Lipopolysaccharide-, granulocyte-monocyte colony stimulating factor and pentoxifylline-mediated effects on formyl-methionyl-leucine-phenylalanine-stimulated neutrophil respiratory burst in the elderly.

The impairment of superoxide anion (O2-) generation by aged polymorphonuclear cells (PMN) stimulated with formyl-methionyl-leucine-phenylalanine (FMLP) has been reported. In this work the effect of lipopolysaccharide (LPS), granulocyte-macrophage colony stimulating factor (GM-CSF) and pentoxifylline (POF) pretreatment on FMLP-triggered neutrophil oxidative metabolism in a group of healthy elderly individuals, was investigated. Results provide evidence that LPS and/or GM-CSF priming was able to enhance O2- production in old PMN, even if values were still lower than those observed in similarly-treated young cells. Moreover, even if the lag period was unaffected by inflammatory mediator treatment, the priming gave rise to a significant increase of maximum O2- release rate. On the contrary, POF pretreatment led to a significant decrease of oxidative responsiveness in either unprimed or primed PMN suspensions. These findings suggest the occurrence of different mechanisms in the imbalance of FMLP-activated neutrophil oxidative responsiveness during senescence. This may be of paramount significance for explaining the augmented frequency of severe infectious diseases with advancing age.

Age-associated changes of neutrophil responsiveness in a human healthy elderly population.

Conflicting results have been reported on polymorphonuclear (PMN) cell responsiveness during senescence. Consequently, neutrophil absolute numbers and PMN-mediated chemotaxis, phagocytosis, killing and superoxide anion (O2-) generation in healthy aged volunteers divided into different groups according to increasing age criteria, were investigated and evaluated. Data provide evidence that absolute amounts of PMN cells declined in a significant manner in donors over 85 years old only when compared with young subjects. On the contrary, regardless of age, the aged individuals exhibited a significant impairment of PMN chemotactic, phagocytic and killing functional capacities. Finally, formyl-methionyl-leucyl-phenylanaline (FMLP)-triggered O2- release was reduced in all elderly groups, while depression of O2- production was seen in subjects between the age of 86 and 104 years using phorbol 12-myristate 13-acetate (PMA) as agonist. These findings indicate that an imbalance in the PMN cell immune reactivity occurs throughout the senescence process.

Redistribution of natural killer (NK) cell frequency and NK cytotoxic activity in primary IgA nephropathy.

Recent findings have indicated an imbalance of immune responsiveness in primary IgA nephropathy (IgAN). Thus natural killer (NK) cell frequency and NK cytotoxicity were evaluated in fifteen IgAN patients. CD8+, CD11+, CD56+ and CD57+ lymphocyte percentages in IgAN individuals fell within normal values, while a significant decrease of CD16+ cells was observed in the same group of patients. In contrast, NK activity overlapped that seen in controls as assessed by an agarose-single cell cytotoxic assay. To further investigate the discrepancy between CD16+ cell level and NK cytotoxic activity in IgAN, the proportion of CD11+ CD57+, CD56+ CD16+ and CD57+ CD16+ lymphocytes was determined. In spite of the unaffected CD56+ CD16+ cell frequency, IgAN subjects exhibited a significant decrease of CD11+ CD57+ and CD57+ CD16+ lymphocyte percentages in comparison to controls. It is suggested that a redistribution of NK lymphocyte subsets occurs in IgAN. This may have an important role in the impairment of the immunoregulatory network.

Role of interleukin 2, interleukin 4 and interleukin 5 in the T helper cell-driven B cell polyclonal differentiation in the elderly.

