Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Keeping venomous snakes in the Netherlands: a harmless hobby or a public health threat?

OBJECTIVE: To describe the incidence of venomous snakebites and the hospital treatment thereof (if any) amongst private individuals who keep venomous snakes as a hobby. STRUCTURE: Descriptive study. METHOD: Private keepers of venomous snakes were invited via the social media Facebook, Hyves, Twitter, Google Plus, Linked In and two large discussion forums to fill in an online questionnaire on a purely voluntary and anonymous basis. RESULTS: In the period from 1 September 2012 to 31 December 2012, 86 questionnaires were completed by individuals who keep venomous snakes as a hobby. One-third of the venomous snake keepers stated that they had at some point been bitten by a venomous snake. Out of those, two-thirds needed hospital treatment and one-third of those bitten required at least one, sometimes more, doses of antiserum. The chances of being bitten increased the more venomous snakes a person kept. An inventory of the collections of venomous snakes being kept further revealed that no antiserum exists for 16 of the species, including for the most commonly held venomous snake, the coral cobra. CONCLUSION: Keeping venomous snakes as a hobby is not without danger. Although in the majority of snakebite cases no antiserum had to be administered, there is nevertheless a significant risk of morbidity and sequelae. Preventing snakebites in the first place remains the most important safety measure since there are no antiserums available for a substantial number of venomous snakes.

[Clinical reasoning and decision-making in practice. A man with hip pain and fever]. / Klinisch denken en beslissen in de praktijk. Een man met pijn in de heup en koorts.

A 42-year-old man was admitted to the hospital because of pain in the left hip. On examination he was febrile at 38 degrees C and he walked with a limp. The chest, abdomen and extremities were normal. Laboratory tests showed an elevated ESR and CRP. The ANA test was positive. CT-scan of the abdomen revealed a mass in the psoas region and some dilatation of the left renal pelvis. Following the histological results of the first and second diagnostic percutaneous biopsies, the clinicians suspected idiopathic retroperitoneal fibrosis. They treated the patient with corticosteroids for a period of 4 weeks. After a short interval of improvement this treatment failed and a third biopsy was taken. Subsequently, the diagnosis of anaplastic large cell lymphoma (ALCL) was made. The patient was successfully treated with combination chemotherapy. Usually, in practice, clinical reasoning and decision-making is carried out in accordance with Bayes' theorem. But when the a priori probability of disease is unknown and the likelihood ratio of a diagnostic test unavailable, one has to combine the available 'evidence' with critical thinking, interdisciplinary communication, judgement, intuition and common sense.

[New treatment methods for autoimmune thrombocytopenia]. / Nieuwe behandelmethoden voor auto-immuuntrombocytopenie.

--For many years, splenectomy has been considered the only therapy with proven efficacy in patients with relapsed/refractory idiopathic thrombocytopenic purpura (ITP) following corticosteroid therapy. --A broad spectrum of (mostly immunosuppressive) agents are available for patients who fail to respond to splenectomy. However, the risks associated with these agents sometimes outweigh their benefits. --Recently, several new or renewed strategies have been evaluated for chronic refractory ITP. --Short-term therapy with high-dose dexamethasone is an effective alternative to long-term treatment with corticosteroids. --Depletion of B lymphocytes with rituximab, an agent that has an established role in the treatment of non-Hodgkin's lymphoma, also appears to be effective in autoimmune disorders, particularly in ITP. --Although the main problem in ITP is the increased destruction of thrombocytes, stimulation of thrombocyte production with thrombopoietin(TPO)-receptor agonists can increase thrombocyte counts. --Two TPO-receptor agonists, AMG531 and eltrombopag, induce responses in 70-80% of ITP patients and are expected to gain approval for use in ITP soon.

[Systematic diagnosis of erythrocytosis]. / Systematische diagnostiek van erytrocytose.

