Circulating human plasmacytoid dendritic cells are highly sensitive to corticosteroid administration.

Plasmacytoid dendritic cells (pDC), the major interferon-producing cell type found in human blood, have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies in SLE have shown substantial deviations from normal in this minor but immunologically important leukocyte population. Many of the lupus patients studied were receiving corticosteroids. To determine the effects of steroid administration on pDC in healthy adults, four volunteers were given prednisone, 15-30 mg daily, for 4 days. Both counts of pDC, and their ability to produce IFN-alpha were significantly reduced (P = 0.02 and 0.004, respectively) during steroid administration, and rapidly recovered after discontinuation of the hormones. The overall reduction in pDC-derived IFN appeared to be attributable to falls of both number of circulating cells and of IFN produced per pDC. The effects observed with pDC were comparable in magnitude but opposite in direction to that observed for granulocytes. In contrast other blood leukocytes were little affected during steroid therapy.

Circulating, interferon-producing plasmacytoid dendritic cells decline during human ageing.

Increased frequency and severity of infections in the elderly have been taken as indicative of declining immune function. Dendritic cells (DCs), the most important antigen-presenting cells, play a central role in initiating and modulating immune responses. One type, DC2, arises from precursor plasmacytoid DCs (pDCs), a rare population of circulating blood cells, whose hallmark function is rapid and copious production of interferon-alpha (IFN-alpha) upon microbial challenge. We found significant decreases of the circulating pDCs during ageing in healthy adult humans, as defined both by flow cytometry and IFN-alpha generation. Mean pDC/mm3 in peripheral blood declined from 7.8 for the youngest age group (18-39 years) to 4.2 for the oldest (60-91 years; P = 0.017). IFN-alpha generation declined similarly, from 3537 to 1201 IU/ml, respectively (P = 0.006). There was also a slight decline over the age range in the amount of IFN generated per pDC (slope = -0.0087; P = 0.046). CD4+ T cells decreased by approximately 20% over the same age range (P = 0.001), while there was no change in the total lymphocyte or monocyte counts.

Interferon-alpha generation and immune reconstitution during antiretroviral therapy for human immunodeficiency virus infection.

OBJECTIVES: To quantify the effect of HIV infection and HIV-suppressive therapy on interferon-alpha (IFN-alpha) production by human blood mononuclear cells; to compare, in parallel, effects on CD4+ T-cell numbers; and to ascertain the relationship of these interferon and CD4 parameters to resistance to opportunistic infections. DESIGN: Serial studies of 294 unselected patients with HIV infection during therapy, with outcomes analysis. METHODS: Determination of IFN generation by blood mononuclear cells via bioassay, and T-lymphocyte subset analysis via flow cytometry; serial studies of individual patients; linear regression and chi2 contingency table analysis. RESULTS: HIV burden is inversely related to interferon-alpha generation, much as it is to CD4+ T-cell counts. Both of these recover during HIV-suppressive therapy. Reconstitution of IFN-alpha generation to levels commensurate with protection against opportunistic infection occurs prior to similar restoration of CD4 counts. In the outcomes analyses, such immune reconstitution was associated with protection from recurrent or new opportunistic infection. Conversely, viral suppression without such immunologic recovery was not protective against opportunistic infection. CONCLUSIONS: Rapidly responding IFN-alpha generating cells appear to participate in resistance to opportunistic intracellular infection. Recovery of IFN-alpha generation may be an early marker of immune reconstitution in AIDS.

Corticosteroids depress IFN-alpha-producing plasmacytoid dendritic cells in human blood.

Glucocorticoids are strongly immunosuppressive and are associated with reactivation of some intracellular infections. The plasmacytoid dendritic cell is a rare blood mononuclear cell detected through its production of IFN-alpha in response to herpes simplex virus and by surface immunophenotyping. We here report that steroid administration results in a decrease of IFN-alpha generation of approximately 25-fold, accompanied by reduction in circulating plasmacytoid dendritic cell numbers. Both parameters return to normal within days after steroid cessation.

Prevalence of HTLV-I-associated T-cell lymphoma.

