HLA-B27 is a MHC Class I molecule. The Major Histocompatibility Complex (MHC) is a large genomic region of 3.6Mb (3.6 million base pairs) situated on the short arm of chromosme 6 and it contains upwards of 140 genes, most having immune or related functions.
MHC Class I genes encode peptide binding proteins that are expressed on all nucleated cells. The molecules consist of an α chain and β2microglobulin (not part of MHC) and present ligands (antigen fragments of 8-10 amino acids long, usually virally derived or ‘self’) to T-cells via CD8 receptors on cytotoxic T-cells and also bind inhibitory receptors on Natural Killers cells. NK cells are cytotoxic lymphocytes, different from B and T lymphocytes and are part of the innate immune system.
The synthesis of HLA B heavy chains, their assembly with β2microglobulin and the loading of the trimmed peptide (ligand) cargo occurs in the endoplasmic reticulum (ER) before being transported to the cell surface. It should be noted here that the gene that encodes for ERAP1 (endoplasmic reticulum aminopeptidase 1, which is a zinc metallopeptidase that is a trans-membrane protein localised to the ER which functions to trim antigenic peptides prior to their binding to MHC Class I molecules, thereby affecting antigen presentation to cytotoxic T lymphocytes) has been implicated in the disease susceptibility to AS.
One of the more unusual properties of the HLA-B27 heavy chain when compared to those of other HLA-B alleles, is its tendency to misfold in the ER with the implication that the spondylarthropathies may belong to a rapidly expanding category of protein misfolding disorders.
Misfolded proteins that accumulate within an effected cell can be toxic and may elicit a cellular response referred to as the Unfolded Protein Response (UPR). Issues regarding the specificity and affinity of the ligand for the peptide binding groove of the B27-β2m complex may be important in relation to the tendency toward UPR.
In the gastrointestinal tract, a low level immune response to bacterial colonization could result in interferon (IFN) and/or natural killer lymphocyte (NK) activation. This would result in up-regulation of MHC Class I expression and, in cells expressing HLA-B27, activation of the UPR. Macrophages would then in response to Toll Like Receptor (TLR) agonists like lipopolysaccharide (LPS, which are endotoxins derived from the outer membranes of Gram Negative bacteria, such as Klebsiella pneumoniae) and other bacterial products, be polarized towards the increased production of interferon and Interleukin 23 (IL-23) and possibly IL-6. IL-23 would then drive IL-17 production form CD4 T-cells that have become committed to the Th17 (T-helper17) cell lineage. And here it should be noted that the polymorphism of the gene encoding IL-23R, the receptor for IL-23 has also been implicated in AS disease susceptibility.
Th17 cells may have evolved as another arm of the adaptive immune response for enhanced protection against extracellular bacteria (eg, Klebsiella pneumonia). What has become very clear is that Th17 cells play a crucial role in chronic inflammation in auto inflammatory diseases such as RA, MS, IBD, psoriasis, uveitis and the SpA’s.
Cells with the capacity to produce IL17 are normally present in the colon. Thus, in the unique mucosal environment of the gut, increased IL23 expression could be sufficient stimulus to establish a chronic gastrointestinal inflammation that is the primary lesion in the group of inflammatory diseases collectively referred to as the spondylarthropathies.
I believe that this paper could be interpreted as providing some sort of scientific basis that would underpin the putative benefits of a No Starch Diet by denying the possibly causative bacteria a substrate and thus limiting their ability to proliferate in the gut, In effect, a NSD could be seen as a probiotic disease modifying anti-rheumatic therapeutic treatment for the SpA’s.
The original article can be viewed in all its complexity, in PDF format, at
http://www.landesbioscience.com/journals/prion/article/8072/Regards David
