We characterized the defects of CD4+ cells in a 17-month-old girl suffering from combined immunodeficiency with hypereosinophilia (Omenn's syndrome). Because the vast majority of peripheral blood CD4+ cells expressed the CD45R0 isoform, we purified circulating CD4+ CD45R0+ cells from the patient and healthy individuals in order to compare their production of cytokines. The patient's CD4+ CD45R0+ cells spontaneously produced high levels of interleukin-5 (IL-5) in vitro (1600 pg/ml after 24 h of culture) and this was associated with the presence of IL-5 in serum (323 pg/ml). After stimulation with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187, they produced higher levels of IL-4 (306 vs. 55 +/- 4 pg/ml) and IL-5 (2900 vs. 213 +/- 72 pg/ml) and lower levels of IL-2 (17 vs. 63 +/- 17 IU/ml) and interferon-gamma (IFN-gamma) (16 vs. 299 +/- 70 IU/ml) than controls CD4+ CD45R0+ cells. This T helper type 2 (Th2) pattern was confirmed by the detection using reverse polymerase chain reaction of IL-4, IL-5 and IL-10 mRNA within peripheral blood mononuclear cells. During a therapeutic trial with human IFN-gamma (40 micrograms/day) which ameliorated the clinical status of the patient, we observed a down-regulation of the in vivo expression of IL-5 and IL-10, a normalization of the eosinophil count and an improvement of the T cell response to phytohemagglutinin. This observation indicates for the first time that Th2-like cells might be involved in certain forms of congenital immunodeficiency and that IFN-gamma might down-regulate their activities in vivo.
Between May 1979 and April 1983, 18 previously healthy African patients were hospitalized in Belgium with opportunistic infections (cryptococcosis, Pneumocystis carinii pneumonia, central-nervous-system toxoplasmosis, progressive cutaneous herpes simplex virus infection, disseminated cytomegalovirus infection, candidiasis, or cryptosporidiosis) or Kaposi's sarcoma, or with both. Ten of them died. During the same period five other patients were hospitalized with an illness consistent with a prodrome of the acquired immunodeficiency syndrome (chronic lymphadenopathy, fever, weight loss, and diarrhea). All patients tested had a marked decrease in helper T cells; an inversion of the normal ratio of helper to suppressor T cells, and a decreased or absent blastogenic response of lymphocytes to mitogens. Twenty patients had anergy. There was no evidence of an underlying immunosuppressive disease and no history of blood-product transfusion, homosexuality, or intravenous-drug abuse. This syndrome in patients originating in Central Africa is similar to the acquired immunodeficiency syndrome reported in American patients.
The IgA, IgM, and IgG antibody responses to pneumococcal polysaccharide vaccine were analyzed in 35 asymptomatic or mildly symptomatic human immunodeficiency virus (HIV)-infected patients stratified according to their CD4 cell counts and in 12 healthy controls. Both the antibody titers in serum and saliva and the numbers of circulating antigen-specific antibody-producing cells (Elispot technique) were measured. At the peak of the antibody responses, HIV-infected patients mounted nearly normal IgG responses, while their IgM responses were significantly depressed, regardless of their CD4 cell counts. The IgA antibody response was decreased in patients with < 500 CD4 circulating cells/mm3. Most IgG antibodies belonged to the IgG2 subclass, and most IgA antibodies were dimeric IgA2 in both controls and patients. Anti-capsular pneumococcal polysaccharide IgG titers decreased much more rapidly in HIV-infected patients so that in all groups they were significantly lower than in controls 9 months after vaccination.
SUMMARYSystemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by polyclonal B cell activation and by the production of anti-double-stranded (ds) DNA antibodies. Given the inhibitory effects of IL-12 on humoral immune responses, we investigated whether IL-12 displayed such an activity on in vitro immunoglobulin production by SLE PBMC. Spontaneous IgG, IgG1, IgG2, IgG3 and IgM antibody production was dramatically reduced by addition of IL-12. These results were confirmed by Elispot assays detecting IgG-and anti-dsDNA-secreting cells. While IL-6 and TNF titres measured in PBMC supernatants were not modified by addition of IL-12, interferon-gamma (IFN-g) titres were up-regulated and IL-10 production down-regulated. Since addition of IFN-g did not downregulate immunoglobulin production and since the inhibitory activity of IL-12 on immunoglobulin synthesis was not suppressed by anti-IFN-g antibody, we concluded that the effect of IL-12 on immunoglobulin production was not mediated through IFN-g. Our data also argue against the possibility that down-regulation of endogenous IL-10 production was responsible for the effect of IL-12. Thus, inhibition of IL-10 production by IFN-g was not accompanied by inhibition of immunoglobulin production, and conversely, restoration of IL-10 production by anti-IFN-g antibody did not suppress the inhibitory activity exerted by IL-12 on immunoglobulin production. Taken together, our data indicate that reduction of excessive immunoglobulin and anti-dsDNA antibody production by lupus PBMC can be achieved in vitro by IL-12, independently of IFN-g and IL-10 modulation.
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