Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients

Abstract

In an attempt to define potential immunological dysfunctions in schizophrenia, we determined the production of interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and soluble IL-2 receptor (sIL-2R) in a whole-blood assay after stimulation with phytohemagglutinin (PHA) as well as the serum concentrations of sIL-2R. Because CD4+CD45RO+T cells are the main producers of IFN-gamma, we determined the percentage of these cells, as well as of panT, CD4+T, and CD8+T cells, by flow cytometry. A whole-blood count was performed in addition. Two groups of patients were examined, paranoid-type and residual-type schizophrenics. The numbers of both monocytes and neutrophils, but not of lymphocytes, were increased significantly in the schizophrenic sample. The IFN-gamma production of the schizophrenics as a whole group, and of the paranoid patients, was reduced significantly in comparison with the control group (p < or = 0.05). The residual patients produced less IFN-gamma than the controls, but more than the paranoid patients. The latter differences did not reach statistical significance. The production of IL-4, which physiologically antagonizes the production of IFN-gamma, was not significantly higher in the patient group. No changes in the lymphocyte subpopulations were observed. The production of IL-2 showed a trend toward reduction in paranoid patients, but not in residual schizophrenics. The serum sIL-2R levels were elevated slightly in schizophrenics when compared with controls. In order to rule out a possible effect of cortisol on cytokine production, 20 schizophrenics were compared with 20 age- and gender-matched controls. However, neither elevated cortisol levels were detected in the schizophrenic sample, nor significant intercorrelations between cortisol levels and cytokine production, or levels of sIL-2R, respectively. In summary, our data reinforce the possibility of immune dysfunction in schizophrenia and point to the possible relevance of disease subgroups in this respect.

Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment

“…Our results confirm the association between acute schizophrenia and low IL-2 production, [8][9][10][11][12][13][14][15] but also clearly confirm our earlier results 30 which showed a decreased IFN-␥ production in acute schizophrenia. Deficient lymphocyte productions of both IL-2 and IFN-␥ were also found throughout the time period of clinical remission, which were also significantly intercorrelated with one another at all three time-points of the investigation.…”

“…This is particularly important, since it suggests an association between lowered IL-2 production and the structural brain abnormalities which are supposed to be associated with these clinical features. However, earlier crosssectional studies by our group 14,15 failed to show such correlations. Also in the present study, no correlations between negative or positive symptoms and production of IL-2 or IFN-␥ could be observed at T1.…”

“…Using the same methods as were used in our pilot study, 14 we have demonstrated a significantly reduced production of IFN-␥ in an acutely ill subsample of a larger group of patients with schizophrenia. 15 Recently this finding could be confirmed in samples of hospitalized acutely psychotic schizophrenics 29 and in acutely schizophrenic members of multiplex families. 30 However, as in the majority of studies in this area, only a cross-sectional approach was employed, which did not yield any information about changes in cytokine production while patients were undergoing remission.…”

“…The data suggesting a decreased production of IFN-␥ during acute schizophrenia directly support the idea that autoimmune activity plays an important role in pathogenesis. 2 The fact that this feature was observed only in the acutely ill, but not in the residual patients 15,30 is also worthy of note. Furthermore, as with type-I diabetes, where low IL-2 production is obviously acquired, and not inherited, 36 we found decreased IFN-␥ production in the acutely schizophrenic, but not in unaffected first degree relatives within families showing multiple occurrence of schizophrenia.…”

“…Six different groups, including our own, have independently demonstrated that mitogen stimulated IL-2 production by peripheral blood mononuclear cells (PBMC) is decreased in patients with schizophrenia. [8][9][10][11][12][13][14][15] This is the most frequently confirmed finding in the immunology of schizophrenia and there has not as yet been a failure in demonstrating this phenomenon. In the cerebrospinal fluid (CSF) of drug-free patients, increased levels of IL-2 were found 16 and also significantly predicted the recurrence of psychotic symptoms in relapse-prone schizophrenics.…”