Erythrocytosis is a phenomenon with life-threatening complications and a broad differential diagnosis. Erythrocytosis is usually secondary to a cardiopulmonary condition leading to a low arterial oxygen tension. A probable diagnosis can often be made on the basis of the history, physical examination, a measurement of the peripheral oxygen saturation, and simple laboratory tests. The differential diagnosis can be narrowed down by a determination of the erythropoietin concentration and the JAK2 mutation. If the erythrocytosis is found to be non-physiological, then reduction of the haematocrit via bloodletting and, depending on the diagnosis, treatment with acetylsalicylic acid are indicated.

[From gene to disease; JAK2 and polycythaemia vera]. / Van gen naar ziekte; JAK2 en polycythaemia vera.

The identification of a point mutation in the JAK2 gene in most patients with polycythaemia vera (PV) has led to increased insight into the pathogenesis of the disease. The mutation causes cytokine-independent growth and proliferation of haematopoietic precursor cells, leading to erythrocytosis. The JAK2-V617F mutation is present in 65-97% of PV-patients and, when found, is indicative for the disease. Future research will have to show if the mutated gene can serve as a target for specific, antiproliferative therapy.

Chronic idiopathic thrombocytopenic purpura: present strategy, guidelines and new insights.

Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated thrombocytopenia. The diagnosis is made after exclusion of other secondary causes of thrombocytopenic disorders. The primary treatment goal is to prevent severe bleeding rather than achieve normal platelet counts. In adults ITP usually has an insidious onset and chronic course. Although ITP is a relatively common haematological disorder, there are important unresolved issues in its management, especially for chronic refractory ITP patients. New therapeutic agents have changed strategies for ITP treatment. This article reviews the treatment indications and options of chronic ITP in adults in the literature and compares them with the treatment indications and treatment options used by the Dutch internist.

[Clinical reasoning and decision making in practice. A 39-year-old woman with somnolence, hypertension and haemolysis]. / Klinisch denken en beslissen in de praktijk. Een 39-jarige vrouw met sufheid, hypertensie en hemolyse.

A 39-year-old woman was admitted with somnolence, severe hypertension and thrombotic microangiopathy. Both malignant hypertension and thrombotic thrombocytopenic purpura (TTP) were considered. Immediate therapy was instituted to treat both diseases because of severe clinical deterioration. Eventually, TTP was considered less likely due to the presence of grade IV hypertensive retinopathy (papilloedema and soft exudates) and a normal Von Willebrand factor-cleaving protease level. Differentiating TTP from malignant hypertension can be difficult as both diseases have similar clinical, laboratory and radiological features. In both diseases, hypertension, thrombotic microangiopathy and encephalopathy with white-matter lesions in the posterior regions of the brain may be apparent. Funduscopic abnormalities consistent with grade III and IV hypertensive retinopathy are rare in TTP, as are normal levels ofVon Willebrand factor-cleaving protease. Therefore, the diagnosis TTP was considered less likely and plasmapheresis was stopped. Hereafter, the laboratory values pointing towards haemolysis remained normal with adequate blood pressure control supporting the rejection of TTP as the cause of the symptoms.

Clearance of red cells by monoclonal IgG3 anti-D in vivo is affected by the VF polymorphism of Fcgamma RIIIa (CD16).

Human red cells (RBC) coated with IgG anti-D are cleared from the circulation to the spleen by macrophages which express IgG receptors (Fcgamma R). Polymorphisms of Fcgamma RIIa and Fcgamma RIIIa affect IgG binding in vitro, and may alter the efficiency of clearance of immune complexes in vivo. In a RBC clearance study, 22 Rh D-negative subjects were given 100-400 micro g human monoclonal or polyclonal IgG anti-D i.m. followed 48 h later by 51Cr-labelled D+ RBC. The half lives of the infused D+ RBC were determined, together with the coating levels of anti-D on the D+ RBC. Fcgamma RIIA and FcgammaRIIIA genotyping was performed. Large ranges of phagocytosis and extracellular lysis of RBC in vitro, and of half lives of RBC in vivo, were observed. Clearance of RBC coated with monoclonal IgG3 anti-D (BRAD-3) was more rapid in five subjects homozygous for Fcgamma RIIIa-F/F158 than in three subjects expressing the Fcgamma RIIIa-V158 allele (P = 0.024). This effect was not observed, however, for those individuals given polyclonal anti-D. There was also no significant difference in the efficiency of RBC destruction in vitro or of RBC clearance in vivo between the subjects analysed for individual genotypes or alleles or combinations of alleles. In conclusion, the presence of the Fcgamma RIIIa-V158 allele compromised the efficiency of removal of RBC coated with IgG3 anti-D.

