Expression and Function of Aminopeptidase N/CD13 Produced by Fibroblast‐like Synoviocytes in Rheumatoid Arthritis: Role of CD13 in Chemotaxis of Cytokine‐Activated T Cells Independent of Enzymatic Activity

Morgan, Rachel L.; Endres, Judith; Behbahani-Nejad, Nilofar; Phillips, Kristine; Ruth, Jeffrey H.; Friday, Sean Celester; Edhayan, Gautam; Lanigan, Thomas M.; Urquhart, Andrew G.; Chung, Kevin C.; Fox, David A.

doi:10.1002/art.38878

Cited by 42 publications

(86 citation statements)

References 37 publications

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“…Whether soluble CD318 is derived by protease-mediated shedding from the synovial fibroblast surface or by secretion of soluble CD318 from the synovial fibroblasts is as yet unknown. The chemotactic effects of soluble CD318 resemble in some respects chemotactic properties of CD13, another membrane protein on synovial fibroblasts that also is present at high concentrations as a soluble molecule in inflammatory joint fluid (48). Neither CD13 nor CD318 show structural resemblance to conventional chemokines, but there is evidence that CD13, like classical chemokines, signals through a G protein-coupled receptor (48).…”

Section: Discussionmentioning

confidence: 99%

CD318 is a ligand for CD6

Enyindah-Asonye

Ruth

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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It has been proposed that CD6, an important regulator of T cells, functions by interacting with its currently identified ligand, CD166, but studies performed during the treatment of autoimmune conditions suggest that the CD6-CD166 interaction might not account for important functions of CD6 in autoimmune diseases. The antigen recognized by mAb 3A11 has been proposed as a new CD6 ligand distinct from CD166, yet the identity of it is hitherto unknown. We have identified this CD6 ligand as CD318, a cell surface protein previously found to be present on various epithelial cells and many tumor cells. We found that, like CD6 knockout (KO) mice, CD318 KO mice are also protected in experimental autoimmune encephalomyelitis. In humans, we found that CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. In addition, soluble CD318 is chemoattractive to T cells and levels of soluble CD318 are selectively and significantly elevated in the synovial fluid from patients with rheumatoid arthritis and juvenile inflammatory arthritis. These results establish CD318 as a ligand of CD6 and a potential target for the diagnosis and treatment of autoimmune diseases such as multiple sclerosis and inflammatory arthritis.C D6 is a marker of T cells and an important T-cell regulator (1). Recent genome-wide association studies also identified CD6 as a risk gene for multiple sclerosis (MS) (2-5), an autoimmune disease in which T cells play a vital role in the pathogenesis. CD6 is composed of three extracellular domains (domains 1, 2, and 3), and it functions by interacting with its ligand(s) (6). The domain 3 of CD6 has been shown to be the site that the identified CD6 ligand, CD166, also known as ALCAM (activated leukocyte cell adhesion molecule), binds to (7). However, anti-CD166 antibodies only partially blocked the binding of thymic epithelial cells to CD6-overexpressing COS cells, and mAbs blocking CD6-CD166 interactions do not abolish CD6 function (8, 9). Itolizumab, an anti-CD6 mAb developed in Cuba and approved in India for treating psoriasis, reduces pathogenic T-cell responses in patients with psoriasis, but this mAb binds to domain 1 of CD6 instead of domain 3, and it does not interfere with the CD6-CD166 interaction. Interestingly, UMCD6, a mouse antihuman CD6 mAb that we found highly effective in treating encephalomyelitis (EAE) in CD6 humanized mice, also fails to block the CD6-CD166 interaction. All these studies suggest the existence of an additional CD6 ligand, other than CD166, that binds to domain 1 of CD6, and could be critical for CD6 function in autoimmune conditions. Further studies using a CD6 fusion protein as a bait to pull down CD6-binding proteins from synovial fibroblast surface proteins showed the binding of three polypeptides (10). One of these polypeptides was identified as CD166, and the identities of the other two were unknown (11). A mAb termed 3A11 was developed, and the antigen recognized by this mAb was identified as the new ligand of ...

