AS of Baths, SpAs and movies @B27

AS of Baths, Spas and movies @ B27

There is just something special about rheumatology.  It has acronyms and associations due to the multisystem nature of the conditions we see.

The spondyloarthropathies (SpAs) are a group of conditions with multiple associations of which Ankylosing Spondylitis (AS) is the hallmark condition. Patients with AS benefit from physio and hydrotherapy. The latter may sometimes take place in a local health spa. We use the Bath AS Scores to assess disease activity. AS has strong genetic association with the gene HLA-B27.

AS of Baths and SpAs – what do we know about B27?

The genetic association between Human Leukocyte Antigen (HLA)-B27 and Ankylosing Spondylitis was first discovered in the Westminster Hospital by Brewerton and Sturrock in 1973 with their publication in the Lancet. It remains one of the strongest associations between gene and disease.

What is known about HLA-B27

·        Present in 95% of patients with AS ·        Present in 8% of normal population ·        1 in 15 people who are HLA-B27 positive go on to develop AS ·        The child who is HLA-B27 positive with a parent with AS has a 15% chance of developing the condition ·        HLA-B27 accounts for up to 50% of overall genetic susceptibility to AS ·        Different subtypes of HLA-B27 have different strengths of association with AS

(HLA)-B27 or B27 is a protein that is expressed on the cells and has function in both health and disease. It can be a double-edged sword. It presents fragments of bacteria or viruses called peptide and present this to active immune cells (T cells) to overcome infection. Aberrations in the structure or processing of B27 are proposed as the mechanism for the development of AS.

Mechanism of action of HLA-B27 in AS

·   Arthritogenic peptide hypothesis – small proteins (peptides) from our own body presented by HLA-B27 become the target of immune cells (CD8+ T cells) because they look like peptides from bacteria or viruses. This results in joint inflammation. ·       HLA-B27 homodimers hypothesis – cell surface HLA-B27 can form homodimers (a pair of two chains of B27 joined together by a bond).  B27 homodimers bind to specific receptors expressed on Natural Killer and T lymphocytes which could play a role in the development of AS. ·  HLA-B27 misfolding hypothesis - accumulation of misfolded HLA-B27 in the endoplasmic reticulum (ER) during protein processing, produces an inflammatory response. ER stress resulting from the accumulation of misfolded HLA-B27 then activates the unfolded protein response (UPR) or the ER-overload response (EOR) that can result in joint inflammation. ·    Enhanced intracellular microbial survival hypothesis - the inability of HLA-B27-positive individuals to eliminate certain bacteria or viruses. Ineffective loading of these pathogens by HLA-B27 leads to reduced clearance and prolonged abnormal immune system activation.

Novel roles – B27 at the movies

These mechanisms have provided the basis for several explanations as to how HLA-B27 might predispose individuals to AS. I am particularly interested in the HLA-B27 homodimer hypothesis having worked on this in my doctoral thesis. The ability of HLA-B27 to form homodimers which are a pair of two chains of B27 joined together by a bond is interesting. Bond and Dimers, proponents of this hypothesis would say 'Dimers are Forever'. But like the secret agent 007, could B27 dimers unlock some secrets to why AS develops?

B27 dimers can interact with Natural Killer (NK) receptors called KIRs which are expressed both on NK and T cells. B27 dimers bind to a specific KIR called KIR3DL2. As of Bond and Dimers, this KIR is the KIR Royale. The new kid on the block in the proinflammatory response is the T helper 17 cells (Th17) which produce IL-17. IL-17 can further induce the secretion of cytokines such as TNF-α which are involved in the pathogenesis of AS. Th17 cells which express KIR3DL2 have been shown to produce increased amounts of IL-17 in response to another cytokine IL-23¹.  B27 dimers also cause an expansion of inflammatory T cells in AS².

Two recent papers also add to our understanding of the HLA-B27 story. Cauli et al² showed that the HLA-B27 subtype 05 forms more B27 dimers than the non-disease related of HLA-B27 subtype 09. B27 dimers promote the survival of KIR3DL2 expressing cells which may result in inflammation seen in AS. Another interesting model is the on the role of mechanical stress in AS. Jacques et al⁴ showed that by reducing mechanical stress and loading on the Achilles tendon in mice, there is reduced inflammation, scarring and new bone formation. HLA-B27 and IL-23 may alter the inflammatory response of joints or tendons to mechanical stress. One can postulate on galactic battles between inflammatory cells taking place at sites of mechanical stress. McGonagle D summarises this in the editorial ‘SpA :May the Force be with you’ ⁵.

Great strides have been made to understand this mechanism of action. The links HLA-B27, inflammatory cells (IL-17/IL-23) and response to mechanical stress could all be targets for future research and treatment.

References:

1. Bowness P et al. J Immunol. 2011 February 15; 186(4): 2672–2680.

2. Wong-Baeza I et al. J Immunol. 2013 Apr 1;190(7):3216-24.

3. Cauli A et al. Rheumatology (Oxford). 2013 Nov;52(11):1952-62

4. Jacques  P et al. Ann Rheum Dis. 2013 Aug 6. 

5. McGonagle et al Ann Rheum Dis. 2013 Nov 12.

@synovialjoints

Views are my own. These are opinions and cannot replace the need to see your physician for review of your individual medical condition.