The metalloproteinase inhibitor GI5402 inhibits endotoxin-induced soluble CD27 and CD16 release in healthy humans.

Metalloproteinases have been implicated in the cleavage of a number of cell surface immune receptors. Oral administration of the metalloproteinase inhibitor GI5402 attenuated the release of soluble CD27 and CD16 into the circulation after intravenous endotoxin injection in healthy humans.

Levels of soluble Fc gammaRIII correlate with disease severity in sepsis.

Neutrophil activation is thought to play a crucial role in the pathogenesis of sepsis. During activation, neutrophils adhere to and migrate through the endothelium. Therefore, the amount of circulating neutrophils does not adequately reflect the total amount of neutrophils that are involved in the pathophysiologic process of this condition. In this study we test the hypothesis that the severity of sepsis is associated with the total body mass of neutrophils as reflected in the plasma concentration of soluble Fc gamma receptor type III (sFc gammaRIII). Nineteen patients with sepsis (12 male, seven female, median age of 69 years, range 29-87 years) were included in this study. Ten healthy volunteers served as controls. Plasma sFc gammaRIII concentrations were measured by ELISA. Other parameters that were studied were leucocyte count, plasma concentrations of lactoferrin and soluble L-selectin, and surface expression of CD11b and CD66b on circulating neutrophils. Disease activity was measured using the Acute Physiology and Chronic Health Evaluation (APACHE) II score. Soluble Fc gammaRIII levels were elevated in sepsis patients whereas soluble L-selectin levels were moderately decreased compared with healthy controls. Markers of cell activation were significantly increased in sepsis patients. Soluble Fc gammaRIII correlated with disease severity as measured by the APACHE score (P<0.05, r=0.53), whereas the other parameters did not correlate with the APACHE score. In conclusion, this study demonstrates that soluble Fc gammaRIII is a useful marker for disease severity in patients with sepsis.

The Fc gammaRIIIA-158F allele is a risk factor for systemic lupus erythematosus.

OBJECTIVE: To study whether the Fc gammaRIIIA-158V/F polymorphism, which affects IgG binding affinity, is a risk factor for systemic lupus erythematosus (SLE). METHODS: We genotyped a group of 70 Caucasian SLE patients for all known Fc gammaR polymorphisms. Of this group, 45 patients (64%) had nephritis. In 35 patients, this diagnosis was confirmed by renal biopsy. RESULTS: In the total group of 70 SLE patients, the frequency of the Fc gammaRIIIA-158F allele was 0.74, versus 0.57 in healthy controls (P = 0.003). The genotype distribution of the Fc gammaRIIIA-158V/F polymorphism was also significantly different from that of the control population (P = 0.004). The distribution of the other Fc gammaR polymorphisms--Fc gammaRIIA-131R/H, Fc gammaRIIIB-NA(1,2), and Fc gammaRIIIA-48L/R/H--was similar in SLE patients and controls. CONCLUSION: In our group of SLE patients, only the distribution of the alleles of the Fc gammaRIIIA-158V/F polymorphism was significantly different from that in the control group. This might indicate that macrophage expression of the Fc gammaRIIIA-158F isoform is involved in the disturbed clearance of immune complexes in patients with SLE.

Clinical value of soluble IgG Fc receptor type III in plasma from patients with chronic idiopathic neutropenia.

