In vivo production of type 1 cytokines in healthy sickle cell disease patients.

Interleukins (IL)-1, 2, 12, and interferon (IFN)-gamma, along with soluble IL-2 receptor (sIL-2R) were measured from sera obtained from healthy sickle cell disease (SCD) patients and comparable healthy control subjects. The cytokines were assessed by enzyme-linked immunosorbent assay (ELISA) in 60 SCD patients and 58 controls. No significant detectable levels of IL-1 or IL-12 were found in the sera of either group of patients. Significantly elevated levels of IFN-gamma were measured in 20 (33%) of 60 SCD patients and 21 (36%) of 58 controls. A large subset of 18 (41%) of 43 healthy controls and a smaller subset of 12 (21%) of 58 SCD demonstrated detectable levels of IL-2. The sIL-2R levels of the SCD group (4465 +/- 552 pg/mL) were significantly higher (P < .0001) than that of controls (3473 +/- 411 pg/mL). The results revealed comparable circulating levels of all type 1 cytokines in both healthy SCD and normal control subjects, with the exception of in vivo sIL-2R production. Elevated serum levels of both IL-6 and tumor necrosis factor (TNF)-alpha have been reported previously in a significant percentage of SCD steady-state subjects. These two cytokines are known to increase sIL-2R expression and may help explain the difference between the patient populations. Immune activation markers such as sIL-2R are produced by cells that mediate host responses to infection or inflammatory stimuli. The implication of higher levels of sIL-2R in SCD is not clear, but chronic parvovirus B19 infection, chronic polyclonal activation of B cells or defective regulation of antibodies are possible explanations for the elevated levels in SCD.

Type 2 cytokine serum levels in healthy sickle cell disease patients.

Sickle cell disease (SCD) is characterized by significant morbidity and early mortality. Children with this hemoglobinopathy exhibit many of the manifestations associated with immunodeficiency disorders. Serum was obtained from 56 healthy SCD subjects and 45 normal healthy controls. Type 2 cytokines interleukin (IL)-4, IL-6, and IL-10 serum levels were measured. Concentrations were determined by reference to a standard curve, and results were expressed in pg/mL. Results revealed significant levels of IL-4 in 6 (13%) of 45 SCD patients compared with 1 (2%) of 45 controls. Increased levels of IL-6 were present in 35 (78%) of 45 SCD patients and 12 (41%) of 29 controls. Elevated levels of IL-10 were detectable in 13 (41%) of 42 SCD patients and 1 (4%) of 25 controls. High circulating levels of type 2 cytokines may suppress both humoral and cell-mediated immune functions in SCD, with resultant increased morbidity.

In vitro lymphocyte blastogenic responses and cytokine production in sickle cell disease patients with acute pneumonia.

BACKGROUND: Pulmonary infections continue to be a major cause of morbidity and mortality in patients with sickle cell disease (SCD). METHODS: In this study cell-mediated immunity in vitro was evaluated in 62 SCD patients (62 steady state and 16 with acute pneumonia) and compared with 44 normal controls (30 healthy and 14 with acute pneumonia). Lymphocyte blastogenic responses to phytohemagglutinin, tetanus toxoid and Candida albicans antigen were assessed in all subjects. In addition production of tumor necrosis factor, alpha- and gamma-interferon (IFN) were assayed. RESULTS: The results revealed comparable blastogenic responses to all three stimuli in all subjects except SCD patients with pneumonia. This group showed poor responses to all stimuli. The mean counts per minute were decreased 65 to 90% when compared with the other patients. Cytokine production of IFN-alpha and TNF was equivalent in all subjects. Conversely IFN-gamma production in both SCD groups, steady state (35 +/- 6 U/ml) and SCD with pneumonia (14 +/- 6 U/ml), was significantly decreased when compared with those in normal healthy controls (65 +/- 14 U/ml) and with pneumonia (48 +/- 17 U/ml). On analysis of individual titers 15 of 62 (24%) steady state and 10 of 16 (63%) SCD patients with pneumonia were deficient in IFN-gamma production in vitro. CONCLUSIONS: Acute pulmonary infections seem to have a profound effect on cell-mediated immunity in SCD. IFN-gamma deficiency, along with quantitative and qualitative T cell abnormalities, may represent significant factors to explain the frequent and severe infections seen in SCD.

