HLA-B27 Misfolding and Spondyloarthropathies

Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Prion (Impact Factor: 2.24). 02/2009; 3(1):15-26. DOI: 10.1007/978-1-4419-0298-6_16
Source: PubMed


HLA-B27 plays a central role in the pathogenesis of many spondyloarthropathies and in particular ankylosing spondylitis. The observation that the HLA-B27 heavy chain has a tendency to misfold has raised the possibility that associated diseases may belong in a rapidly expanding category of protein misfolding disorders. The synthesis of the HLA-B27 heavy chain, assembly with beta(2)m and the loading of peptide cargo, occurs in the endoplasmic reticulum (ER) before transport to the cell surface. The evidence indicates that misfolding occurs in the ER prior to beta(2)m association and peptide optimization and is manifested in the formation of aberrant inter- and intra-chain disulfide bonds and accumulation of heavy chain bound to the chaperone BiP. Enhanced accumulation of misfolded heavy chains during the induction of class I expression by cytokines, can cause ER stress resulting in activation of the unfolded protein response (UPR). Effects of UPR activation on cytokine production are beginning to emerge and may provide important missing links between HLA-B27 misfolding and spondyloarthritis. In this chapter we will review what has been learned about HLA-B27 misfolding in human cells and in the transgenic rat model of spondyloarthritis-like disease, considering it in the context of other protein misfolding disorders. These studies provide a framework to support much needed translational work assessing HLA-B27 misfolding and UPR activation in patient-derived material, its consequences for disease pathogenesis and ultimately how and where to focus intervention strategies.

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Available from: Monica L DeLay, Jan 15, 2015
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    • "For example, the HLA-B27 heavy chain has a tendency to misfold in the endoplasmic reticulum, prior to conjugation with b2 microglobulin (b2 m) and its cargo peptide. Misfolded heavy chains can accumulate in the endoplasmic reticulum, causing stress, cytokine production by macrophages and resultant inflammation (Colbert et al., 2009 "
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    ABSTRACT: It is now over forty years since the first associations between particular HLA antigens and disease susceptibility were described, and the identification of large numbers HLA-associated diseases parallels our increased understanding of the genetic complexity of the HLA system and its extensive polymorphism. However, surprisingly and frustratingly, clear identification of the underlying mechanisms resulting in a causative role for HLA polymorphism in the molecular immunopathogenesis of individual HLA-associated diseases remains the exception rather than the rule. This review, while not intended to be a comprehensive catalogue of HLA-associated diseases, aims to revisit a number of well known and more recently described HLA-associated diseases as exemplars of our current understanding of the underlying molecular mechanisms which may result in genetic disease predisposition. Such mechanisms may act as pointers for further investigations in other HLA-associated diseases. The clinical utility of specific HLA disease associations in disease diagnosis/exclusion is also considered.
    International Journal of Immunogenetics 09/2013; 41(1). DOI:10.1111/iji.12088 · 1.25 Impact Factor
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    • "The HLA-B27 misfolding hypothesis proposes that AS results from an accumulation of aberrantly-folded HLA- B27 in the endoplasmic reticulum (ER), that produces an inflammatory response [33]. ER stress resulting from the accumulation of misfolded heavy chains then activates the unfolded protein response (UPR), triggering a series of signaling pathways that culminate in the induction of ERresident chaperones (BiP), which may induce cytokine production by macrophages, thereby promoting inflammation [34] [35]. Another pathway that can activate ER stress is the ER-overload response (EOR) to excessive membrane protein trafficking within the ER, which involves activation of the transcription of nuclear factor kappa B (NF-í µí¼…B) that can stimulate the synthesis of proinflammatory cytokines such as TNF-í µí»¼, IL-1 and IL-6 in certain cell types [36]. "
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    ABSTRACT: Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown etiology, though it is considered an autoimmune disease. HLA-B27 is the risk factor most often associated with AS, and although the mechanism of involvement is unclear, the subtypes and other features of the relationship between HLA-B27 and AS have been studied for years. Additionally, the key role of IL-17 and Th17 cells in autoimmunity and inflammation suggests that the latter and the cytokines involved in their generation could play a role in the pathogenesis of this disease. Recent studies have described the sources of IL-17 and IL-23, as well as the characterization of Th17 cells in autoimmune diseases. Other cells, such as NK and regulatory T cells, have been implicated in autoimmunity and have been evaluated to ascertain their possible role in AS. Moreover, several polymorphisms, mutations and deletions in the regulatory proteins, protein-coding regions, and promoter regions of different genes involved in immune responses have been discovered and evaluated for possible genetic linkages to AS. In this review, we analyze the features of HLA-B27 and the suggested mechanisms of its involvement in AS while also focusing on the characterization of the immune response and the identification of genes associated with AS.
    07/2013; 2013(4):501653. DOI:10.1155/2013/501653
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    ABSTRACT: Ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are immune-mediated inflammatory joint diseases with the potential for significant target organ damage. Genetic factors play an important role in defining disease susceptibility. Both diseases are mediated in part by TNF, since anti-TNF therapies have proved effective in both AS and RA. Despite their similarities, the genetic elements associated with the respective diseases differ, most notably in HLA associations, with AS being associated with class I HLA alleles and RA associated with class II HLA alleles. AS has a predilection for axial joints whereas RA targets peripheral joints, but the immunological basis of that distinction is unknown. Autoantibody formation is the immunological hallmark of RA, whereas AS is notable for being a "seronegative" disease. Growing knowledge of new aspects of the host immune response (such as innate immune responses and Th17 cells) is adding to new insights into shared mechanisms of pathogenesis between these two diseases.
    Clinical and experimental rheumatology 01/2009; 27(4 Suppl 55):S26-32. · 2.72 Impact Factor
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