The term spondylarthritis (SpA) encompasses the closely related diseases ankylosing spondylitis (AS), reactive arthritis (ReA), psoriatic arthritis, arthritis associated with bowel diseases, and undifferentiated arthritis. Several decades ago, the discovery of a strong association of these entities with the expression of HLA–B27 led to different hypotheses regarding HLA– B27–based pathology (1). HLA–B27 is a class I major histocompatibility complex (MHC) molecule consisting of a heavy chain bound to 2-microglobulin. To date, 24 different HLA– B27 subtypes are known; HLA–B2705 is the dominant subtype, from which the other allelic variants were generated by mutation. However, despite the vast number of published articles on this topic, there is no widely established pathogenic concept of the association of HLA–B27 in SpA. The “arthritogenic peptide hypothesis” suggests an antigen-specific immunopathology based on the presentation of specific autologous or microbial arthritogenic peptides by disease-associated HLA–B27 molecules. Given the inflammatory reaction that is most prominent at the cartilage–bone interface, cartilagederived autoantigens are interesting candidates in SpArelated autoimmunity. In particular, the G1 domain of the proteoglycan aggrecan was of high interest since immunization of mice led to an experimental disease resembling SpA (2). However, this immunoreaction was neither HLA–B27 restricted nor CD8 T cell driven. Furthermore, other rheumatic diseases were also associated with an immunoreaction against the G1 domain of aggrecan. Collagen as an integral part of cartilage structures and collagen-derived peptides are also of interest. Derivatives of type II collagen and type XI collagen bind to HLA–B27, but no consistent reaction of cytotoxic T lymphocytes toward these HLA–B27–bound peptides occurs (3). Atagunduz et al (4) performed a screening analysis in order to identify autoreactive CD8 T cells specific for cartilage-derived peptides in patients with AS and identified nonamer peptides derived from type VI collagen and type II collagen as being stimulatory for CD8 T cells. Previous studies described HLA–B27–restricted T cell clones with specificity for microbial antigens and the potential for autoreactivity in patients with SpA (5). Furthermore, activation of HLA–B27–specific cytotoxic T lymphocytes occurred after exposure to Chlamydia trachomatis in HLA–B27–transgenic animals (6), pointing to a molecular mimicry mechanism with the breakdown of the peripheral immune tolerance, and highlighting HLA–B27 as an autoantigen itself. Several investigators observed a strong similarity between peptides derived from the autologous HLA–B27 molecule and arthritogenic peptides derived from chlamydial or enterobacterial antigens (7). Another mimicry mechanism is deducible from the sequence homology between the pLMP2 antigen derived from the latent membrane protein 2 of Epstein-Barr virus and a self peptide generated from the vasoactive intestinal peptide type 1 receptor presented by distinct HLA–B27 subtypes (8). The “autodisplay hypothesis” offers an additional link between HLA–B27 and immunopathology. LuthraGuptasarma and coworkers described an autocatalyzed conformational change of HLA–B27 heavy chains leading to occupation of the molecule’s own peptide-binding groove (9). Thus, HLA–B27 might be a gatekeeper for autoimmunity by presenting arthritogenic peptides. Furthermore, HLA–B27–derived peptides could act as autoantigens as well. However, the classic CD8 T cell– mediated immunoreactivity expected after presentation by class I MHC molecules is not required for SpArelated immunopathology, since depletion of CD8 T Lars C. Huber, MD, Falk Moritz, MD, Steffen Gay, MD: University Hospital Zurich, Zurich, Switzerland. Address correspondence and reprint requests to Lars C. Huber, MD, Center of Experimental Rheumatology, University Hospital Zurich, and Zurich Center of Integrative Human Physiology, Gloriastrasse 25, 8091 Zurich, Switzerland. E-mail: lars.huber@usz.ch. Submitted for publication July 3, 2006; accepted in revised form September 15, 2006.
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Apr 23, 2012
David A Slatter + 6
Open Access
