What is the role of human leukocyte antigen (HLA) B27 in triggering an inflammatory disease-causing response?

Updated: Oct 30, 2018
  • Author: Anna Luisa Di Lorenzo, MBBCh; Chief Editor: Andrew A Dahl, MD, FACS  more...
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Answer

Answer

The actual role of HLA-B27 in triggering an inflammatory response causing disease is still not precisely known. The oldest theory is that of molecular mimicry, in which an autoimmune response initially is mounted against a peptide from an infectious agent and is subsequently directed against HLA-B27 itself due to epitopic similarities. At least two self-peptides have been identified in patients with ankylosing spondylitis, which supports this hypothesis.

A second theory, referred to as the HLA-B27 misfolding hypothesis, is based on a peculiar biochemical property of the HLA-B27 molecule. These unfolded HLA-B27 proteins accumulate in the endoplasmic reticulum (ER). A proinflammatory stress response called the endoplasmic reticulum unfolded protein response (ERUPR) ensues. As a result, interleukin 23 (IL-23) is released, activating a proinflammatory response via interleukin-17+ T lymphocytes.

Another potential pathological mechanism of HLA-B27 is called the HLA-B27 heavy chain homodimer hypothesis. It is suggested that B27 heavy chains can form stable dimers, which tend to dimerize and accumulate in the endoplasmic reticulum. In turn, this initiates the proinflammatory ERUPR. In addition, these heavy chains and dimers can bind to other regulatory immune receptors such as the natural killer receptors (NKRs). This causes the expression and survival of more proinflammatory leukocytes and subsequent production of proinflammatory mediators.

Other theories suggest that the T-cell antigen is the true susceptibility factor or imply an innate etiology unrelated to HLA. Finally, HLA-B27 may simply represent a marker locus, closely linked to the as yet unidentified true immune response gene responsible for the inflammatory response. [6]


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