HLA-B27 is a specific human leukocyte antigen strongly associated with the risk of SpA, but the mechanisms by which it contributes to disease remain incompletely understood. Several leading hypotheses have been proposed and are summarized below.
The pathogenesis of SpA involves several interrelated mechanisms centered around HLA-B27. The arthritogenic peptide hypothesis suggests that HLA-B27 presents unique peptides, derived either from self or pathogens, on the cell surface. Some of these peptides mimic bacterial or viral sequences, leading to the aberrant activation of autoreactive CD8+ T cells through molecular mimicry and thereby triggering the chronic inflammation characteristic of SpA.
In parallel, HLA-B27 misfolding within the endoplasmic reticulum contributes to disease pathogenesis. Misfolded HLA-B27 accumulates in the ER, activating the UPR, which increases the production of inflammatory cytokines, particularly IL-23. This, in turn, drives Th17 cell activation and sustains chronic inflammation.
Additionally, HLA-B27 homodimer formation on the cell surface further promotes immune activation. These unusual disulfide-bonded homodimers interact with receptors on immune cells, such as natural killer cells and Th17 cells, stimulating the survival and activation of pro- inflammatory immune cells and enhancing cytokine production, including IL-17 and TNF-α. Collectively, these processes amplify the inflammatory cascade in SpA.
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