Altered expression of the receptor-ligand pair CXCR5/CXCL13 in B cells during chronic HIV-1 infection

Abstract

IntroductionHIV-1 infection is associated with extensive B-cell abnormalities, manifested by phenotypic alterations and polyclonal B-cell activation, increased frequencies of B-cell malignancies, hypergammaglobulinemia, as well as poor antigen-specific immune responses to recall and de novo antigens. [1][2][3][4][5] In secondary lymphoid tissue, HIV-1 infection induces follicular hyperplasia and alterations in the architecture of germinal center (GC) 6 and splenic marginal zones. 7 Defects in the B-cell compartment become overt already during primary HIV-1 infection 8 as measured by a decline of B-cell number, increased expression of activation, and apoptosis markers. 9 The mechanisms by which HIV-1 impairs humoral immunity may be the result of intrinsic B-cell defects and/or a lack of functional dialogue between B and T cells in secondary lymphoid organs.Lymphocyte migration and recirculation between the periphery and lymphoid tissue are critical for effective immunity and are in part regulated by chemokine receptors on lymphocytes together with the expression of their respective ligands (chemokines) in different tissue compartments. 10,11 In recent years, increasing attention has been given to the potential role of viruses to interfere with chemokine receptor expression, binding, and signaling. [12][13][14] In this respect, HIV-1 has been extensively studied because the virus uses CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5) as coreceptors for entry into target cells, in addition to the main receptor, the CD4 molecule. 15 However, the expression of chemokine receptors in the context of B-cell trafficking is still poorly studied in chronic HIV-1 infection.The chemokine receptor CXCR4 is broadly expressed on a majority of B cells in the bone marrow (BM), as well as in the periphery, and plays an important role for early B-cell development 16,17 and plasma cell homing to the BM. 18,19 On the other hand, CXCR5 is expressed by mature B cells and contributes to the recruitment of naive B cells into the lymph nodes 20 where the GC reaction occurs with class switch, somatic hypermutation, and affinity maturation. The microanatomic organization of GCs into light and dark zones has been attributed to the expression of CXCR4 and CXCR5. 21,22 B cells also express a moderate amount of CCR7, which contributes to the migration within the lymph node. 23 In the present study, we examined the cell surface expression of chemokine receptors CXCR4, CXCR5, and CCR7 on B cells isolated from the blood of HIV-1-infected patients because these receptors mediate important events of B-cell homing to lymphoid tissue. 20,[23][24][25][26] Using gene expression profiling of chemokine receptors and chemokines, we found a high level of CXC chemokine ligand 13 (CXCL13) mRNA in B cells from HIV-1-infected patients compared with controls; in addition, these cells secreted a high level of the CXCL13 protein after in vitro activation. Histopathology studies performed in lymphoid tissues revealed the presence of CXCL13 ϩ B cel...

Early Preservation of CXCR5 + PD-1 + Helper T Cells and B Cell Activation Predict the Breadth of Neutralizing Antibody Responses in Chronic HIV-1 Infection

“…In contrast, mean IP-10 plasma levels were associated with mean plasma viremia (r ϭ 0.61, P ϭ 0.01) (data not shown), as previously reported (51). While plasma CXCL13 levels have been shown to be significantly associated with viral load during chronic HIV-1 infection (48,52,53), CXCL13 plasma levels did not significantly correlate with viral loads in the subjects studied here. Therefore, the plasma levels of CXCL13 were uniquely associated with the development of BNAR and with the frequency of CXCR5 ϩ CD4 ϩ T cells and CXCR5 ϩ PD-1 ϩ CD4 ϩ T cells in a virus load-independent manner.…”

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

“…Together, these results suggest that abatacept acts to modulate the function of B cells rather than reduce B cell numbers. It remains possible that in the T and B cell cotransfer experiments, T cell migration into follicles was increased as a result of the effects of chemotactic factors, such as CXCL13, which can be expressed by activated B cells (47). It is also interesting to speculate that because B cells express CD80/CD86, abatacept could prevent phenotypic maturation of B cells, which may relate to the reduced levels of Ab production observed.…”

Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children

“…In this respect, we have recently shown that during chronic HIV-1 infection, both CD27 ϩ and CD27-B cells present alterations in the expression of the receptor-ligand pair CXCR5/CXCL13 and have altered migration patterns probably as a result of B cell hyperactivation and exhaustion (35). This may lead to defective B/T cell contacts during germinal center reactions thus impairing the maintenance of specific antibodies during secondary immune responses (35).…”