An exploratory, prospective, open-label trial of ingenol mebutate gel 0.05% for the treatment of external anogenital warts.

BACKGROUND: Anogenital warts (AGW) can cause physical discomfort and decreased quality of life. Recent case reports suggest that ingenol mebutate gel might be an effective treatment of AGW. OBJECTIVE: To explore primarily the safety, and secondarily the efficacy of ingenol mebutate gel 0.05% in patients with AGW. METHODS: This was an exploratory, open-label, 1-arm trial of ingenol mebutate gel 0.05% administered up to three times to patients with AGW. Safety was assessed by occurrence and severity of local skin reactions (LSRs) and treatment-related adverse events (AEs). Efficacy was assessed by complete clearance and reduction in AGW count 14 days after last treatment, and recurrence 12 weeks after clearance. RESULTS: Of 41 patients enrolled, 40 received treatment and 26 completed the trial. Patients had a median AGW count of 11.0 and AGW duration of 3.0 years at baseline. All patients experienced transient LSRs following treatment with a maximum composite LSR score of 7.5 (on a scale from 0 to 18). A total of 93% of patients reported treatment-related AEs, most frequently pain (85%) and procedural complications (35%) due to smearing of the gel. 78% of patients took mild analgesics for the pain, typically for 1-2 days following treatment. The majority of AEs were of moderate-to-severe intensity. Seventeen of 39 patients (43.6%) had complete clearance 14 days after last treatment, and AGW count was reduced by 90.9%. There was a tendency towards lower clearance rate in patients with longer duration of AGW. Eight of 14 patients (57.1%) had AGW recurrence 12 weeks after clearance. CONCLUSION: Ingenol mebutate gel was associated with a high number of AEs and withdrawals due to painful local and adjacent skin reactions. Furthermore, it showed promising efficacy in reducing AGW despite a difficult-to-treat population. Optimization of the formulation is warranted to improve the safety profile of the treatment.

An observational study to evaluate the long-term outcomes of treatment with etanercept in patients with plaque-type psoriasis.

BACKGROUND: There is an unmet need for long-term, real-life data on the effect of a drug-free interval between treatment cycles in patients with plaque psoriasis being treated with etanercept, which is licensed for intermittent and continuous treatment. OBJECTIVE: The aim of this study was to determine the average duration of the drug-free interval between etanercept treatment cycles in patients with plaque psoriasis. METHODS: This was a non-interventional, open-label, multicentre, prospective study in patients for whom the decision had already been made to initiate treatment with etanercept during routine practice in German centres. Clinical outcomes were documented over 36 months with study visits every 12 weeks. The primary endpoint was the duration of the treatment-free interval between etanercept treatment cycles (24 weeks/cycle). Secondary endpoints assessed efficacy [Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), static Physician's Global Assessment (sPGA)], health-related outcomes [EuroQol-5 Dimensions (EQ-5D), Dermatology Life Quality Index (DLQI)] and safety. RESULTS: A total of 955 patients were enrolled from 224 centres; 926 of these were included in the safety analyses and 720 patients from the safety population were included in the efficacy analysis. The mean duration of drug-free intervals was 12.9 ± 12.8 weeks. Efficacy and health-related quality of life outcomes measures showed consistent improvement that occurred within 12 weeks of treatment with etanercept. There was a descriptive difference between the continuous and intermittent treatment subgroups, as subjects in the latter showed a deterioration at the first visit following an interval. However, retreatment with etanercept resulted in a clinical efficacy identical to the initial effect. The incidence of physician-assessed, drug-related adverse events and serious adverse events was 13.1% and 1.9%, respectively. CONCLUSION: The mean duration of drug-free intervals was relatively short, most patients experienced improvements in disease activity and health-related quality of life within 12 weeks of either continuous or intermittent treatment with etanercept, and there were no new safety signals. ClinicalTrials.gov identifier: NCT00708708.

Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study.

