Spondyloarthritis: update on pathogenesis and management John D. Reveille, MD, Frank C. Arnett, MD  The American Journal of Medicine  Volume 118, Issue 6, Pages 592-603 (June 2005) DOI: 10.1016/j.amjmed.2005.01.001 Copyright © 2005 Elsevier Inc. Terms and Conditions

Figure 1 The crystallized structure of HLA-B27, looking down into the antigen binding cleft. Seen here is the crystallized HLA-B27 molecule, with the viewer looking down into the antigen binding cleft. The positions in the molecule of the amino acid differences defining first 11 HLA-B27 subtypes are depicted, as well as the “B” pocket of the antigen binding cleft, which has a unique structure in HLA-B27 molecules, and the lysine amino acid residue at position 70, unique to HLA-B27.10,116 The American Journal of Medicine 2005 118, 592-603DOI: (10.1016/j.amjmed.2005.01.001) Copyright © 2005 Elsevier Inc. Terms and Conditions

Figure 2 Unique intracellular and extracellular functions of HLA-B27 which may affect susceptibility of spondyloarthritis. a) The HLA-B27 heavy chain is transcribed off of ribosomes in macrophages, folded onto B2 microglobulin, and antigenic peptide loaded via the TAP proteins onto it in the endoplasmic reticulum. Thence the trimolecular peptide complex (HLA-B27 heavy chain, B2 microglobulin and peptide) travels to the cell surface, where the antigenic peptide is presented either to the α:β T cell receptor on CD8 positive T lymphocytes or to the killer immunoglobulin (KIR) receptor on natural killer (NK) cells; b) the HLA-B27 heavy chain misfolds in the endoplasmic reticulum, forming B27 homodimers and other misfolding, where it either: b1) accumulates there causing a proinflammatory ER stress response; or b2) the B27 homodimers migrate to the cell surface where they either become antigenic themselves or present peptides to receptors on other inflammatory cells; c) intracellular impairment of peptide processing or loading into HLA-B27 by viruses or intracellular bacteria causes a selective impairment of the immune response; or d) the trimolecular complex present processed peptide to the α:β T cell receptor on CD4 positive T lymphocytes, or free HLA-B27 heavy chains or HLA-B27 homodimers are recognized as antigenic by the T cell receptor thence, or processed antigenic fragments of HLA-B27 are presented to the T cell receptor of CD4 positive T lymphocytes. The American Journal of Medicine 2005 118, 592-603DOI: (10.1016/j.amjmed.2005.01.001) Copyright © 2005 Elsevier Inc. Terms and Conditions

Figure 3 Chromosomal regions implicated in susceptibility to spondyloarthritis and related diseases. Included here are regions on chromosomes 2q, 6p (the major histocompatibility complex [MHC]), 6q, 10q, 11q and 16q where linkage to ankylosing spondylitis (AS) have been reported; regions on 1q and 9p in acute anterior uveitis (AAU); a region on 9q linked to spondyloarthritis (SpA); 9 regions linked to psoriasis susceptibility (PSORS 1-7; PSORS 9); a locus on 16q linked to psoriatic arthritis (PsA) susceptibility; and (IBD 1-6, IBD 9). Chromosomal locations of IBD and PSORS genes are listed at www.ncbi.nlm.nih.gov/entrez/dispomim.cg. The American Journal of Medicine 2005 118, 592-603DOI: (10.1016/j.amjmed.2005.01.001) Copyright © 2005 Elsevier Inc. Terms and Conditions

Figure 4 Sacroiliac joints before (L) and after 3 months (R) of infliximab treatment. The arrows refer to areas of enhancement seen in bone marrow and subchondral bone seen on T2 weighted fat suppressed images that improve post-infliximab therapy. The American Journal of Medicine 2005 118, 592-603DOI: (10.1016/j.amjmed.2005.01.001) Copyright © 2005 Elsevier Inc. Terms and Conditions