Previous studies have shown that the plasma level of soluble IgG Fc receptor type III (sFcgammaRIII) is a measure of the total body neutrophil mass. The aim of this study was to determine whether the plasma level sFcgammaRIII is associated with the risk of contracting bacterial infections in patients with neutropenia. We collected blood from 66 patients suffering from acquired idiopathic neutropenia, whose blood was sent to our laboratory for diagnostic evaluation of neutropenia (neutrophil count <1,500 cells/microL). Soluble FcgammaRIII levels were measured in plasma. Genotype distibutions of FcgammaR polymorphisms were determined. Clinical data were obtained from the patient files. Patients were assessed as to whether or not they had suffered from a bacterial infection 3 months before to 3 months after a single sFcgammaRIII measurement. In addition, longitudinal data were obtained from 21 patients. Of the 66 neutropenic patients who were included, 15 had suffered from a bacterial infection in the period 3 months before to 3 months after sFcgammaRIII measurement. The age and sex distribution was equal among the groups with and without infections, as were the genotype frequencies of neutrophil FcgammaR polymorphisms. Both neutrophil count and plasma level sFcgammaRIII were significantly lower in the patient group with infections, compared with the noninfected group (P = .03 and P < .0001, respectively). No infections were reported for patients who had plasma sFcgammaRIII levels above 100 arbitrary units (AU; normal value, 30 to 200). After matching each infected patient with two noninfected patients having the same neutrophil count, sFcgammaRIII plasma levels remained significantly lower in the group with infections (P = . 0001). For the patients who were followed in time, no infections were reported when sFcgammaRIII levels were above 100 AU. In conclusion, our population of patients with chronic idiopathic neutropenia with plasma sFcgammaRIII levels above 100 AU did not show an increased risk of contracting bacterial infections.

[Immunology in clinical practice. XI. IgG receptors: the role of polymorphism in autoimmune and infectious diseases]. / Immunologie in de medische praktijk. XI. IgG-receptoren: de rol van polymorfismen in auto-immuun- en infectiezieken.

Receptors for the constant part of IgG (Fc gamma R) are implicated in the pathogenesis of a number of diseases. Children from mothers with an Fc gamma RIIIb deficiency may suffer from neonatal neutropenia due to an alloimmune reaction. Interindividual differences (polymorphisms) for a number of Fc gamma R represent risk factors for several infectious and autoimmune diseases. Immunotherapeutic use of several monoclonal antibody subclasses is affected by Fc gamma R polymorphisms. Fc gamma R can be used for cellular entrance by lymphotropic viruses (such as HIV) and appear to be involved in the pathogenesis of fulminant Dengue virus infections.

Fc gamma RIIIB gene duplication: evidence for presence and expression of three distinct Fc gamma RIIIB genes in NA(1+,2+)SH(+) individuals.

Recently, a new alloantigen on IgG Fc receptor type IIIb (Fc gamma RIIIb), SH, was described (Bux et al, Blood 89:1027, 1997). We identified three healthy individuals whose neutrophils reacted positively with the SH antiserum. The neutrophil antigen (NA) phenotype of all three donors was NA(1+,2+). Analysis of genomic DNA showed that the three donors were positive for the described SH-encoding mutation in the NA2-Fc gamma RIIIB gene, 266C-->A. However, NA(1,2) genotyping and nucleotide sequencing of an NA2-specific fragment amplified from the genomic DNA fragment showed that these individuals carried three Fc gamma RIIIB genes, namely, NA1-Fc gamma RIIIB, NA2-Fc gamma RIIIB, and SH-Fc gamma RIIIB, encoding NA1-Fc gamma RIIIb, NA2-Fc gamma RIIIb, and SH-Fc gamma RIIIb, respectively. Southern blot analysis confirmed these findings. Furthermore, all three transcripts were isolated from neutrophil mRNA. To investigate whether the presence of three Fc gamma RIIIB genes resulted in a higher membrane expression of Fc gamma RIIIb, we measured the reactivity of neutrophils from NA(1+,2+)SH(+) individuals with a panel of CD16 monoclonal antibodies (MoAbs) in comparison with neutrophils from NA(1+,2+)SH(-) controls. Reactivity of four different anti-pan-Fc gamma RIII MoAbs and NA2-specific MoAb GRM1 was higher with SH(+) neutrophils compared with controls, whereas that of NA1-specific MoAbs was similar, which is in concordance with the results from the genomic analysis. We observed that reactivity with NA2-specific CD16 MoAb PEN1 was sixfold higher in SH(+) individuals compared with controls. Apparently, the 60Ala-->Asp substitution in SH-Fc gamma RIIIb influences the epitope recognized by PEN1. In conclusion, we identified three NA(1+,2+)SH(+) individuals carrying three Fc gamma RIIIB genes and observed a clear gene-dosage effect on the level of expression of neutrophil Fc gamma RIIIb.

