Polyspecific Self‐Reactive Antibodies in Individuals Infected with Human Immunodeficiency Virus Facilitate T Cell Deletion and Inhibit Costimulatory Accessory Cell Function

Wang, Zhiqin; Horowitz, Harold W.; Orlikowsky, Thorsten; Hahn, Beom-Ik; Trejo, V.; Bapat, Abhijit S.; Mittler, Robert S.; Rayanade, Ravi J.; Yang, Soo Young; Hoffmann, Michael K.

doi:10.1086/314974

Cited by 19 publications

(20 citation statements)

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“…25 The plasma IgG in HIV-1-infected subjects contains both anti-HIV Abs and other antibodies like PSA and autoantibodies. 38,43 In parallel, a loss of specific humoral immunity may occur as indicated by low levels of antibodies against several pathogens 26,27,44 and by the rapid loss of antigen-specific antibodies following immunization. [9][10][11]27 We measured antibodies to TT, a common vaccination antigen and to measles, a naturally acquired infection in our cohort, and found that the levels of IgG to both antigens were significantly reduced in HIV-1-infected individuals with low memory B cells.…”

Section: Discussionmentioning

confidence: 99%

“…High levels of PSA have been detected in HIV-1 infection and these autoantibodies have been shown to bind lymphocytes and mediate T-cell death. 38 Human PSA from HIV-1-infected subjects showed a higher reactivity (defined as MFI) as compared with healthy subjects (11.8 [range, 4.6-53.9] vs 7.8 [range, 4.1-12.60; P Ͻ .01). In the HIV-1 population, the MFI of PSA was correlated to the plasma IgG (rho ϭ 0.547, P ϭ .001) and PSA reactivity was similar between HIV-1 NM subjects and HIV-1 LM subjects (15.9 [range, 10.3-23.8] vs 7.5 [range, 7-21.6]; P ϭ .226; Figure 6B).…”

Section: Polyclonal B-cell Activation and Naive/memory B Cellsmentioning

confidence: 93%

“…37,38 Measurement of PSAs was performed as previously described. 37 Buffy coat preparations from healthy donors were used to obtain target lymphocytes.…”

Section: Determination Of Polyspecific Self-reactive Antibodiesmentioning

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

282

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: Discussionmentioning

confidence: 99%

Section: Polyclonal B-cell Activation and Naive/memory B Cellsmentioning

confidence: 93%

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

Milito

Nilsson

Titanji

et al. 2004

Blood

282

280

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“…M⌽ that lack CD80 and CD86 expression are incapable of preventing the induction of anergy or apoptosis in conjugated T cells and act as negative immune regulators (42)(43)(44). In addition, M⌽ have the capacity to actively destroy T cells that they target for conjugate formation (44).…”

mentioning

confidence: 99%

Effect of Dexamethasone on B7 Regulation and T Cell Activation in Neonates and Adults

et al. 2005

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The safety of dexamethasone for neonates has been questioned, partly because of its multiple unspecific effects on the immune system. Specific effects of dexamethasone on costimulatory and immune suppressive functions of neonatal compared with adult macrophages (M⌽) are not known. We evaluated the effect of dexamethasone on the expression and regulation of M⌽ B7 family receptors (B7-1, CD80; B7-2, CD86) and on their ability to co-stimulate T cells. Cord blood macrophages (CBM⌽) and M⌽ from healthy adults (PBM⌽) were isolated, and cell surface markers were phenotyped by flow cytometry. In tissue culture, cells were exposed to dexamethasone, interferon-␥ (IFN-␥), cAMP, or a T cell mitogen (␣CD3) and examined for their capacity to activate or destroy T cells. CBM⌽ were less able to up-regulate CD80 and CD86 than PBM⌽ (p Ͻ 0.05). Dexamethasone inhibited the up-regulation of CD80, CD86, and HLA-DR on PBM⌽ and even more so on CBM⌽ (p Ͻ 0.05 versus PBM⌽ for CD80 and CD86). In the presence of dexamethasone, stimulation with ␣CD3 MAb enhanced cytotoxic functions of PMBM⌽ and CB⌴⌽ with an increase in deleted T cells, a reduced fraction of enlarged T cells, and an inhibition of T cell CD28 up-regulation, which again were more pronounced with CBM⌽ (p Ͻ 0.05 versus PBM⌽). In conclusion, neonatal M⌽ are exquisitely sensitive to the inhibitory effects of dexamethasone on B7 expression. Although perhaps producing the desired therapeutic effect, dexamethasone may do so in newborns at the expense of a near complete paralysis of M⌽-dependent T cell function. Preterm newborns have been exposed to dexamethasone for the prevention or treatment of bronchopulmonary dysplasia (BPD) for many years (1,2). Dexamethasone is a synthetic glucocorticoid that reduces the recruitment of inflammatory cells (3,4) and thereby is thought to inhibit the development of BPD. Its effects on other developing organs such as the CNS were only recognized much later. Because follow up-studies provided evidence of abnormal neurodevelopment, early postnatal use of dexamethasone is not recommended any more (2). Nevertheless, glucocorticoids continue to be given to pregnant women to accelerate fetal lung development.Besides the endocrinium, the primary target of dexamethasone is the immune system, which is incompletely developed in neonates. Evidence that the immunosuppressive effects of dexamethasone are primarily mediated via an inhibition of cytokine production has been produced. Mononuclear cells from adults and neonates respond differently to treatment with dexamethasone. With respect to proinflammatory cytokines, cord blood cells show an increased sensitivity toward the inhibitory action of dexamethasone compared with cells from adult donors, resulting in a more pronounced inhibition of IL-1␤, IL-6, tumor necrosis factor-␣, 6).Dexamethasone may directly inhibit T cell proliferation (7), induce apoptosis (8), promote long-lasting changes in the T cell receptor v␤ repertoire (9), or decrease the CD4/CD8 ratio in infants with BPD (10). Dexamethasone also infl...