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Section: Discussionmentioning

confidence: 99%

CD318 is a ligand for CD6

Enyindah-Asonye

Ruth

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to RA CD13 has also recently been implicated in osteoarthritis (OA) through a role on chondrocytes [ 9 ]. CD13 is primarily a cell surface molecule that was originally identified on myeloid cells [ 1 ], but is now known to be expressed by other cell types, including FLS [ 10 ]. It has also been identified in soluble fractions of biological fluids.…”

Section: Introductionmentioning

confidence: 99%

Localization, Shedding, Regulation and Function of Aminopeptidase N/CD13 on Fibroblast like Synoviocytes

et al. 2016

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Aminopeptidase N/CD13 is highly expressed by fibroblast like synoviocytes (FLS) and may play a role in rheumatoid arthritis (RA). CD13 was previously detected in human synovial fluid where it was significantly increased in RA compared to osteoarthritis. In this study we found that CD13 in biological fluids (plasma, synovial fluid, FLS culture supernatant) is present as both a soluble molecule and on extracellular vesicles, including exosomes, as assessed by differential ultracentrifugation and density gradient separation. Having determined CD13 could be released as a soluble molecule from FLS, we examined potential mechanisms by which CD13 might be shed from the FLS membrane. The use of protease inhibitors revealed that CD13 is cleaved from the FLS surface by metalloproteinases. siRNA treatment of FLS revealed one of those proteases to be MMP14. We determined that pro-inflammatory cytokines (TNFα, IFNγ, IL-17) upregulated CD13 mRNA in FLS, which may contribute to the increased CD13 in RA synovium and synovial fluid. Inhibition of CD13 function by either inhibitors of enzymatic activity or anti-CD13 antibodies resulted in decreased growth and diminished migration of FLS. This suggests that CD13 may be involved in the pathogenic hyperplasia of RA FLS. This data expands potential roles for CD13 in the pathogenesis of RA.

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“…1). CD13 is released into synovial fibroblast culture supernatants by MMP-14 mediated shedding of CD13 from the FLS membrane[27, 28] and is found in high Other chemoattractant proteins, distinct from conventional chemokines, also may have important roles in RA. For example, aminopeptidase N/CD13, an ecto-peptidase expressed by myeloid cells and FLS, has recently been examined in RA (Fig.…”

Section: Fls In Ramentioning

confidence: 99%

“…1). CD13 is released into synovial fibroblast culture supernatants by MMP-14 mediated shedding of CD13 from the FLS membrane[27, 28] and is found in high concentrations in RA synovial fluid. Using an as yet unidentified G-protein-coupled receptor and independent of its enzymatic activity, CD13 induces chemotaxis of cytokine-activated T cells, a T cell population similar to that found in RA synovium, at a concentration that is similar to the gradient between the CD13 concentration in RA serum versus RA synovial fluid, suggesting that CD13 could play an important role as a T cell chemoattractant in a positive feedback loop that contributes to RA synovitis[27].…”

Section: Fls In Ramentioning

confidence: 99%

Synovial cellular and molecular markers in rheumatoid arthritis

2017

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Summary The profound alterations in the structure, cellular composition and function of synovial tissue in rheumatoid arthritis (RA) are the basis for the persistent inflammation and cumulative joint destruction that are hallmarks of this disease. In RA the synovium develops characteristics of a tertiary lymphoid organ, with extensive infiltration of lymphocytes and myeloid cells. Concurrently the fibroblast-like synoviocytes undergo massive hyperplasia and acquire a tissue-invasive phenotype. In this review we summarize key components of these processes, focusing on recently-described roles of selected molecular markers of these cellular components of RA synovitis.

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Expression and Function of Aminopeptidase N/CD13 Produced by Fibroblast‐like Synoviocytes in Rheumatoid Arthritis: Role of CD13 in Chemotaxis of Cytokine‐Activated T Cells Independent of Enzymatic Activity

Cited by 42 publications

References 37 publications

CD318 is a ligand for CD6

CD318 is a ligand for CD6

Localization, Shedding, Regulation and Function of Aminopeptidase N/CD13 on Fibroblast like Synoviocytes

Synovial cellular and molecular markers in rheumatoid arthritis

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