Addition of granulocyte colony-stimulating factor to chemotherapy in patients with AIDS-related lymphoma: effects on neutrophil Fc gamma receptor expression and soluble Fc gammaRIII plasma levels.

AIDS-related neutropenia and neutrophil dysfunction can (partly) be reversed by granulocyte-colony stimulating factor (G-CSF). We studied the effect of G-CSF on neutrophil increment and levels of soluble Fc gamma receptor type III in 15 patients with AIDS-related lymphoma (ARL) undergoing chemotherapy. In six of these patients we performed a detailed kinetic analysis of the membrane expression of the functionally important Fc gamma-receptors type I, II and III. In all these patients G-CSF induced Fc gammaRI positive neutrophils with a decreased expression of the Fc gammaRIII receptor. These changes were similar to those seen both in healthy volunteers and in non-HIV-infected individuals treated with chemotherapy. Interestingly, the mean neutrophil and sFc gammaRIII increment were significantly lower and more patients had a nadir granulocyte count < 0.5 x 10(9)/l after the first cycle than after the second cycle of chemotherapy. This may be related to a therapy-associated decrease in HIV-1 viral load. The conclusion is that patients treated with chemotherapy for ARL have a qualitatively normal response to G-CSF.

Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype.

We analyzed a genetic polymorphism of Fc gamma receptor IIIa (CD16) that is present on position 158 (Phe or Val) in the membrane-proximal, IgG-binding domain. With a polymerase chain reaction-based allele-specific restriction analysis assay we genotyped 87 donors and found gene frequencies of 0.57 and 0.43 for Fc gammaRIIIA-158F and -158V, respectively. A clear linkage was observed between the Fc gammaRIIIA-158F and -48L genotypes on the one hand and the Fc gammaRIIIA-158V and -48H or -48R genotypes on the other hand (chi2 test; P < .001). To determine the functional consequences of this Fc gammaRIIIa-158V/F polymorphism, we performed IgG binding experiments with natural killer (NK) cells from genotyped donors. All donors were also typed for the recently described triallelic Fc gammaRIIIa-48L/R/H polymorphism. NK cells were treated with lactic acid to remove cell-associated IgG. Fc gammaRIIIa(NK)-158F bound significantly less IgG1, IgG3, and IgG4 than did Fc gammaRIIIa(NK)-158V, irrespective of the Fc gammaRIIIa-48 phenotype. Moreover, freshly isolated NK cells from Fc gammaRIIIa-158VV individuals carried significantly more cytophilic IgG than did NK cells from Fc gammaRIIIa-158FF individuals. In addition, CD16 monoclonal antibody (MoAb) MEM154 bound more strongly to Fc gammaRIIIa-158V, compared with -158F, again independently of the Fc gammaRIIIa-48 phenotype. The binding of MoAb B73.1 was not influenced by the Fc gammaRIIIa-158V/F polymorphism, but proved to depend solely on the amino acid present at position 48 of Fc gammaRIIIa. In conclusion, the previously reported differences in IgG binding among the three Fc gammaRIIIa-48L/R/H isoforms are a consequence of the linked, biallelic Fc gammaRIIIa-158V/F polymorphism at amino-acid position 158.