There is evidence for an impaired T cell-mediated B cell response during senescence. In thirty aged donors, pokeweed mitogen (PWM)-driven immunoglobulin (Ig) synthesis by B cells co-cultured with autologous enriched CD4+ lymphocytes and low amounts of monocytes, was evaluated. Under such experimental conditions, elderly cultures displayed a reduced IgG and/or IgM production when compared with the younger counterpart. Moreover, interleukin (IL)-2 and/or IL-5 addition to cultures led to an enhancement of Ig release. In contrast, IL-4 supplementation failed to positively modulate B cell differentiation. At the same time, aged cells cultured in the presence of IL-2 + IL-5 exhibited an increased Ig synthesis, while the addition of IL-2 + IL-4 or IL-4 + IL-5 mixtures did not induce any significant effect in comparison with homologous untreated samples. The results suggest a critical role for IL-2, IL-4 and IL-5 in the modulation of T helper cell-driven B cell polyclonal responsiveness in the elderly.

Modulating effects on CD25 and CD71 antigen expression by lectin-stimulated T lymphocytes in the elderly.

During the last few years, several observations outline that the impaired T lymphocyte proliferative capacity in the elderly is due to a reduced interleukin 2 (IL-2) release. To further investigate the activation process during lectin stimulation, aged peripheral blood mononuclear cells (PBMC) were stimulated with phytohemagglutinin (PHA) and assessed for CD25 (IL-2 receptor) and CD71 (transferrin receptor) expression at different intervals of time. Our results provided evidence for a significant decline of both structure induction, above all in the later phase of culture. Indomethacin (INDO) treatment gave rise to an enhancement of CD71 antigen expression only, while prostaglandin E2 (PGE2) supplementation to culture media further decreased either CD25 or CD71 receptor induction. Interferon (IFN)-alpha and IFN-gamma treatment failed to modulate the frequency of CD25+ and/or CD71+ cells. Finally, the expression of CD71 receptor was increased by deferoxamine supplementation, this suggesting a partial involvement of iron overload in the depressed function. Although further studies are required to evaluate at a molecular level the decreased antigen expression, these findings indicate that several mechanism are involved in the elderly-related decline of T lymphocyte activation structures during lectin stimulation.

Evaluation of phagocyte functions, inflammatory lymphokine activities and in vitro antibody synthesis in patients with active and chronic pulmonary tuberculosis.

In fourteen patients with pulmonary tuberculosis (TBC) (seven active and seven chronic cases) non-specific immunity and B cell function were evaluated. Polymorphonuclear cell (PMN) and monocyte chemotaxis, phagocytosis and killing were depressed to a different extent regardless of the disease status. Additionally, determination of lymphocyte-derived chemotactic factor and leukocyte inhibitory factor activities indicated a reduced production of these two lymphokines. This may also explain the impairment of phagocyte functions. Furthermore, the frequency of T cell subsets was slightly modified except for the increased number of CD25+ cells. The in vitro antibody response was analysed in a plaque-forming cell system using pokeweed mitogen (PWM) as a polyclonal activator and purified protein derivative (PPD) as a specific antigen. Results show that in patients with active TBC the anti-PPD antibody response was markedly enhanced, while in both groups of patients PWM-induced antibody synthesis was normal. These findings indicate several immune deficiencies related to phase activity which occur during the course of the disease.

Serum suppressive factors may account for the reduced polymorphonuclear cell function in haemophilia.

Haemophiliacs exhibit a broad range of immune defects. In this regard we have investigated the functional capacity of purified polymorphonuclear (PMN) cell suspensions in a group of Human Immunodeficiency Virus (HIV)+ or HIV- patients. Our results provide evidence for a significant reduction of PMN-mediated chemotactic responsiveness, phagocytosis and killing in haemophiliacs regardless of HIV infection. The depressed response does not reflect a PMN intrinsic dysfunction, since respiratory burst activity and lysosomal enzyme release from haemophilic PMN are unaffected in comparison to healthy donors. Quite interestingly the pretreatment of PMN from normal donors with either HIV+ or HIV- haemophilic sera gives rise to a reduction of PMN activity. Moreover, the suppressive effect is abrogated by serum heat inactivation. Taken together, these findings indicate a role for serum suppressive factors in the imbalance of PMN functional capacity in haemophilia regardless of HIV infection.

Senile dementia, Alzheimer type: a distinct entity in the immunosenescence?