In order to assess the prevalence rate of HTLV-1-associated T-cell lymphomas and human retrovirus infection in general, approximately 21,000 individuals representing various patient populations, retroviral risk groups, and blood donors were examined for HTLV-I, HTLV-II, HIV-1, or HIV-2 infection using serologic and PCR assays. The prevalence rates among volunteer blood donors were 0.02% and 0% for HTLV and HIV, respectively. Significantly increased HTLV prevalence rates were observed among paid blood donors, African American health care clinic patients, Amerindians, recipients of HTLV-positive cellular blood products, intravenous drug users, sexual contacts and family members of HTLV-positive people, and patients with primary thrombocytosis and other-than-low-grade non-Hodgkin's lymphoma (NHL). Among some of these groups there were significant differences in the prevalence of HTLV-I versus HTLV-II. The eight HTLV-positive NHL patients all had mature, high-grade, CD4+ T-cell lymphomas with clonally integrated HTLV-I, for a prevalence of 4% among other-than-low-grade NHL patients. Seven of the eight died from their disease within 2 years despite treatment. Interestingly, two groups at risk for HTLV infection, namely needle stick victims and recipients of HTLV-infected and/or pooled plasma products, showed no evidence for infection. Significantly increased HIV-1 prevalence was observed among paid blood donors, African Americans, homosexuals, female prostitutes, hemophiliacs, and other-than-low-grade NHL patients. Only one patient was infected with HIV-2. Of the nine HIV-positive, other-than-low-grade NHL patients, seven HIV-1 positives had B-cell lymphomas, one HIV-1 positive had an HTLV-I-positive CD4+ T-cell lymphoma, and one infected with HIV-2 had a CD4+ T-cell lymphoma that was HTLV negative. The data indicate that HTLV-I lymphoma, while uncommon, is not necessarily rare among other-than-low-grade NHL cases in the United States and, given its poor prognosis, should probably be studied separately in clinical trials.

The nature of the principal type 1 interferon-producing cells in human blood.

Interferons (IFNs) are the most important cytokines in antiviral immune responses. "Natural IFN-producing cells" (IPCs) in human blood express CD4 and major histocompatibility complex class II proteins, but have not been isolated and further characterized because of their rarity, rapid apoptosis, and lack of lineage markers. Purified IPCs are here shown to be the CD4(+)CD11c- type 2 dendritic cell precursors (pDC2s), which produce 200 to 1000 times more IFN than other blood cells after microbial challenge. pDC2s are thus an effector cell type of the immune system, critical for antiviral and antitumor immune responses.

Absence of age-related increase in systolic blood pressure in ambulatory patients with HIV infection.

BACKGROUND: Systolic blood pressure is well known to increase significantly with age and is strongly correlated with stroke and coronary artery disease. We and other investigators have reported a low prevalence of hypertension in subgroups of patients with HIV infection. In the present study, we examined an ambulatory population of patients with HIV infection to determine whether in the outpatient setting they may lack an age-related increase in systolic blood pressure. METHODS: In an ambulatory outpatient practice, medical records of 178 consecutive patients with HIV infection and those of 200 control subjects were examined. Systolic and diastolic blood pressure and other clinical and laboratory variables were recorded. Scatter plots were generated to compare age with systolic blood pressure. Spearman rank correlation analysis was carried out to determine the relationship between systolic blood pressure and age and other variables. RESULTS: Patients ranged in age from 13 to 69 years. There was only a very slight increase (which did not achieve statistical significance) in systolic blood pressure with aging in the patients with HIV infection, in contrast to the control population, in which an age-related increase in systolic blood pressure was seen that was comparable to published Framingham data. Mean systolic blood pressure for the group as a whole was 118.2 +/- 1.1 mm Hg. Mean serum albumin was 4.2 +/- 0.04 g/dL and was only slightly diminished in older patients. Mean serum cholesterol was 176.8 +/- 3.4 mg/dL and this bore no relationship to aging. More advanced stages of HIV infection also did not correlate with the lack of age-associated systolic hypertension. CONCLUSION: The present population of ambulatory patients infected with HIV seem to lack an age-related increase in systolic blood pressure; this may be caused by such variables as autonomic dysfunction or factors that may attenuate the development of atherosclerosis.

AIDS-associated membranous nephropathy with advanced renal failure: response to prednisone.

We report the case of a patient with acquired immunodeficiency syndrome (AIDS) who developed nephrotic syndrome and progressive renal failure mimicking human immunodeficiency virus (HIV)-associated focal segmental glomerulosclerosis (FSGS) who required initiation of hemodialysis and was found on renal biopsy to have membranous nephropathy. Hepatitis B and C serologies were negative. Although she required hemodialysis, she was treated with prednisone and experienced a progressive decline in her serum creatinine from 10.1 mg/dL to 1.9 mg/dL, which permitted the discontinuation of hemodialysis. After she abruptly discontinued prednisone, her creatinine level increased to 4.8 mg/dL, and she experienced marked worsening of her nephrotic syndrome. Resumption of prednisone resulted in normalization of serum creatinine and reduction in urine protein excretion. No adverse effects of prednisone occurred during this time. She remains off of hemodialysis for 1 year with a serum creatinine level of 1.0 mg/dL and urine protein excretion of 0.4 g/d. Although most patients with HIV infection, nephrotic-range proteinuria, and renal failure have FSGS, a minority may have membranous nephropathy. Although typically not a steroid-responsive lesion in the setting of advanced renal failure, membranous nephropathy may be a highly steroid-responsive lesion in the HIV-infected patient, and treatment may help avert the need for dialysis in a patient population that generally has a poor outcome on dialysis.