Mechanism of Hypergammaglobulinemia by HIV Infection: Circulating Memory B-Cell Reduction with Plasmacytosis

Nagase, Hisashi; Agematsu, Kazunaga; Kitano, Kiyoshi; Takamoto, Masaya; Okubo, Yoshio; Komiyama, Atsushi; Sugane, Kazuo

doi:10.1006/clim.2001.5054

Cited by 114 publications

(97 citation statements)

References 38 publications

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“…49,52 Such a mechanism could be mediated by viral proteins like gp120 or by virus-induced T-cell activation, as shown by increased CD70 expression on T cells. 6,31 In the group of treatment-naive patients we observed that the percentage of circulating memory B lymphocytes is inversely correlated with HIV viremia, indicating that virus-induced immune activation may directly contribute to the loss of memory B cells and to B-cell dysfunctions, as recently suggested. 24 On the other hand and perhaps simultaneously, high antigenic pressure might be a bystander driving force to activate B cells to produce polyclonal Abs.…”

Section: Discussionsupporting

confidence: 67%

“…28,29 We have recently shown that memory B lymphocytes are significantly reduced during HIV-1 infection and are prone to undergo spontaneous apoptosis in vitro. 6,30 The loss of memory B cells may be mediated by overexpression of CD70 on activated T lymphocytes 6,31 which may induce terminal differentiation to plasma cells and/or by lack of survival factors leading to apoptosis. 30 In the present study, we investigated the phenotype and function of naive B cells isolated from HIV-1-infected persons and evaluated the status of antigen-specific humoral immunity in relation to hypergammaglobulinemia and loss of memory B cells.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection

Milito

Nilsson

Titanji

et al. 2004

Blood

279

280

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IntroductionA profound impairment of immune functions occurs in individuals infected with human immunodeficiency virus type 1 (HIV-1). Both the cellular and the humoral arms of the immune system are unable to control the infection, which ultimately results in severe exhaustion of several lymphocyte functions and increased susceptibility to secondary and opportunistic infections. Major immunologic defects occur in the B-cell compartment. 1 Polyclonal B-cell activation is demonstrated by hypergammaglobulinemia and spontaneous antibodies' (Abs) production by cultured peripheral lymphocytes 2,3 ; additional signs of B-cell abnormality are the high incidence of B-cell tumors 4 and the deregulated expression of several surface molecules like Fas, Fas ligand (FasL), CD5, CD21, and CD27. 5-8 B-cell hyperactivity is also accompanied by functional defects since humoral immune responses following immunization are severely impaired in HIV-1-infected subjects and B lymphocytes from patients are poorly responsive to in vitro stimulation. [9][10][11] Several mechanisms may account for the B-cell abnormalities in HIV-1 infection. A direct effect of virus replication or viral proteins on B-cell function has been shown 12 and sustained by the observation that polyclonal B-cell activation is strongly reduced following effective antiretroviral treatment. 13-15 HIV-driven unbalanced production of several cytokines like tumor necrosis factor ␣ (TNF-␣), interleukin 6 (IL-6), IL-10, and IL-15 has also been involved in B-cell dysfunctions. [16][17][18] Defective T-cell help may account for B-cell unresponsiveness to T-cell-dependent antigens. 19,20 The defect of B cells in HIV-1 infection appears, however, to be intrinsic since it begins early during infection preceding functional and quantitative defects in T-helper activity and cannot be restored by allogenic normal CD4 ϩ T cells in vitro. 3,21 The mechanisms inducing hypergammaglobulinemia in HIV-1 infection are only partially known. Activation driven by CD4 ϩ T cells, monocytes, and natural killer (NK) cells through CD40-CD40 ligand (CD40L) interaction and an inappropriate cytokine supply may have a relevant role in inducing abnormal differentiation of B cells. 17,22 In addition, HIV-1 itself may directly affect B-cell activation and dysfunction, inducing the appearance of a subset of CD21 Ϫ B cells which have been proposed to contribute to increased antibody production. 23,24 A recent work by Hunziker et al 25 has suggested that naive B cells represent an important source of hypergammaglobulinemia and autoantibody production in chronic viral infections.Because of the lack of protective humoral immunity, HIV-1-infected individuals receive vaccination against several pathogens. However, many studies have reported an impaired humoral immune response in most of the patients after vaccination. [9][10][11]26,27 From the Microbiology and Tumor Biology Center, Karolinska Institutet, and the Gay Men's Health Clinic, The Soder Hospital, Stockholm, Sweden; the Swedish Institute for Infectious...

