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Figure 12.8 Evolutionary relationships of HLA-B27 molecular subtypes in the context of the 'parent' subtype HLA-B*2705. Three major families of HLA-B27 subtypes are shown together with HLA-B*2713 and B*2718, which are assumed to have evolved separately. Subtypes differ from B*2705 by amino acid substitutions in the al and a2 domains with the number of differences shown. The predominant ethnic group in which the subtype was described is also listed. Reprinted from Reveille (2006), copyright 2006, with permission from Elsevier.

Figure 12.8 Evolutionary relationships of HLA-B27 molecular subtypes in the context of the 'parent' subtype HLA-B*2705. Three major families of HLA-B27 subtypes are shown together with HLA-B*2713 and B*2718, which are assumed to have evolved separately. Subtypes differ from B*2705 by amino acid substitutions in the al and a2 domains with the number of differences shown. The predominant ethnic group in which the subtype was described is also listed. Reprinted from Reveille (2006), copyright 2006, with permission from Elsevier.

disease but there are some notable examples of this, such as *2706 found in South East Asia and the *2709 subtype common in Sardinia, which are not associated with disease risk and their structural analysis has led to intriguing insights into disease mechanism (Montserrat et al. 2003; Goodall et al. 2006).

The particular subtypes result from polymorphism in the amino acid composition of the antigenic cleft of the B27 molecule, changing the potential peptides presented or the interaction with the peptide loading complex molecule tapasin (Fig. 12.9). For example, the only difference between the disease associated *2705 subtype and the non-associated *2709 subtype is an aspartate to histidine polymorphism in the peptide binding groove at a position important to anchoring the C-terminal peptide residue; this change alters the repertoire of peptides bound by the two molecules.

Given the extent of research effort directed at HLA-B27 it is perhaps surprising that we still do not understand the mechanism underlying the undoubted association between the possession of HLA-B27 and ankylosing spondylitis. A number of models have been proposed but none have been conclusively demonstrated (Box 12.10). Animal studies have given some insight into the

Antigenic peptide

Antigenic peptide

Enlargement of peptide binding groove

Figure 12.9 Structure of the HLA-B27 molecule. Ribbon diagram showing the HLA heavy chain (a1, a2, and a3 domains) of HLA-B27 molecule, P2 microglobulin (light grey), and the bound peptide. Reprinted from Bowness et al. (1999), with permission from Cambridge University Press.

Enlargement of peptide binding groove

Figure 12.9 Structure of the HLA-B27 molecule. Ribbon diagram showing the HLA heavy chain (a1, a2, and a3 domains) of HLA-B27 molecule, P2 microglobulin (light grey), and the bound peptide. Reprinted from Bowness et al. (1999), with permission from Cambridge University Press.

Box 12.10 Models of HLA-B27 and disease mechanism in ankylosing spondylitis

• Arthritigenic peptide hypothesis. The antigen presenting ability of HLA-B27 may be crucial to disease pathogenesis. The presentation of particular 'arthritogenic' peptides by HLA-B27 following infection could result in inflammation. Certain disease associated subtypes will, for example, present peptide from Chlamydia trachomatis (*2705, *2702, *2704) while others (*2706 and *2709) will not (Ramos et al. 2002).

• Molecular mimicry. Homology was noted between a particular amino acid sequence of HLA-B27 and Klebsiella pneumoniae, with antibody raised to the homologous peptide antigen cross-reacting with HLA-B27 (Schwimmbeck and Oldstone 1988). Cross reactivity by pathological antibodies to foreign antigens may invoke an autoimmune response resulting in disease. If foreign antigens mimicked self peptide constitutively presented by HLA-B27, this could break tolerance and induce chronic inflammation through an autoimmune response (Benjamin and Parham 1990).

• 'Altered self' model of disease. This model involves the unique property of HLA-B27 molecules to misfold and form homodimers, rather than the usual association with P2 microglobulin. This is promoted by oxidizing conditions such as within activated macrophages and can promote a proin-flammatory unfolded protein, intracellular stress response or act as an antigen if presented on the cell surface.

• Host defence. HLA-B27 may alter intracellular invasion and killing of pathogens such as Salmonella.

molecular mechanism underlying the HLA-B27 association. Informative studies have been predominantly limited to rats where arthritic disease could be experimentally induced. Transgenic rats expressing B27 and human P2 microglobulin showed a phenotype with most of the features of HLA-B27 associated disease seen in humans (Hammer et al. 1990). Peripheral and axial arthritis, gut inflammation, and genital and skin lesions were observed. The penetrance of the transgene is, however, affected by the genetic background of the rat studied.

Ankylosing spondylitis is one of a number of rheumatic diseases called seronegative spondyloarthropathies. These are common, chronic inflammatory disorders characterized by inflammation of the spine and sacroiliac joints leading to bone and joint erosions and ankylosis of the spine. Peripheral joint arthritis is also commonly found, with ocular (uveitis), cardiovascular, and pulmonary involvement seen more rarely. In the same year that Brewerton and colleagues reported the association between HLA-B27 and ankylosing spondylitis, they also found significant overrepresentation of HLA-B27 among cases of Reiter syndrome (reactive arthritis) and an inflammatory disorder affecting the eye, anterior uveitis. These results have since been substantiated with significant associations between HLA-B27 and reactive arthritis, juvenile spondyloarthrthritis, psoriatic arthritis and spondylitis, and enteropathic arthropathy (Reveille and Arnett 2005). The underlying pathogenic role of the HLA-B27 molecule in disease pathogenesis remains unresolved but the clinical utility of typing HLA-B27 in the diagnosis of spondyloarthropathies is substantial.

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