BACKGROUND: Interleukin (IL)-17A has major proinflammatory activity in psoriatic lesional skin. OBJECTIVES: To assess the efficacy and safety of secukinumab, a fully human IgG1κ monoclonal anti-IL-17A antibody, in moderate-to-severe plaque psoriasis in a phase II regimen-finding study. METHODS: A total of 404 patients were randomized to subcutaneous placebo (n = 67) or one of three secukinumab 150 mg induction regimens: single (week 0; n = 66), early (weeks 0, 1, 2, 4; n = 133) and monthly (weeks 0, 4, 8; n = 138 patients). The primary outcome was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75) at week 12. PASI 75 responders from active treatment arms at week 12 were rerandomized to either a fixed-interval (secukinumab 150 mg at weeks 12 and 24; n = 65) or a treatment-at-start-of-relapse maintenance regimen (secukinumab 150 mg at visits at which a start of relapse was observed; n = 67). RESULTS: At week 12, early and monthly induction regimens resulted in higher PASI 75 response rates vs. placebo (54·5% and 42·0% vs. 1·5%; P < 0·001 for both). Among PASI 75 responders at week 12 entering the maintenance period, PASI 75 and PASI 90 achievement at least once from week 20 to week 28 was superior with the fixed-interval regimen [85% (n = 55) and 58% (n = 38), respectively] vs. the start-of-relapse regimen [67% (n = 45), P = 0·020, and 21% (n = 14), respectively]. Fifteen weeks after last study drug administration, < 10% of patients in the fixed-interval and start-of-relapse groups experienced a start of relapse. No immunogenicity was observed, and no injection-site reactions were reported. Reported cases of neutropenia were mild-to-moderate (≤ grade 2); none was associated with clinically significant adverse events or resulted in study discontinuation. Due to the brief duration of the safety assessment, no firm conclusions can be drawn regarding long-term safety. CONCLUSIONS: Secukinumab shows efficacy for induction and maintenance treatment of moderate-to-severe plaque psoriasis.

Stimulus-dependent increased generation of oxygen intermediates in monocytes and polymorphonuclear leukocytes in psoriasis.

Based on recent findings indicating increased respiratory burst activity of monocytes (M phi) and polymorphonuclear leukocytes (PMN) in psoriasis upon stimulation with zymosan particles, we examined the question of whether incubation with various stimuli always results in augmented oxidative metabolism in psoriatic phagocytes. We compared M phi and PMN isolated from the peripheral blood of 12 patients with psoriasis and 12 control individuals. We measured the generation of oxygen intermediates of resting and stimulated M phi and PMN by luminol-enhanced chemiluminescence. The stimulants applied were: (1) aggregated immunoglobulin (aggIg), (2) zymosan, (3) zymosan opsonized with autologous serum, (4) phorbol myristate acetate (PMA), and (5) concanavalin A (ConA). We found no difference between patients and controls in the generation of oxygen intermediates by resting M phi and PMN. Stimulation by aggIg and zymosan yielded an increased chemiluminescent response in psoriatic M phi and PMN. Serum-treated zymosan effected increased light generation in M phi but not in PMN of patients. By contrast, PMA, and in particular ConA, brought about markedly increased generation of oxygen intermediates in PMN only of patients with psoriasis. Our results indicate control of the increased generation of oxygen intermediates of M phi and PMN by different stimuli. The metabolic events underlying the augmented phagocytic response may be similar to abnormalities found in involved psoriatic skin.

TNF alpha primes polymorphonuclear leukocytes for an enhanced respiratory burst to a similar extent as bacterial lipopolysaccharide.

We examined whether preincubating polymorphonuclear leukocytes (PMN) with TNF alpha would result in an enhanced respiratory burst upon subsequent stimulation by various agents. Bacterial lipopolysaccharide (LPS), a known primer of PMN, was used as control. We found that both LPS (0.01 to 10.0 microgram/ml) and recombinant TNF alpha (0.001 to 1.0 microgram/ml) act as direct stimulants of PMN as measured by chemiluminescence. Sixty minutes of preincubation of PMN with 1 microgram/ml TNF alpha or 10 micrograms/ml LPS resulted in similar priming for the respiratory burst elicited by opsonized zymosan, phorbol myristate acetate, zymosan, zymosan-activated serum, aggregated immunoglobulin, and f-met-leu-phe (FMLP) depending on the method of measurement used, i.e., chemiluminescence, production of O2-, and H2O2. Priming with TNF alpha for an enhanced response to stimulation by FMLP could be abrogated by anti-TNF alpha antibody. Cell-surface receptor numbers and binding-affinity constants for FMLP remained stable under conditions leading to priming. We conclude that TNF alpha is able to prime PMN for an enhanced respiratory burst to a similar extent as with LPS. Because PMN cell-surface receptors for FMLP are unaltered by priming, the enhanced respiratory burst seems to be due to changes in intracellular metabolism.

