In vitro Cytokine Treatment of B Cell Defects in HIV‐Infected Hemophilia Patients

Abstract

HIV-infected patients exhibit defects in B cell differentiation and in the IL-6 response of B cells, in association with autoantibody formation against T cells. These autoantibodies have been implicated as important factors in the development of immunodeficiency disease. As the restoration of defective B cell responses might prevent autoantibody formation and the resulting immunosuppression, we studied whether in vitro treatment with recombinant IL-2 (rIL-2), recombinant IL-4 (rIL-4) or recombinant IL-6 (rIL-6) might restore the response of B cells of HIV-infected patients. B cells of 6 HIV-negative hemophilia patients, 4 HIV-positive patients at CDC stage II, III, 4 HIV-positive patients at CDC stage IV, and 6 healthy controls were tested in Staphylococcus aureus Cowan I (SAC-I)-stimulated B cell cultures and Pokeweed mitogen (PWM)-stimulated allogeneic B and T cell cocultures. B cell differentiation was assessed in a reverse hemolytic plaque assay and by ELISA determination of IgM, IgG and IL-6 in culture supernatants. In vitro application of rIL-6 resulted in suppression of both elevated unstimulated and mitogen-stimulated B cell responses in a dose-dependent manner which was in part due to feedback inhibition. PWM- and SAC-I-stimulated IgG and IgM responses, respectively, could be restored after addition of 10 U/ml rIL-2 in HIV-negative patients, but not in HIV-positive patients. Addition of rIL-4 to cultures resulted in suppression of both unstimulated and mitogen-stimulated IL-6 secretion and B cell responses. Severely depressed B cell responses in CDC IV patients were not significantly affected by cytokine application. These results indicate that defective Ig responses in HIV-negative patients may be restored by rIL-2 treatment whereas HIV-induced B cell defects are not corrected by supply of T cell help or cytokines promoting B cell growth and differentiation.

CD4 depletion in HIV-infected haemophilia patients is associated with rapid clearance of immune complex-coated CD4+ lymphocytes

“…Firstsignal stimuli are provided by structural homologies of virus peptides with autoantigens as well as autoantigens unmasked during protein degradation after cell death. As a consequence, autoantibodies against several cellular and humoral autoantigens are formed [6,7,[14][15][16][17][18][19][20][21]. In addition, gp120 of HIV activates the complement system directly [22,23].…”

HIV-induced IL-6/IL-10 dysregulation of CD4 cells is associated with defective B cell help and autoantibody formation against CD4 cells

“…A role of IL-6 in the defective B cell help, but also in polyclonal B cell stimulation, impaired mitogenstimulated B cell responses and autoantibody formation of HIVinfected patients, has been suggested [19][20][21][22]. However, we showed subsequently that in vitro application of rIL-2, rIL-4 and rIL-6 did not restore B cell responses in HIV-infected patients [23]. Thus, the impaired IL-2, IL-4 and IL-6 responses observed upon stimulation do not appear to be the cause of defective HIV-induced B cell responses.…”

Safety and immunogenicity of subcutaneous hepatitis A vaccine in children with Haemophilia

“…As all of the children in the present study, both haemophilic and nonhaemophilic, were anti‐HIV negative, HIV immunosuppression does not explain the antibody titre differences observed. It is known that individuals with Haemophilia with chronic exposure to clotting factor concentrates have depressed immune system function, as measured by CD4 number, cytokine production, and monocyte function, in the absence of HIV infection [ 15–18]. Although no previous studies have compared haemophilic children with their nonhaemophilic siblings, studies of anti‐HIV negative Haemophiliacs at this Center have found reduced antibody responses to influenza and pneumococcal vaccines in anti‐HIV negative haemophilic subjects as compared with normal, nonhaemophilic subjects [ 15].…”