Alterations Of Structure And Function Of The Lymph Node In Human Immunodeficiency Virus Infection

Objective:To evaluate the situations of lymph nodes fibrosis in different stages of HIV infection, and to investigate the pathogenesis of lymph nodes fibrosis in chronic HIV infection. Moreover, to assess the alterations of chemokine secretion and distribution, and the contribution of translocation of microbic products to impairment of Tfh functions.Methods:In the first study,43 HIV-infected individuals, which were divided into asymptomatic HIV carriers or AIDS patients, and 12 subjects without HIV infection as control group were recruited into this investigation to obtain peripheral superficial lymph nodes(LNs). Then, immunohistochemistry was used to detect expression and distribution of CD4+T cell, collagen and IL-7 in these LNs.In the second study, the expression of TGF-β1 was determined in the LNs of 32 HIV-infected individuals including 10 asymptomatic HIV carriers or 22 AIDS patients by immunohistochemistry and flow cytometry. The effect of stimulated CD8+T cells on collagen secretion by fibroblasts was detected using immunofluorescence staining and Western blotting assays.In the third study,43 HIV-infected individuals were recruited into this investigation, and were divided into two groups, asymptomatic HIV carriers or AIDS patients, basing on CD4+T cell count by flow cytometry and clinical symptom. Then, immunohistochemistry was used to detect secretion and distribution of chemokines in LNs.In the fourth study,20 LNs of non-HIV infected individuals were recruited, and then ground gently and isolated into single lymphocytes. Ki67, CXCR5 and BcL6 expressions of Tfh were determined by flow cytometry after stimulation of LPS and R848, or along with HIV-1 infection, respectively.Results:Following disease progression, collagen deposition in LNs of HIV-infected individuals gradually increased, and difference between three groups were significant. CD4+T cell count in LNs of AIDS patients were lower comparing with asymptomatic group and control group, but difference between asymptomatic group and control group were not significant. CD4+ T cells count of LNs of HIV-infected individuals had a strong negative linear correlation with collagen deposition, and a strong positive linear correlation with CD4+ T cells count of peripheral blood. Expression of IL-7, which presents local aggregation in some AIDS patients, was not different among three groups in LNs.There were a large number of cells which expressed TGF-β1 in LNs of three groups. However, the distribution of TGF-β1+cells was disorder in HIV-infected individuals. Although the frequency of Tregs was not significantly different between asymptomatic group and control group in LNs, the frequency of TGF-β1+Tregs was higher in former than in latter. In AIDS group, the frequency of Tregs was significantly lower than the other two groups. In addition, although AIDS patients had a significantly lower proportion of TGF-β1+Treg cells compared to asymptomatic HIV carriers, they were comparable to that in the control group. LNs of HIV-infected individuals had a significantly higher proportion of CD8+ T cells with high TGF-β1 expression. These CD8+ T cells showed higher CD38 and PD-1 expression and lower CD 127 expression compared to controls. CD8+ T cells from LNs of non-HIV infected individuals expressed high TGF-β1 level after stimulating and induced the secretion of a large amount of type I collagen in fibroblasts from the lymphatic system.Comparing to control group, only CCL21 expression decreased in peripheral superficial LNs of asymptomatic chronic HIV-infected individuals, CCL19 and CXCL13 expression markedly increased in AIDS patients. And secretion level of CCL19, CCL21, CXCL12 and CXCL13 in peripheral superficial LNs of asymptomatic carriers is profoundly less than AIDS patients. These differences were significant. Moreover, domain boundary of these chemokines was indefinite in AIDS patients.The stimulation of LPS and R848 induced the expansion and BcL6 expression of Tfh. The stimulating effect of R848 started late but was stronger comparing to LPS. HIV-1 was intrinsic reason which downregulated the expression of BcL6 in Tfh, but LPS played a synergetic role in that. Moreover, the stimulation of LPS and R848 also downregulated the expression of CXCR5 in Tfh surface, which could impeded the ability of Tfh locating in lymphoid follicle.Conclusion:Gradually increasing collagen deposition destroys construction of LNs after HIV infection which could be one of important reasons of CD4+T cells depletion in LNs. Although expression of IL-7 has a rising tendency in LNs of HIV-infected individuals with progression of infection stages, this is not enough to remedy effect of destruction of LNs construction. CD8+T cells with high TGF-β1 played an important role in LNs fibrosis after HIV infection. CD8+T cells not only exert anti-HIV infection effect, but play a crucial role in the pathogenesis after HIV infection. Alterations of chemokines in peripheral superficial LNs of HIV-infected individuals, which promote failure of immune function and depletion of CD4+T cells, could result from compensatory and adaptive response of body and disorganization of LNs. HIV is the intrinsic reason which results in the abnormal function of Tfh, but the translocation of microbic products play a synergetic role. Therefore, inhibiting the transloction of microbic products could improve the adaptive immunity and the capability against HIV of host, and reduce opportunistic infections.