that are also playing a role. One such gene lies on chromosome 9 that is strongly asso- ciated with acute anterior uveitis in patients with AS. 8 HLA-B27 HOMOZYGOSITY AND DISEASE ASSOCIATION Many years ago, we first reported that B27 homozy- gosity increases the likelihood of disease by a factor of more than 3. 9 This aspect was not thoroughly pursued by other investigators since then, but finally this observation has recently been confirmed. 10 Why is it that homozygous indi- viduals with B27 are at least 3 times more likely to get the disease as opposed to heterozygous individuals? If some of the B27-extended haplotypes carry additional genetic risk factors for AS, both inside and outside the MHC region on chromosome 6, it would not be surprising that an individual From Rheumatology Grand Rounds at Rush University Medical Center, Chicago, IL USA. Editors: Robert S. Katz, MD, and Joel A. Block, MD. From the Case Western Reserve University, MetroHealth Medical Center, Division of Rheumatology, Cleveland, OH. Reprints: Muhammad Asim Khan, MD, MACP, FRCP, Case Western Reserve University, MetroHealth Medical Center, Division of Rheuma- tology, 2500 MetroHealth Drive, Cleveland, OH 44109-1998. E-mail: mkhan@metrohealth.org. Copyright © 2008 by Lippincott Williams & Wilkins ISSN: 1076-1608/08/1401-0050 DOI: 10.1097/RHU.0b013e3181637a38 JCR: Journal of Clinical Rheumatology • Volume 14, Number 1, February 2008 50