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“…Hallmarks of B cell abnormalities in HIV disease include hypergammaglobulinemia (2)(3)(4), increased expression of activation markers (5), increased levels of autoantibodies (6,7), increased risk of developing B cell lymphomas (8), and decreased responsiveness to in vivo vaccination and ex vivo stimulation (9,10). The range of defects in B cell responses includes both T cell-dependent and -independent pathways (1,11,12), suggesting that along with defects in CD4 ϩ T cell help, HIV infection causes intrinsic B cell defects.…”

mentioning

confidence: 99%

Perturbations in B cell responsiveness to CD4⁺T cell help in HIV-infected individuals

Moir

Ogwaro

Malaspina

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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T he scope of B cell abnormalities in HIV-infected patients, first described almost 20 years ago (1), has come to define a pervasive paradigm in HIV infection, namely that of immunodeficiency in the setting of virus-driven immune activation. Hallmarks of B cell abnormalities in HIV disease include hypergammaglobulinemia (2-4), increased expression of activation markers (5), increased levels of autoantibodies (6, 7), increased risk of developing B cell lymphomas (8), and decreased responsiveness to in vivo vaccination and ex vivo stimulation (9, 10). The range of defects in B cell responses includes both T cell-dependent and -independent pathways (1, 11, 12), suggesting that along with defects in CD4 ϩ T cell help, HIV infection causes intrinsic B cell defects. Recent studies have shown that the majority of these abnormalities are attributable to ongoing viral replication and are reversible by the suppression of plasma viremia with effective antiretroviral therapy (2, 6, 13-15). In light of similar abnormalities described in the CD4 ϩ and CD8 ϩ T cell compartments of HIV-infected individuals (16-18), there is clear evidence that immune activation brought on by unchecked HIV-1 replication has widespread deleterious effects on the immune system.Insight into the apparent paradox that in vivo B cell hyperactivity translates into poor response to immunogens and ex vivo stimuli has remained elusive for almost two decades. However, with the availability of antiretroviral therapies that can effectively sustain the suppression of virus replication, it has become apparent that B cell hyperactivity and poor responsiveness to stimulation are directly linked to ongoing virus replication by mechanisms that may include cytokine deregulation, loss of memory B cells, and induction of terminal differentiation (15,19,20). However, most studies on B cell function have been based primarily, if not exclusively, on responsiveness of B cells to exogenous surrogates of antigenic stimulation, such as soluble anti-Ig antibodies and trimeric CD40 ligand (CD154), triggers of the B cell receptor (BCR) and CD40, respectively.The initiation of a humoral immune response to T celldependent antigens requires cognate interactions between antigen-specific B cells and activated antigen-specific CD4 ϩ T cells involving both cell-contact interactions and soluble factors. One of the most important contact-mediated interactions between B cells and CD4 ϩ T cells involves CD40 expressed constitutively on B cells and its membrane-bound ligand CD154 expressed on activated CD4 ϩ T cells (21). The expression of CD154 on activated CD4 ϩ T cells is induced after T cell receptor triggering by antigen-presenting cells, likely dendritic cells, and requires key costimulatory interactions between CD80͞CD86 on mature antigen-presenting cells and CD28 on CD4 ϩ T cells (22). These interactions also induce CD4 ϩ T cells to secrete cytokines, which, together with expression of CD154, provide CD4 ϩ T cells with full helper function. T helper (Th) cells can be divided into ...

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Polyspecific Self‐Reactive Antibodies in Individuals Infected with Human Immunodeficiency Virus Facilitate T Cell Deletion and Inhibit Costimulatory Accessory Cell Function

Cited by 19 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

Effect of Dexamethasone on B7 Regulation and T Cell Activation in Neonates and Adults

Perturbations in B cell responsiveness to CD4⁺T cell help in HIV-infected individuals

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Polyspecific Self‐Reactive Antibodies in Individuals Infected with Human Immunodeficiency Virus Facilitate T Cell Deletion and Inhibit Costimulatory Accessory Cell Function

Cited by 19 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

Effect of Dexamethasone on B7 Regulation and T Cell Activation in Neonates and Adults

Perturbations in B cell responsiveness to CD4+T cell help in HIV-infected individuals

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Perturbations in B cell responsiveness to CD4⁺T cell help in HIV-infected individuals