This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Ankylosing spondylitis AS is not fully explained by inflammatory processes. Clinical, epidemiological, genetic, and course of disease features indicate additional host-related risk processes and predispositions. Collectively, the pattern of predisposition to onset in adolescent and young adult ages, male preponderance, and widely varied severity of AS is unique among rheumatic diseases.
SpA primarily manifests as inflammation and new bone formation at the entheses, which are connecting tendons or ligaments with bone. In SpA patients, joint inflammation is frequently accompanied by extra-articular manifestations, such as inflammatory bowel disease or psoriasis. Indeed, the cell types that are chiefly involved in local inflammation in human SpA still remain largely unclear.
Introduction Spondyloarthritis SpA encompasses a group of human rheumatic diseases that typically manifest as inflammation and new bone formation at axial joints, leading to severe lower back pain and impaired spinal mobility. Thereby, inflammation starts from entheses, the tendon to bone attachment sites.
Enthesis organ concept SpA pathologies demonstrate similar disease patterns and similar genetic associations. The Enthesis organ concept is particularly interesting, because single nucleotide polymorphisms in ILR were associated not only with AS 7 or PsA 8 but also with psoriasis 9 and IBD 10hence pathologies that frequently accompany articular inflammation in SpA.
By contrast, IL inhibition presented ambiguous results 18 — 21 ClinicalTrials. If these drugs should completely replace old treatment modalities in the future, it still needs to be validated further 22 — Enthesitis 25thus entheseal inflammation, represents a main characteristic of SpA.
It was suggested that mechanical stress and local microdamage might initiate entheseal inflammation 2627proposing the enthesis as primary lesion in SpA-associated joint inflammation 28 — However, the link between host genetics, e.
IL cytokines are usually produced by lymphocytes, although earlier studies observed ILproducing mast cells 38neutrophils, and myeloperoxidase-expressing cells 39 in SpA synovia. So, who does it? Genetic and epigenetic predisposition, altered microbial composition, and entheseal microdamage can influence the induction and progression of tissue inflammation in SpA.
Innate Lymphoid cells Innate lymphoid cells were identified around 10 years ago 69but might have played important roles in joint inflammation even before adaptive immune cells developed over million years ago. By now, it is clear that ILCs are crucially involved in the pathogenesis of a variety of inflammatory diseases, but also in tissue homeostasis 70 For example, different ILC subsets were implicated in human and experimental rheumatic diseases Interestingly, this further implies that final ILC3 maturation might only occur directly at the site of inflammation, presumably directly in the joints.
Although tissue residency is not well established for human ILCs, there is good evidence that ILCs in mice are generally tissue-resident 87 However, photoconversion experiments in mice could reveal CCR7-dependent ILC3 migration from gut to mesenteric lymph nodes 89supporting the notion that intestinal ILCs can, at least to some extent, traffic to distant sites.
For instance, NKp44 ligand was shown to be expressed by chondrocytes, even in non-inflamed joints The migration of peripheral ILC3s into inflamed tissues in the context of SpA appears to be an interesting hint.
Supposing that increased numbers of TH17 cells promote SpA—how to keep these cells in check?
In fact, miRb-5p and ILproducing B cells were recently proposed as putative negative regulators trying to control TH17 cells from SpA patients. However, enthesis-resident MAIT cells have not been described so far.
Together, this indicates that TH17 cells might rather not mediate the first line of action when local entheseal immune cells are provoked by the various environmental triggers, such as mechanical stress, dysbiosis, or genetic and epigenetic predisposition Figure 1.
Overall, recent studies collectively favor innate and innate-like immune cell involvement rather than adaptive T cells 631 As opposed to conventional B and T cells, innate and innate-like lymphocytes are commonly enriched in non-lymphoid tissues, and thus association with autoinflammatory diseases affecting particular tissues appears feasible In this respect, it is worth considering the differential effects that genetics and environmental factors might elicit in innate versus adaptive immune traits Still, the relative contributions of tissue-resident cells, i.
In this regard, one might hypothesize that mechanical stress triggers resident immune cell activation—either directly or indirectly via stromal cell activation. Since human tissues are generally difficult to obtain, various animal studies experimentally addressed immune pathways associated with SpA.
However, it should be noted that many animal models only work in a specific genetic background, and vast differences exist between individual SpA models. Consequently, experimental data might be controversial: In the human system, many traits originate from analysis of circulating immune cell populations.
However, such data remain inherently difficult to interpret: Altered gut epithelial and vascular barrier integrity in SpA patients might further promote intestinal immune cell emigration Whether SpA-associated joint-infiltrating lymphocytes enter tissues as already activated and functionally mature cells also remains an open question.In the literature, the term enthesitis (i.e.
inflammatory involvement of the enthesis) and enthesopathy (i.e. pathological involvement of the enthesis whatever the cause) are often used as synonyms; however, we prefer to use enthesitis only for inflammatory involvement related to SpA.
The ‘enthesis organ’ concept: why enthesopathies may. In my last post I introduced the enthesis, explaining that it is the site where the tendon (or other soft tissues) joins onto bone (hard tissue) to transmit force, which is either wanted or unwanted.
In addition, I highlighted the close relationship between the enthesis and surrounding structures, such as the bursa and fat, forming what is known as the enthesis organ.
The concept of an enthesis organ is of general significance in understanding attachment sites and may explain the diverse pathologic changes, including synovitis, bursitis, and extracapsular changes, seen adjacent to tendon/ligament entheses in SpA.
The application of the 'enthesis organ' concept (a collection of tissues adjacent to the enthesis itself, which jointly serve the common function of stress dissipation) to understanding enthesopathies is considered and novel roles of adipose tissue at entheses are reviewed.
The intimate relationship between enthesis, organs, and synovial cavities and the presence of enthesis organ components in joint capsules may have important implications for understanding the clinical pattern [10, 11].
In our case genetic analysis showed a MV mutation and a . This results in an articular inflammatory response in the adjacent synovial tissue, driving the concept of the synovio–entheseal complex. 19 x 19 Benjamin, M., Moriggl, B., Brenner, E. et al. The “enthesis organ” concept: why enthesopathies may not present as focal insertional disorders.