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection

Milito

Nilsson

Titanji

et al. 2004

Blood

279

280

View full text Add to dashboard Cite

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“…Among B cell subsets HIV-infected children show a significant loss of relative and absolute numbers of switched memory B cells. In adults, a loss of memory B cell function has been reported (6,7,26), but data in children have not been published yet. Insufficient differentiation of naive to memory B cells, terminal differentiation of memory B cells to plasma cells, and apoptosis of memory B cells have been discussed explaining memory B cell loss.…”

Section: Discussionmentioning

confidence: 99%

“…An increased CD70 expression (CD27 ligand) on CD4 T cells has been associated with increased plasma cell numbers (28). In addition, plasmocytosis in bone marrow samples was observed in infected adults (26). For further evaluation, bone marrow and peripheral blood samples would need to be examined simultaneously.…”

Section: Discussionmentioning

confidence: 99%

Memory B Cell Function in HIV-Infected Children—Decreased Memory B Cells Despite ART

et al. 2009

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B cell dysfunction is a well-studied complication of HIV infection in adults. Data on B cell differentiation in normal and HIV-infected children are lacking. We show the distribution of B cell subsets and immunoglobulin levels in HIV-infected children compared with controls. Furthermore, we observe the long-term B cell reconstitution of vaccine-specific immunity after antiretroviral therapy (ART). Phenotype of B cells (naive, non-switched memory, switched memory) was analyzed in 48 infected children and 62 controls. In nine HIV-infected children, functional reconstitution was quantified by tetanus-specific antibodies and by performing a lymphocyte transformation test (LTT) in a longitudinal approach.

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“…Phenotypic perturbations of B cells circulating in the peripheral blood include over-representation of activated, exhausted, and terminally differentiated B cells associated with HIV viremia [3][4][5] ; over-representation of immature/ transitional B cells associated with HIV-induced CD4 ϩ T-cell lymphopenia 6,7 ; and reduced representation of CD27 ϩ memory B cells associated with most stages of HIV infection. [8][9][10][11][12][13] Most of these studies, whether longitudinal or cross-sectional, have been conducted on chronically HIV-infected individuals, whereas only a few studies, generally with small sample sizes, have addressed the effect of duration of infection and initiation of antiretroviral therapy (ART) on perturbations of B-cell subpopulations in HIVinfected individuals. 9,14,15 Functional perturbations of B cells in HIV-infected individuals include hypergammaglobulinemia associated with polyclonal and HIV-specific activation of B cells induced by ongoing HIV replication, 15,16 as well as decreased B-cell responses to specific immunogens and non-HIV pathogens.…”

Section: Introductionmentioning

confidence: 99%

B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy

Moir

Buckner

et al. 2010

Blood

240

263

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IntroductionNumerous perturbations of B-cell phenotype and function have been described in HIV-infected individuals (reviewed in Cagigi et al 1 and Moir and Fauci 2 ). Phenotypic perturbations of B cells circulating in the peripheral blood include over-representation of activated, exhausted, and terminally differentiated B cells associated with HIV viremia 3-5 ; over-representation of immature/ transitional B cells associated with HIV-induced CD4 ϩ T-cell lymphopenia 6,7 ; and reduced representation of CD27 ϩ memory B cells associated with most stages of HIV infection. [8][9][10][11][12][13] Most of these studies, whether longitudinal or cross-sectional, have been conducted on chronically HIV-infected individuals, whereas only a few studies, generally with small sample sizes, have addressed the effect of duration of infection and initiation of antiretroviral therapy (ART) on perturbations of B-cell subpopulations in HIVinfected individuals. 9,14,15 Functional perturbations of B cells in HIV-infected individuals include hypergammaglobulinemia associated with polyclonal and HIV-specific activation of B cells induced by ongoing HIV replication, 15,16 as well as decreased B-cell responses to specific immunogens and non-HIV pathogens. 11,17,18 The latter is likely a reflection of both CD4 ϩ T-cell dependent and independent defects in B cells that arise in HIV-infected individuals, and especially in individuals with ongoing viral replication. Many of the functional B-cell defects described in HIV-viremic individuals can be improved with ART, although there is 1 important exception that has received relatively little attention. While B-cell responses against non-HIV antigens are either stabilized or increased after initiation of ART, 19-22 the reverse is often observed for B-cell responses against HIV antigens,15,23,24 suggesting that the humoral response against HIV is dependent on continuous HIV replication. In the most comprehensive study on B-cell responses after ART, Morris and colleagues described a rapid loss of HIV-specific B cells (actively secreting plasmablasts) during therapy, followed by a more gradual decrease in antibody titers against HIV in chronically infected individuals; the loss was even more rapid in early-treated individuals. 15 In a previous study of chronically HIV-infected individuals, we reported a reduction in B-cell numbers and the presence of perturbed B-cell subpopulations before initiation of ART followed by partial normalization 1 year after successful reduction in viremia by ART. 25 In a more recent study, 5 we identified a subpopulation of CD27 Ϫ tissue-like memory B cells within an abnormal CD21 lo B-cell compartment of the peripheral blood of chronically HIVviremic individuals; this subpopulation had been included within the activated B-cell compartment that we had previously described. 25 These CD27 Ϫ tissue-like memory B cells bore many features of exhausted cells, arising in the context of chronic immune activation, and with features that include expression of multiple inhibitory...

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Mechanism of Hypergammaglobulinemia by HIV Infection: Circulating Memory B-Cell Reduction with Plasmacytosis

Cited by 114 publications

References 38 publications

Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection

Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection

Memory B Cell Function in HIV-Infected Children—Decreased Memory B Cells Despite ART

B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy

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