Since previous data have provided conflicting results on immunoresponsiveness in senile dementia, Alzheimer type (SDAT), we evaluated the immune function in groups of SDAT patients and aged and young donors. In comparison to the younger subjects, SDAT and aged subjects did not exhibit significant differences in lymphocyte surface markers. Both groups of aged donors showed decreased B cell polyclonal responsiveness in a nonspecific T cell-driven B lymphocyte differentiation system. The use of an antigen-specific induction assay revealed an imbalance of T helper (Th) or T suppressor function in the elderly, while SDAT individuals were characterized by decreased Th activity. At the same time, aged individuals manifested an impairment of leukocyte-inhibiting factor (LIF) and lymphocyte-derived chemotactic factor production; a selective deficit of LIF release was seen in SDAT. Finally, elderly individuals displayed a decline of polymorphonuclear cell (PMN)-mediated functions and monocyte phagocytosis; only a decrease in PMN response was observed in SDAT. These results reveal discrepancies in impaired immune responses between SDAT and aging.

Cell-mediated immune response in psoriasis and psoriatic arthritis.

It has been previously described an impairment of cell-mediated immune response in psoriasis. In the present paper we have evaluated lymphocyte surface markers, non specific immunity, lymphokine secretion and antibody synthesis in a group of patients with psoriasis (PS) and with anti-inflammatory drug treated or gold-treated psoriatic arthritis (PsA). No significant differences are found in terms of T lymphocyte subpopulation frequency, even if a lower CD8+/CD4+ ratio was observed in all patients. In spite of an increased percentage of B lymphocytes, B cell polyclonal response is significantly decreased in the presence of either T cell-independent or T cell-dependent polyclonal activator. Further studies provide additional supports to these findings, since all psoriatic patients exhibit a deficit of T helper function in an antibody-specific induction system. Gold therapy in PsA led to a partial recovery of T helper function, without affecting the immunoglobulin reduced synthesis. With particular reference to non-specific activities mediated by monocytes and polymorphs (PMN), PMN chemotaxis, phagocytosis and killing and monocyte-mediated phagocytosis are reduced, except for monocyte phagocytosis in anti-inflammatory treated PsA or PMN chemotaxis in gold-treated PsA. Finally, lymphokine release is significantly decreased in all patients. In conclusion, our data provide further evidence for the impairment of immune response in psoriasis and PsA, which may in turn play a key role in the pathogenesis of psoriasis.

Monocyte- and cytokine-mediated effects on T immunoregulatory activity in the elderly.

Aged individuals exhibit an impairment of T helper and/or T suppressor activity on B cell function in an antibody-specific induction system. Further evidence is now provided that soluble suppressive factors acting on monocytes play a key role in such deficits. In fact, overnight preincubation of isolated monocytes and supplementation of autologous lymphocytes reverses the immunoregulatory imbalance. The suppressive factors are also responsible for a decreased interleukin 2 (IL-2) synthesis since a similar pretreatment of cell suspensions or exogenous human IL-1 and/or IL-2 supplementation of aged cell cultures leads to a recovery of T regulatory effects on B cell differentiation. Similar effects are observed in the presence of thymopentin, a well known IL-2 inducer. Interferon alpha and gamma addition to cultures gives rise to a restoration of T immunoregulatory effects. These findings suggest that several mechanisms are involved in the depressed T immunoregulatory activity in the elderly.

Cell-mediated immune response in patients with type IIa, type IIb and type IV primary hyperlipoproteinaemia.

Plasma lipoproteins inhibit immune function. Polymorphonuclear cell (PMN) and monocyte activities, and pokeweed mitogen (PWM)-driven B cell differentiation in patients with type IIa, type IIb and type IV primary hyperlipoproteinaemia were evaluated. Evidence is provided for a selective impairment of these functional capacities in type IIa and type IIb hyperlipoproteinaemic patients, while immune responsiveness is unaffected in type IV primary hyperlipoproteinaemia. The data suggest a specific immune dysfunction in patients with type IIa and type IIb primary hyperlipoproteinaemia.