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Arthritis Research & Therapy
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Volume 4 Supplement 3

The Scientific Basis of Rheumatology

Arthritis Research & Therapy volume 4, Article number: S153 (2002) Cite this article

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The human leukocyte antigen HLA-B27 is strongly associated with development of a group of inflammatory arthritides collectively known as the spondyloarthritides. We have set out to define the natural immunological function of HLA-B27, and then to apply this knowledge to understand its pathogenic role. Human leukocyte antigen class 1 molecules bind antigenic peptides for cell surface presentation to cytotoxic T lymphocytes. HLA-B27 binds and presents peptides from influenza, HIV, Epstein-Barr virus, and other viruses. This leads to for 1 last update 2020/07/02 vigorous and specific cytotoxic T lymphocyte responses, which play an important role in the body''arthritogenic''arthritogenic''arthritogenic''B''45''escape''search''standard''HC-B27''s antigen-presenting function is impaired (Bird et al., unpublished observations).The human leukocyte antigen HLA-B27 is strongly associated with development of a group of inflammatory arthritides collectively known as the spondyloarthritides. We have set out to define the natural immunological function of HLA-B27, and then to apply this knowledge to understand its pathogenic role. Human leukocyte antigen class 1 molecules bind antigenic peptides for cell surface presentation to cytotoxic T lymphocytes. HLA-B27 binds and presents peptides from influenza, HIV, Epstein-Barr virus, and other viruses. This leads to vigorous and specific cytotoxic T lymphocyte responses, which play an important role in the body''arthritogenic''arthritogenic''arthritogenic''B''45''escape''search''standard''HC-B27''s antigen-presenting function is impaired (Bird et al., unpublished observations).

Figure 1 shows an example of HLA-B27 heavy chain homodimer expression in the cell line LBL721.220. A key role for the unpaired cysteine at position 67 of the HLA-B27 alpha 1 helix is suggested by site-directed mutagenesis (Bird et al., unpublished observations). Figure 2 shows a molecular model of a HLA-B27 homodimer. A disulfide bond is shown between position 67 of the two HLA-B27 heavy chains. It is not yet known whether HC-B27 homodimer expression is specific for, or indeed correlates with, spondyloarthropathy, or whether HLA-B27-negative patients with spondyloarthritis express homodimers of other HLA alleles. Interestingly, we have recently observed HLA-B27 homodimer expression at the cell surface of HLA-B27+/β2m knockout mice.

Figure 1

Disulfide-bonded HLA-B27 heavy chain homodimers are present in HLA-B*2705 transfected LBL721.220 cells. HC-10 western blot shown under non-reducing (upper panel) and reducing (lower panel) conditions. The left-hand lane shows untransfected 721.220 cells.

Figure 2

Hypothetical molecular model of the HLA-B27 heavy chain homodimer structure. The alpha 1, 2, and 3 domains of two HLA-B27 molecules are shown in ribbon form, bound peptide shown. Orientation: cell surface at bottom of picture.

These and other findings have lead to two novel hypotheses for disease causation. Colbert and colleagues have proposed that homodimer formation is a symptom of HLA-B27 '' within the endoplasmic reticulum, and that accumulation of misfolded protein results in a potentially proinflammatory intracellular stress response [39]. Alternatively, we have suggested that HLA-B27 heavy chain homodimers may be expressed at the cell surface, where they may act as a proinflammatory target or receptor for humoral or cell-mediated autoimmune responses.

We have recently shown that tetrameric complexes of HLA-B27 heavy chain homodimers bind to certain natural killer (NK) and related receptors, expressed on lymphocytes, NK cells and cells of the monocyte/macrophage lineage. (Kollnberger et al., unpublished data). The functional outcome of the interaction of HLA-B27 with NK receptors and other immunoreceptors is as yet unclear. Although many killer immunoglobulin-like receptors have inhibitory effects, there is accumulating evidence that expression of certain receptors is associated with prolonged survival of memory T cells [40].

One possible model of disease causation is presented in Figure 3. We first show infection of HLA-B27-expressing cells by an organism capable of triggering spondyloarthropathy. This infection results in interference of the cellular antigen-presenting function and consequent expression of aberrant HLA-B27 homodimers [2]. Notably, other stresses at other sites (e.g. mucosae) could have similar effects. Cell-surface B27 homodimers engage NK or related immunoreceptors expressed on lymphocytes or other cells within the joint, resulting in local cytokine production or enhanced cellular activity [4], and hence perpetuating joint inflammation. Since both CD8 and CD4 T cells can express NK receptors, such a hypothesis could explain the involvement of either cells in disease pathogenesis (expanded populations of both CD4 and CD8 T cells are found in reactive arthritis [31]).

Figure 3

Hypothetical model for the role of HLA-B27 homodimers in the pathogenesis of spondyloarthritis. NK, natural killer.

knee issues runninghow to knee issues running for An alternative explanation for the involvement of CD4 T cells in spondyloarthropathy has been suggested by recent evidence from Gaston''double-edged sword''Callaghan CA, McMichael AJ, Bowness P: Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. J Immunol. 1999, 162: 5045-5048.

  • 39.

    Mear JP, Schreiber KL, Munz C, Zhu X, Stevanovic S, Rammensee HG, Rowland-Jones SL, Colbert RA: Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol. 1999, 163: 6665-6670.

  • 40.

    Young NT, Uhrberg M, Phillips JH, Lanier LL, Parham P: Differential expression of leukocyte receptor complex-encoded Ig-like receptors correlates with the transition from effector to memory CTL. J Immunol. 2001, 166: 3933-3941.

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    Boyle LH, Goodall JC, Opat SS, Gaston JS: The recognition of HLA-B27 by human CD4(+) T lymphocytes. J Immunol. 2001, 167: 2619-2624.

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    Acknowledgement

    knee issues runninghow to knee issues running for This work was funded by the Medical Research Council and Arthritis Research Campaign.

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    1. MRC Human Immunology Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
      • Andrew McMichael
      •  & Paul Bowness
    2. Nuffield Orthopaedic Centre, Oxford, UK
      • Paul Bowness
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    1. Andrew McMichael
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    Correspondence to Paul Bowness.

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    McMichael, A., Bowness, P. HLA-B27: natural function and pathogenic role in spondyloarthritis. Arthritis Res Ther 4, S153 (2002). https://doi.org/10.1186/ar571

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    Keywords

    • cytotoxic C cell
    • HLA-B27
    • knee issues runninghow to knee issues running for peptide
    • spondyloarthritis

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