Investigations On The Roles And Clinical Significance Of ICAM-1 In T-B Cell Interaction And Antibody Production

Systemic lupus erythematosus(SLE)is an antibody-mediated autoimmune disease.Abnormal B cell hyper-activation leads to the generation of autoantibodies and immune complexes,which deposit in blood vessels,kidneys,skin,nerves and otherwhere and cause damages to multiple organs.As a typical autoimmune disease,exploring the pathogenesis of SLE is an important prerequisite for an effective intervention in the occurrence and the development of the disease.B cell activation and subsequent antibody production mostly depend on the interaction between CD4~+T cells and B cells.Therefore,dissection of the molecule mechanisms of T-B cell interaction is helpful for elucidating the pathogenesis of SLE.Firstly,ICAM-1 expression on the surface of peripheral CD4~+T cells in SLE patients was detected by using flow cytometry,and the soluble ICAM-1(sICAM-1)level in the serum was detected by ELISA.The correlation analysis was conducted between ICAM-1 expressions and the clinical data of SLE patients.The results showed that both the percentages of ICAM-1~+CD4~+T cells in periphery of SLE patients and the sICAM-1 level in serum were significantly higher than those in healthy subjects(P<0.01).They were significantly positively correlated with ESR,an indicator reflecting SLE activity.The serum level of sICAM-1 was also significantly positively correlated with the levels of anti-ds DNA autoantibody and total IgG in SLE patients(P<0.05),and negatively correlated with C3 and C4 contents with no significant difference.The up-regulation of ICAM-1 on the surface of peripheral CD4~+T cells and the increase of sICAM-1 in the serum of SLE patients strongly suggested that ICAM-1 might participate in the activation of CD4~+T cells and function as a costimulatory molecule for B cell activation.Therefore,we stimulated peripheral blood mononuclear cells(PBMCs)from healthy subjects with anti-CD3/28 antibodies for 24 h,48 h and 72h.Cells were collected to detect the expression of ICAM-1 on the surface of CD4~+T cells and the content of sICAM-1 in the co-culture supernatant was detected by ELISA.The results showed that the expression levels of ICAM-1 on CD4~+T cell were upregulated gradually along with the stimulation time with statistical significance between group48h and group 24h(P<0.01).Meanwhile,sICAM-1 content in the supernatant increased as well with significant differences among three groups(P<0.001).To further investigate whether the upregulation of ICAM-1 on CD4~+T cells is involved in the production of antibodies by B cells,a CD4~+T-B cells co-culture system was established in vitro.CD4~+T cells with or without anti-CD3/28 antibody stimulation were co-cultured with B cells.ICAM-1 blockade antibody was added in parallel.After12 days,the IgG content in the co-culture supernatant was detected by ELISA.It was shown that the IgG level in the supernatant of B cells with activated CD4~+T cell co-culture systems was significantly higher than that with na?ve CD4~+T cells(P<0.05).ICAM-1 blockade led to the dramatic decreases in IgG content(P<0.05).In conclusion,our study reveals that ICAM-1 is dramtically upregulated on CD4~+T cells in SLE patients together with the increasing level of soluble ICAM-1 in the periphery.The upregulation of ICAM-1 on CD4~+T cells is associated with the activation of CD4~+T cells and involved in the help for B cell activation and antibody production.Considering the role of ICAM-1 in cell adhesion,upregulation of ICAM-1 on CD4~+T cells in SLE patients makes it a new target for the interruption of T-B interaction for the amelioration treatment of SLE.Furthermore,the sICAM-1 has a positively correlation with SLE disease activity,suggesting that sICAM-1 may be a candidate biomarker for the diagnosis of SLE activity.