A TNF-alpha promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis.

Tumor necrosis factor-alpha is considered to be one of the important mediators in the pathogenesis of psoriasis. A strong association of juvenile onset psoriasis with the major histocompatibility complex encoded HLA-Cw6 antigen has been reported but it is unclear whether Cw6 itself or a closely linked gene is involved in the pathogenesis. This study has focused on the association of promoter polymorphisms of the major histocompatibility complex encoded tumor necrosis factor-alpha gene with psoriasis and psoriatic arthritis. Tumor necrosis factor-alpha promoter polymorphisms were sought by sequence-specific oligonucleotide hybridization and by direct sequencing in Caucasian patients with juvenile onset psoriasis and with psoriatic arthritis and in healthy controls. A mutation at position -238 of the tumor necrosis factor-alpha promoter was present in 23 of 60 patients (38%; p < 0.0001; p[corr] < 0.008) with juvenile onset psoriasis and in 20 of 62 patients (32%; p < 0.0003; p[corr] < 0.03) with psoriatic arthritis, compared with seven of 99 (7%) Caucasian controls. There was a marked increase of homozygotes for this mutation in the psoriasis group. Another mutation at position -308 was found in similar proportions of patients and controls. Our study shows a strong association of the tumor necrosis factor-alpha promoter polymorphism at position -238 with psoriasis and psoriatic arthritis. Our findings suggest that this promoter polymorphism itself or a gene in linkage disequilibrium with tumor necrosis factor-alpha predispose to the development of psoriasis.

Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism.

Genes encoded on chromosome 6 within the major histocompatibility complex region are thought to play an important role in the pathogenesis of psoriasis. A potential candidate gene is tumor necrosis factor alpha. The tumor necrosis factor alpha promoter contains several polymorphisms including two G-->A transitions at position -308 and -238, which are the most common in Caucasian populations. The TNF238.2 (-238A) allele has been strongly associated with psoriasis. We have investigated the effect of the -238 and -308 variants on transcription of the tumor necrosis factor alpha gene in luciferase reporter gene assays. In addition, peripheral blood mononuclear cells of 47 patients with psoriasis and 43 controls were stimulated with different antigens and mitogens (streptococcal sonicate and superantigen, lipopolysaccharide, phorbol-12-myristate, phytohemagglutinin, CD3 antibodies) and tumor necrosis factor alpha production was measured in supernatants by enzyme-linked immunosorbent assay. The psoriasis-associated tumor necrosis factor alpha promoter allele TNF238.2 showed a significantly decreased transcriptional activity. Peripheral blood mononuclear cells carrying this allele produced significantly less tumor necrosis factor alpha after stimulation with T cell mitogens and streptococcal antigens in comparison to controls. The promoter allele TNF238.2 seems to influence tumor necrosis factor alpha production; a possible role in the pathogenesis of psoriasis has to be further evaluated.

Transglutaminase and polyamine dependence of effector functions of human immunocompetent cells. The effect of specific inhibitors on lymphocyte proliferation and granulocyte chemiluminescence.

The effects of the transglutaminase inhibitor dansyl cadaverine (DC) and the polyamine antagonist methyl glyoxal-bis-(guanylhydrazone) (MeGbG) on the response of lymphocytes towards allogeneic and lectin stimulation and on the zymosan-induced chemiluminescence of neutrophilic granulocytes was studied. Application of DC resulted in dose-dependent suppression of chemiluminescence and lymphocyte proliferation; no difference of inhibitory potential occurred with variation of incubation time in the latter system. MeGbG was inactive in granulocytes, but inhibited lymphocyte proliferation; its effect increased with time. The experiments provide further evidence for the importance of transglutaminases and polyamines for the function of immunocompetent cells.

Measurement of the respiratory burst in human monocytes and polymorphonuclear leukocytes by nitro blue tetrazolium reduction and chemiluminescence.

