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

Abstract

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...

Laboratorial atopy markers in children with human immunodeficiency virus

“…In the HIV-infected patient, this sensitivity seems to disappear with disease progress (Goetz et al 1997), presumably due to the destruction of memory clones that occurs with the progressive loss of CD4 + T lymphocytes. This is the same phenomenon that occurs in the case of lost responses to antigen-based vaccines (Douek et al 2000, Feeney et al 2003, De Milito et al 2004, Rosenblatt et al 2005. Since immunoglobulin production is T lymphocyte-dependent, a reduction in Th2 CD4 + lymphocyte clones decreases B lymphocyte stimulation, thus resulting in reduced IgE levels.…”

Loss of Discrete Memory B Cell Subsets Is Associated with Impaired Immunization Responses in HIV-1 Infection and May Be a Risk Factor for Invasive Pneumococcal Disease

“…Intrinsic defects in B cell function resulting in failure of this cell population to respond to accessory CD4 T cell help (7,8) and inhibition of Ig isotype class switching by HIV viral proteins may play a role in the development of impaired humoral immune responses seen in HIV-1 infection (9). Memory B cell (CD19 ϩ CD27 ϩ ) counts are reduced in HIV-1-infected individuals (10 -12) and are associated with reduced measles and tetanus Ab concentrations (13). Plasma levels of IgM and IgG pneumococcal Ab are reduced in HIV-1 infection and the capacity of PBMC to produce IgG and IgM pneumococcal Ab following in vitro B cell polyclonal stimulation is impaired (14).…”

Virus-induced polyclonal B cell activation improves protective CTL memoryvia retained CD27 expression on memory CTL

“…+ CTL is characterized by the persistent expression of CD70, mainly on B cells [24]. We therefore assessed the expression of CD70 at different time points after infection of C57BL/6 and CD27 -/-mice with LCMV ( Fig.…”