Serum interleukin-6 levels in the steady state of sickle cell disease.

In patients with childhood sickle cell disease (SCD) serum interleukin-6 (IL-6) levels were measured during the steady (healthy) state of disease. The corresponding measurements were made in comparable healthy normal controls. Serum IL-6 levels were assessed via ELISA in 27 SCD patients and 19 controls. Results revealed significantly higher circulating levels of IL-6 in the SCD patients (60 +/- 7 pg/ml) compared with the healthy controls (12 +/- 5 pg/ml). IL-6 is a multifunctional cytokine that plays a central role in host defense mechanisms. The impact of high circulating levels of IL-6 may be deleterious to humoral and cell-mediated immune functions in SCD, with resultant heightened risk for morbidity.

Interferon production in sickle cell disease.

There is limited data on cytokine production in sickle cell disease (SCD). In this study, both alpha (Poly IC-induced) and gamma (PHA-induced) interferon (IFN) were measured in 62 SCD steady state patients, and 21 in the crisis state associated with infections. Comparable normal controls (30 healthy and 14 with infections) were assessed in a similar manner. Gamma IFN production in both SCD groups, steady state (35 +/- 6 U/ml) and crisis state (24 +/- 11 U/ml) was significantly diminished when compared to the normal healthy controls (65 +/- 14 U/ml) with P less than .005. Both SCD groups were also less than normals with infections (56 +/- 23 U/ml) with P less than .005. On closer analysis of individual titers, 15/62 (24%) in the steady state, 11/21 (52%) of SCD patients with infection and 2/14 (14%) of normals with infection, showed impaired gamma IFN when compared to normals without infection (range 27-2187 U/ml). Alpha IFN production in the SCD groups; steady state (512 +/- 113 U/ml) and SCD crisis with infection (559 +/- 110 U/ml) was virtually equivalent to normals (524 +/- 170 U/ml) and normals with infection (509 +/- 116 U/ml). Analysis of individual titers, in contrast to gamma IFN, also showed no significant differences. These results indicate that a significant percentage of SCD patients in both the steady state and infectious state associated with crisis, have impaired gamma IFN production. In view of the known immunomodulatory functions of gamma IFN, this apparent defect may be another factor to explain the increased frequency and severity of infections in SCD.

Increased serum IgG4 levels in acute Epstein-Barr viral mononucleosis.

Changes in serum IgG4 levels during heterophil-positive infectious mononucleosis were recorded. Pre-illness serial acute and convalescent specimens were evaluated. Mean IgG4 levels increased by 75% during acute infectious mononucleosis, reached a peak 21/2 to 3 weeks post-onset, and declined to baseline by 60 days. IgG4 peaked independently of other immunoglobulin classes.

Studies on the immune status of patients with renal adenocarcinoma.

Thirty-one patients with renal carcinoma were divided into 3 groups according to the stage of the disease and evaluated with skin tests to determine cell-mediated immunity and an in vitro chemostaxis assay to measure monocyte function. The patients demonstrated a significant defect in monocyte function, that is the ability to undergo chemotaxis when compared to healthy controls and patients with non-neoplastic disease (p less than 0.001). The defect tended to be more severe in patients with advanced disease. Improvements in monocyte function occurred following nephrectomy in patients with localized disease. The patients were skin tested with recall antigens and dinitrochlorobenzene to determine the presence of a delayed cutaneous hypersensitivity response. Croton oil was used to evaluate the non-specific inflammatory response. These studies indicate that a defect exists in cellular immunity as well as the inflammatory response. Patients with advanced disease tend to be unresponsive to these skin tests while those with localized disease are more likely to react to dinitrochlorobenzene and croton oil.