Role of EFNB1 and EFNB2 in Mouse Collagen‐Induced Arthritis and Human Rheumatoid Arthritis

Abstract

Objective EFNB1 and EFNB2 are ligands for Eph receptor tyrosine kinases. This study was undertaken to investigate how the expression of Efnb1 and Efnb2 on murine T cells influences the pathogenesis of collagen‐induced arthritis (CIA) and to assess correlations between the T cell expression of these 2 molecules and measures of disease activity in patients with rheumatoid arthritis (RA). Methods CIA was studied in mice with T cell–specific deletion (double gene knockout [dKO]) of both Efnb1 and Efnb2. Expression of EFNB1 and EFNB2 messenger RNA (mRNA) in peripheral blood T cells from patients with RA was determined by quantitative reverse transcription– polymerase chain reaction. Results In dKO mice, clinical scores of arthritis were reduced compared to those in wild‐type (WT) control mice. Serum collagen‐specific antibody titers in dKO mice were lower than those in WT mice. In analyses based on equal cell numbers, dKO mouse T cells, as compared to WT mouse T cells, provided vastly inferior help to B cells in the production of collagen‐specific antibodies in vitro. T cells from dKO mice were compromised in their ability to migrate to the arthritic paws in vivo and in their ability to undergo chemotaxis toward CXCL12 in vitro. Deletion mutation of Efnb1 and Efnb2 intracellular tails revealed critical regions in controlling T cell chemotaxis. T cells from RA patients expressed higher EFNB1 mRNA levels, which correlated with RA symptoms and laboratory findings. Conclusion Efnb1 and Efnb2 in T cells are essential for pathogenic antibody production and for T cell migration to the inflamed paws in mice with CIA. These findings suggest that the expression of EFNB1 in T cells might be a useful parameter for monitoring RA disease activity and treatment responses.

Altered Maturation of Medullary TEC in EphB-Deficient Thymi Is Recovered by RANK Signaling Stimulation

“…Other mice deficient in several Eph have no phenotype ( 59 , 60 ), and in other experimental models, altered mature mTEC do not course with autoimmune reactivity ( 63 ). Other authors however, have concluded that ephrin-B1 and ephrin-B2, the main ligands of EphB2 and EphB3, are necessary for the proper development of Th1 and Th2 cell subsets ( 64 – 66 ). Some authors have explained these results indicating that defects in some thymic areas do not affect the functional maturation of thymocytes ( 67 , 68 ).…”

Netrin‐1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis

“…In different settings, both up‐ or down‐regulation of che‐ morepellent factors, such as Netrin‐1, during organ injury may exacerbate inflammation (3, 5). It has been also observed that ephrins (EFNB1 and EFNB2) in T cells are essential for pathogenic antibody production and for T‐cell migration to inflamed paws in mice with collagen‐induced arthritis; T cells from patients with RA expressed higher EFNB1 mRNA levels, which correlate with RA symptoms and biomarkers (38).…”

Can a Proper T-Cell Development Occur in an Altered Thymic Epithelium? Lessons From EphB-Deficient Thymi

“…However, other authors have found poor in vitro responses of EphB6 −/− T cells after anti-CD3 plus anti-CD28 stimulation together as well as in vivo decreased hypersensitivity and autoimmune responses ( 35 ). On the other hand, the deletion of either ephrin-B1 or ephrin-B2 in thymocytes does not course with thymus phenotypes ( 36 , 37 ) but the lack of two molecules results in alterations in thymocytes and thymic structure ( 38 ), and low sensitivity to different autoimmune models, including experimental autoimmune encephalomyelitis ( 39 ) and collagen-induced arthritis ( 40 ). We also observed decreased values of positive selected TCRαβ hi CD69 + thymocytes in ephrin-B1 and/or ephrin-B2 deleted in TECs, particularly when using outbred mouse strains.…”