We compared measurements of chemiluminescence (CL) assessing the rate of production of oxygen intermediates at a given instance, and of nitro blue tetrazolium (NBT) reduction detecting total superoxide produced during the assay period, for the assessment of the respiratory burst of both human monocytes (M phi) and polymorphonuclear leukocytes (PMN). In the CL experiments, opsonized and non-opsonized zymosan was used to stimulate peripheral blood M phi and PMN. Opsonized zymosan yielded an earlier and 2-fold higher peak response than non-opsonized zymosan. The stimulatory action of zymosan in CL varied with the time of incubation and depended on the concentration of cells and zymosan. No light generation was observed in the absence of viable cells. In contrast to NBT reduction, incubation of PMN with dextran sulfate did not result in increased light generation but rather in a quenching of the response in CL. Opsonized zymosan also yielded a higher level of NBT reduction than non-opsonized zymosan. Comparing NBT reduction with CL in 21 healthy individuals, with 2 X 10(5) M phi and 2.5 X 10(5) PMN for NBT and 5 X 10(5) PMN for CL tests, we found that NBT brings about spontaneous oxidative metabolism, possibly reflecting the intracellular compartment, the chemiluminescent response of resting cells being only marginal. The data suggest higher sensitivity of the CL method. These results provide useful comparative data for 2 established methods used to document the respiratory burst in phagocytic cells.

TAP-polymorphisms in juvenile onset psoriasis and psoriatic arthritis.

Juvenile onset psoriasis is strongly associated with the HLA-class I genes Cw6 and B57 whereas patients with psoriatic arthritis show an increased frequency of HLA-B27. It is unclear whether additional major histocompatibility genes also increase disease susceptibility. The TAP genes (transporter associated with antigen processing) encode two membrane-spanning proteins that translocate antigenic peptides from the cytoplasm into the endoplasmic reticulum. Comparison of 60 patients with juvenile onset psoriasis, 63 psoriatic arthritis patients, and 101 caucasoid controls revealed an increase of the TAP1*0101 allele in the psoriasis group, that could not be explained by linkage to other investigated HLA genes. There were no differences for TAP2 alleles.

Asphyxiation by laryngeal edema in patients with hereditary angioedema.

OBJECTIVE: To describe the occurrence of fatal laryngeal edema in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. PATIENTS AND METHODS: We describe 6 patients from various regions of Germany who died from laryngeal edema within the last 10 years. Furthermore, we conducted a retrospective survey of 58 patients with hereditary angioedema, originating from 46 affected families. The data were obtained from the attending physicians and from the patients' relatives. RESULTS: Among the 6 reported patients, aged 9 to 78 years, hereditary angioedema had been diagnosed in 3 and was undiagnosed in 3. None of them had an emergency cricothyrotomy or received C1 inhibitor concentrate. The interval between onset of the laryngeal edema and asphyxiation was 20 minutes in a 9-year-old boy, and in the other patients, the interval was 1 to 14 hours (mean for all, 7 hours). The retrospective survey of 58 patients with hereditary angioedema revealed 23 deaths by asphyxiation (40%). The average age of all 29 patients at the time of asphyxiation was 39 years. CONCLUSION: Laryngeal edema in hereditary angioedema may be fatal. Most of the patients asphyxiated between their 20th and 50th years of life, but asphyxiation can occur even in children. The possibility that the first episode of laryngeal edema may be fatal must be emphasized to the relatives, and attending physicians must have a high degree of awareness.

IDEC-114 (IDEC).

IDEC is developing a PRIMATIZED-anti-B7 antibody (IDEC-114) for the treatment of autoimmune and inflammatory diseases, such as psoriasis and rheumatoid arthritis. It is currently undergoing phase II trials in patients with psoriasis [395813]. A randomized, blind, placebo-controlled, multiple-dose phase II study was initiated in January 2001 to evaluate the potential clinical activity and safety of IDEC-114 in patients with moderate-to-severe psoriasis [395813]. The antibody targets the B7 antigen on the surface of antigen-presenting cells that normally interact with T-cells to initiate an immune response. Antibodies directed at B7 may be useful in preventing unwanted immune responses in autoimmune diseases such as systemic lupus erythematosus, idiopathic thrombocytopenic purpura as well as transplant rejection [178382], [178929]. PRIMATIZED antibodies, genetically engineered from cynomolgus macaque monkey and human components, are structurally indistinguishable from human antibodies. They may, therefore, be less likely to cause adverse reactions in humans, making them potentially suited for long-term, chronic treatment [244805]. IDEC has signed an antibody humanization patent licensing agreement with Protein Design Labs [240591]. IDEC is also collaborating with Mitsubishi-Tokyo (formerly Mitsubishi Kasei) on the development of this antibody [178382].

Crystal-phagocyte interaction in calcinosis interstitialis.

