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 HLA-B27     April 22, 2018  

HLA-B27: The Facts

HLA-B27 is an abbreviation for "Human Leukocyte Antigen B27", an HLA class I surface antigen that is encoded in the B locus in the major histocompatibility complex (MHC) on the short arm of chromosome (Fig. 1). It is distributed worldwide but with variable prevalence. One of its functions is to present antigenic peptides to T-lymphocytes (Fig. 2).

Antigen-binding cleft of HLA-B27 with bound antigenic peptide

                Figure 2
         Figure 1  

HLA-B27 was discovered in 1969,  and 4 years later was found to show a remarkable association with ankylosing spondylitis (AS), and related diseases called spondyloarthropathies (SpA). But more than 95% of the individuals in the general population with this gene never develop these diseases.

The strength of this disease association of HLA-B27 does vary, not only among the various forms of SpA but also among the many ethnic and racial groups worldwide. For example, among northern Europeans only 8% of the general population possesses HLA-B27, but more than 90% of the patients with AS possess this gene. In contrast, among African Americans 2% to 4% of the general population and only 50% to 60% of patients with AS possess this gene. The precise biological explanation for this remarkable association remains elusive.

The presence of HLA-B27 influences the clinical manifestations of AS because, although there are many similarities, the HLA-B27–positive patients have a significantly younger age at onset of their disease and a higher prevalence of episodes of eye inflammation (acute anterior uveitis) and hip joint involvement. Of interest, HLA-B27 homozygosity (inheriting HLA-B27 from both parents) does not affect the clinical manifestations of AS, but it does triple the risk of disease occurrence.

Remarkable polymorphism of HLA-B27

HLA-B27 shows a remarkable polymorphism, with an ever-increasing number of alleles. show an extremely varied racial and ethnic prevalence throughout the world, and it has now been established that not all of them are disease associated, although some of them may differ from the disease-associated subtype by only a single amino acid. Thus far, there are more than 133 known alleles of HLA-B27 based on nucleotide sequence differences. However, at the translated protein level, there are at least 106 known subtypes of HLA-B27 based on amino acid sequence differences because some of the mutations are located within introns and thus are silent, or they occur in exons but do not cause amino acid changes. These 106 subtypes can be encompassed by the numbering system HLA-B*27:01 to HLA-B*27:107 because one of the assignments—HLA-B*27:22—was subsequently withdrawn when it was found to be identical to HLA-B*27:06.

HLA-B*27:05 (specifically the HLA-B*27:0502 allele) is the most widely distributed disease-associated subtype in the world and has been the subject of most studies. The other common disease-associated subtypes are HLA-B*27:02 (Mediterranean populations) and HLA-B*27:04 (Chinese and other Asian populations). HLA-B*27:01, HLA-B*27:03, HLA-B*27:07, HLA-B*27:08, HLA-B*27:10, HLA-B*27:13, HLA-B*27:14, HLA-B*27:15, HLA-B*27:19, HLA-B*27:23, HLA-B*27:24, HLA-B*27:25 and HLA-B*27:49 are also known to be disease associated, or at least one or more AS patients possessing these subtypes have been observed. Most of the remaining subtypes are either too rare or are too recently described to have been evaluated for disease presence or association.

There are also differences among some of the HLA-B27 subtypes when it comes to disease association. Thus, whereas HLA-B*27:05 and HLA-B*27:02  seem to confer equal susceptibility to AS in Caucasian populations, HLA-B*27:06 (a common subtype in south-east Asia) and HLA-B*27:09 (a rare subtype found primarily on the Italian island of Sardinia) seem to lack association with typical AS. On the other hand, among Chinese populations, HLA-B*27:04 has been clearly demonstrated to show a stronger association with AS than HLA-B*27:05.

In conclusion, HLA-B27 represents a family of closely related proteins encoded by an ever-increasing number of alleles; not all of them are disease associated and an overwhelming majority of patients with this gene remain unaffected. Clinical diagnoses can be made in most patients with AS on the basis of the clinical history, physical examination, and radiographic and MRI findings. The HLA-B27 test cannot be used to screen an asymptomatic population to detect AS and related diseases, and the test should not be used as a routine diagnostic test. In certain patients the HLA-B27 test, when used properly, is of clinical value as an aid to further supporting or rejecting a diagnosis of AS. The HLA-B27 positive test result does not absolutely confirm the presence of AS; it merely provides a statement of increased probability of the existence of AS in the symptomatic patient. The test is therefore most useful to physicians who understand the use of probability reasoning in clinical decision making. 

This summary has been excerpted from the following REFERENCES
Khan MA. Remarkable Polymorphism of HLA-B27: An Ongoing Saga. Curr Rheumatol Report. 2010; 12: 337-41.
Khan MA. Ankylosing spondylitis and related spondyloarthropathies: The dramatic advances in the last decade.  Rheumatol. 2011;50:637-9.
Khan MA. HLA and spondyloarthropathies. In Mehra N (Ed). The HLA Complex in Biology and Medicine  Jaypee Brothers Medical Publishers, New Delhi, India. 2010: pp. 422-446.
Khan MA. ANKYLOSING SPONDYLITIS. Oxford University Press, New York, NY. 2009; pp. 1-147.

Khan MA. Polymorphism of HLA-B27:105 subtypes currently known. Curr Rheumatol Rep. 2013, 15(10):362. doi: 10.1007/s11926-013-0362-y.

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