The CD27–CD70 pathway and pathogenesis of autoimmune disease

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Abstract

Objective

To critically examine current evidence regarding the role of the CD27–CD70 pathway in the pathophysiology of autoimmune disease with a focus on understanding the contributions of this pathway as a potential new therapeutic target for systemic lupus erythematosus and rheumatoid arthritis.

Methods

A PubMed search for articles was conducted using the following key words: (“CD27” OR “CD70”) AND (“autoimmune disease” OR “systemic lupus erythematosus” OR “rheumatoid arthritis”). The search was limited to publications in English and included human and animal studies. The reference lists of identified articles were searched for further relevant citations. Publications on the list that was developed by this approach were assessed and those with relevance to CD27–CD70 pathway mediated pathophysiology in autoimmune disease were chosen for the detailed review.

Results

Data from human diseases and animal models document a major role for the CD27–CD70 receptor–ligand pair in providing signals that regulate T and B lymphocyte activation. The membrane receptor CD27 and its soluble form (sCD27) transmit co-stimulatory signals and induce activation and proliferation of T and B lymphocytes. CD70-expressing CD4 T lymphocytes are increased in autoimmune disease including systemic lupus erythematosus and rheumatoid arthritis and have been shown to produce pro-inflammatory cytokines. At the same time, preclinical evidence suggests that the outcome of CD27–CD70 signals may vary qualitatively between cell subsets and differentiation stages, especially for B lymphocytes. Blockade of the CD27–CD70 pathway has been shown to ameliorate disease manifestations in animal models including murine collagen-induced arthritis and experimental colitis.

Conclusion

Current evidence from animal models and human diseases suggests that CD27–CD70 pathway contributes to the pathophysiology of autoimmunity. Although a number of basic questions still remain open, the available findings suggest that targeting the components of this pathway could provide useful and novel therapeutic interventions.

Section snippets

CD27–CD70 pathway in T lymphocyte responses

CD27 is constitutively expressed on naïve T lymphocytes, and is downregulated only after prolonged stimulation [4], [19]. Its ligation by CD70 expressed on activated antigen presenting cells (APCs) including dendritic cells and B lymphocytes provides costimulatory signals in addition to T cell receptor (TCR) engagement through the NF-kappaB (NFκB) and c-Jun N-terminal kinase (JNK) pathways via TRAF2 and TRAF5 [20], [21]. Thus, CD27 acts in parallel to a large array of other costimulatory

CD27–CD70 pathway in B lymphocyte responses

In both human and murine B lymphocytes, CD70 is primarily up-regulated upon activation, although lower levels are found in some human lymphoid tissue-resident memory B lymphocytes, and some CD70 is constitutively on the surface of many B lymphocyte malignancies [1], [38], [39]. CD27 is more widely expressed on human B lymphocytes than those in the mouse. After initial upregulation from basal levels during the germinal center reaction, CD27 persists at high levels on a major fraction of both

Systemic lupus erythematosus

In patients with systemic lupus erythematosus (SLE), CD27-high plasma cells were increased in the periphery and correlated with SLE disease activity index (SLEDAI) and serum levels of anti-double stranded DNA (anti-dsDNA) autoantibodies [52], [53]. Of note, SLE patients with long-term clinical remission and reduction in autoantibody titers following B lymphocyte depletion therapy displayed delayed reconstitution of peripheral CD27+ memory B lymphocytes and an expansion of transitional B

Rheumatoid arthritis

CD70 was found to be upregulated on both naïve and memory CD4 T lymphocytes of RA patients compared to healthy controls, and higher CD4 T cell surface CD70 expression correlated with increased IFNγ and IL-17 production after short-term activation [67]. However, no correlation was observed between expression of CD70 and DAS28 disease activity scores. The findings suggest that CD70 upregulation could be an early marker for CD4 T lymphocytes activation in RA patients, with potential pathogenic

Inflammatory bowel diseases

It has been reported that CD70 is constitutively expressed on APCs in the intestinal lamina propria. These cells drive T lymphocyte responses to Listeria infection [15], and differentiation of Th17 cells via IL-6 and IL-23 production in response to ATP stimulation in germ-free mice [70]. These findings suggest an important role of the CD27–CD70 axis in the intestinal immune response and in homeostatic mechanisms in response to microbiome-derived signals. In this context, the CD27–CD70 pathway

Conclusions

The CD27–CD70 pathway plays an important role in activation of both T and B lymphocytes by providing co-stimulatory and differentiation signals, and substantial evidence links dysregulation of this pathway with inflammatory and autoimmune diseases in both animal models and human patients. The CD27–CD70 pathway offers an attractive therapeutic target for autoimmune diseases, modeled on the success of abatacept, CTLA-Ig, which targets the CD28-B7 co-stimulation pathway and is used for the

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