Based on recent findings indicating the stimulation of the respiratory burst in human neutrophils by crystal phagocytosis, ectopic calcified nodules of a patient with calcinosis interstitialis were exposed to autologous granulocytes and monocytes in vitro. The activity of the respiratory burst was determined by luminol-enhanced chemiluminescence. Controls included amorphous monosodium urate, microcrystalline monosodium urate, hydroxyapatite, and zymosan. Microcrystalline monosodium urate elicited a marked stimulation of both granulocytes and monocytes as did hydroxyapatite in granulocytes. Hydroxyapatite caused no stimulation of monocytes, possibly reflecting selective functional modulation. On the other hand, amorphous monosodium urate failed to induce a respiratory burst with granulocytes or monocytes. Likewise, the contents of the nodule evoked only marginal stimulatory activity on the phagocytes. Stimulation by zymosan was normal with both cell types. The finding that material of the excised nodule failed to induce a respiratory burst in phagocytes may explain the lack of inflammatory reaction in vitro around the nodules on histologic examination, particularly since products of stimulated phagocytes have been described as causing tissue destruction.

Enhanced procoagulant activity of mononuclear leukocytes in patients with atopic dermatitis and psoriasis.

Fibrin deposition is an important histopathological feature of inflammatory skin lesions and is mediated in part, by procoagulants generated by mononuclear leucocytes (MNL). We examined whether MNL from patients with atopic dermatitis or psoriasis generate enhanced procoagulant activity (PCA). MNL isolated from the peripheral blood of 15 healthy control individuals, 15 patients with atopic dermatitis and 15 patients with psoriasis were incubated for 24 h in the presence or absence of bacterial lipopolysaccharide (LPS). MNL or the cell culture supernatants were then added to recalcified human plasma to determine the clotting time. We found that in both atopic dermatitis and psoriasis MNL cultured in the presence or absence of LPS expressed greatly enhanced PCA (p < 0.01 to < 0.002). Supernatants from MNL cultures from patients with psoriasis, but not those from patients with atopic dermatitis, also generated augmented PCA (p < 0.002). In psoriasis, PCA normalized after successful topical treatment with anthralin. We conclude that enhanced PCA is a characteristic feature of MNL in both atopic dermatitis and psoriasis. In psoriasis the enhanced PCA is directly related to disease activity.

Augmented glucose-6-phosphate dehydrogenase activity and normal penetration and metabolism of dehydroepiandrosterone in mononuclear leukocytes in psoriasis.

The aim of the study was to determine a biochemical basis for the augmented oxidative metabolism found in mononuclear leukocytes (MNL) of patients with active psoriasis. Dehydroepiandrosterone (DHEA) is known to inhibit glucose-6-phosphate dehydrogenase (G-6-PDH). We determined the activity of G-6-PDH as well as the penetration and metabolism of DHEA - diminished plasma concentrations of which have been found in psoriatics previously - in 16 patients with active psoriasis and 16 controls. MNL in patients with psoriasis possessed 52% more (p less than 0.05) G-6-PDH activity, based on cell number, and 34% more (p less than 0.05) activity, based on soluble protein. No difference in DHEA penetration and metabolism in MNL was found between psoriatics and controls, in contrast with previous findings of reduced penetration and increased reduction in erythrocytes of psoriatics. We conclude that the enhanced G-6-PDH activity in MNL of patients with active psoriasis is not due to altered DHEA penetration or metabolism.

Stimulation of T cells by autologous mononuclear leukocytes and epidermal cells in psoriasis.

Based on reports suggesting aberrant cell-mediated immunity and altered infiltration of immunocompetent cells into the skin in psoriasis, we studied the stimulation of T cells by autologous non-T mononuclear leukocytes (autologous mixed lymphocyte reaction, AMLR) and by epidermal cells isolated from lesional and clinically uninvolved skin in psoriasis (autologous mixed epidermal cell lymphocyte reaction, AMECLR). Age- and sex-matched individuals served as controls. We found that the AMLR in psoriasis (n = 11) was similar to that in healthy controls (n = 16); furthermore, cell proliferation was alike in the presence of either 5% AB-serum or autologous serum. By contrast, while the AMECLR in healthy controls (n = 9) resembled that in psoriatics employing epidermal cells from univolved skin, epidermal cells from lesional sites (n = 10) induced a significantly higher proliferation of autologous T cells in the AMECLR (P less than 0.01). We conclude that the in vitro stimulation of T cells by non-T mononuclear leukocytes is normal in psoriasis and is not regulated by autologous serum. Lesional psoriatic epidermal cells, however, are more active in stimulating autologous T cell proliferation than cells from univolved psoriatic or normal epidermis.

Effects of ethanol and acetaldehyde on phagocytic functions.

Although a number of skin diseases are characterized by the presence of an increased number of phagocytes in their lesions, the effects of alcohol on phagocytic functions are not clearly understood. Therefore, we measured the influence of ethanol and acetaldehyde on the generation of oxygen radicals, chemotaxis and the release of lysosomal enzymes from human phagocytes. We added 0.03%-3% ethanol and 0.005%-0.25% acetaldehyde to cell cultures. We found that both ethanol and acetaldehyde suppressed the generation of oxygen radicals from granulocytes and monocytes; the ID50 was achieved at concentrations of approximately 0.25% for ethanol and 0.03% for acetaldehyde. A significant inhibition of granulocyte chemotaxis was first noted with 0.063% ethanol and 0.016% acetaldehyde. Ethanol and acetaldehyde inhibited the release of the lysozyme of monocytes at concentrations of greater than 0.75% and greater than 0.03% respectively, but granulocytes were unaffected; the release of beta-glucuronidase and lactate dehydrogenase remained stable. Due to the high volatility of the agents, especially acetaldehyde, under the experimental procedures employed, the actual concentrations of the agents were probably lower and similar to those measured in vivo. Our results indicate that defined phagocytic functions are strongly inhibited by concentrations of ethanol and acetaldehyde which are associated with moderate to severe inebriation.

Etretinate or cyclosporin-A treatment normalizes the enhanced respiratory burst of polymorphonuclear leukocytes in psoriasis.

During a therapeutic trial to treat psoriasis with either etretinate or cyclosporin A (CyA) we measured the respiratory burst activity of polymorphonuclear leukocytes (PMN). Six patients received 0.5-0.75 mg/kg etretinate and 14 patients 2.5-5.0 mg/kg CyA over a period of 10 weeks. The extent of psoriasis was graded by the psoriasis area-and-severity index (PASI score). The respiratory burst of PMN isolated from the peripheral blood was measured employing luminol-enhanced chemiluminescence at weeks 0, 3 and 10 and compared with that of 26 healthy control individuals. PMN were stimulated with zymosan particles, aggregated immunoglobulin (aggIg) and concanavalin A (ConA). Both treatment regimens improved psoriasis; at 10 weeks there was an approximate 40% PASI score reduction under etretinate and an 80% improvement under CyA. Before treatment the respiratory burst was abnormally high under stimulation with the three stimuli in patients (p = 0.021 to less than 0.0001). After 3 to 10 weeks PMN activity normalized in all patients and even tended to drop below values correlating with an improvement in skin lesions. We conclude that the elevated respiratory burst of PMN in psoriasis normalizes under treatment with both etretinate and CyA.

Impaired function of numerically augmented Fc-receptors on granulocytes in a HLA B8+ patient with palmoplantar pustulosis.

We examined granulocytes or polymorphonuclear leukocytes (PMN) in an HLA B8+ patient with palmoplantar pustulosis (PPP). Controls included another patient with PPP, however, lacking this antigen and a healthy, HLA B8+ person. Chemiluminescence (CL) served to monitor the respiratory burst in PMN comparing as stimuli zymosan, opsonized zymosan, phorbol myristate acetate, as well as aggregated immunoglobulin (aggIg), the latter as Fc-receptor (FcR) stimulus. FcR density on PMN was determined using 125I-IgG and expressed in the form of Scatchard plots. The effects of serum on the aggIg-induced CL were also measured. We found both control individuals to respond to stimulation by aggIg as a function of a dose-dependent increase of CL. By contrast, the HLA B8+ patient with PPP failed to respond to aggIg; only the highest concentration of aggIg induced marginal CL. Conversely, stimulation by the other agents was similar in all three individuals. The patient with the functional FcR defect expressed 2.5 times more FcR/PMN than the controls. No difference emerged in comparing autologous serum with a reference normal serum on the aggIg-induced CL, ruling out saturation by serum factors alone to be a cause for the defect. In remission, the functional FcR was absent. Our results suggest a defect of signal transduction in PMN from numerically enhanced FcR to the cytosol in the patient with PPP.