Identification of an unusual Fc gamma receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections.

We found an unusual fc gamma receptor IIIa (CD16) phenotype on the natural killer (NK) cells of a 3-year-old boy, who suffered from recurrent viral respiratory tract infections since birth. He also had severe clinical problems after Bacille Calmette-Geérin (BCG) vaccination and following Epstein-Barr virus and Varicella Zoster virus infections. His peripheral blood lymphocytes contained a normal percentage and absolute number of CD3-CD7+ cells, which were positively stained with the CD16 monoclonal antibodies (MoAbs) 3G8 and CLBFcRgran1, but did marginally stain with the CD16 MoAb Lau11c/B73.1. Fc gamma RillIb expression on granulocytes appeared to be normal. NK cell function, analyzed in vitro by direct cytotoxicity on K562 target cells and ADCC-activity on P815 target cells, was normal compared with an age-matched healthy control. Sequence analysis of the Fc gamma RIIIA gene, encoding CD16 on NK cells and macrophages, showed a T to A nucleotide substitution at position 230 on both alleles, predicting a leucine (L) to histidine (H) amino acid change position 48 in the first extracellular lg-like domain of Fc gamma RIIIa, which contains the Leu11c/B73.1 epitope. The combined use of CD16 and CD56 MoAbs labeled with the same fluorescent dye, as often applied in routine immunophenotyping procedures, will leave these homozygotes undiagnosed. The pattern of infections in this patient is in agreement with the postulated function of NK cells in the immunological defense against viruses and other intracellular microorganisms. Further analysis of the NK cell function in vitro and follow-up of the clinical course of Fc gamma RIIIA-48H/H homozygotes is required to ascertain whether this genotype is causally related to an NK cell immunodeficiency.

NA-phenotype-dependent differences in neutrophil Fc gamma RIIIb expression cause differences in plasma levels of soluble Fc gamma RIII.

Soluble Fc gamma RIII in plasma is primarily derived from neutrophils and is a measure of the total body neutrophil mass. We have developed a new, sensitive 'sandwich' ELISA to measure soluble Fc gamma RIII in plasma and released Fc gamma RIII in cell supernatants. Both sFc gamma RIIIa, derived from NK cells and sFc gamma RIIIb, derived from neutrophils are detected in the assay. However, plasma analysis of Fc gamma RIIIB gene-deficient donors suggested that sFc gamma RIIIa contributes only marginally to the total amount measured in healthy individuals. Furthermore, we observed that plasma of homozygous NA1-positive donors contained lower amounts of sFc gamma RIII than plasma of homozygous NA2-positive donors. Heterozygous donors were found to have intermediate levels of sFc gamma RIII in their plasma. Hemizygous Fc gamma RIIIB gene-deficient donors were found to have half the amount of sFc gamma RIII in their plasma compared to donors with two Fc gamma RIIIB alleles. These NA phenotype-dependent differences in plasma sFc gamma RIII could not be contributed to either an assay artefact or NA-dependent differences in shedding of Fc gamma RIIIb upon neutrophil activation. Calibration curves constructed with plasma of homozygous donors did nor reveal NA-dependent differences in antibody affinity. Measurement of released Fc gamma RIIIb in supernatants of neutrophils stimulated with PMA, and inhibition of this signal with human IgG revealed no NA-dependent differences. However, NA-dependent differences in neutrophil Fc gamma RIIIb expression were present, comparable to the differences found in plasma levels of sFc gamma RIII. Differences in the amounts of released Fc gamma RIII in supernatants of NA-typed apoptotic neutrophils were similar to initial differences in Fc gamma RIIIb expression, again being lower in NA1-positive than in heterozygous and NA2-positive donors. In conclusion, NA-dependent differences in plasma levels of soluble Fc gamma RIII seem to be caused by differences in expression of the receptor on the neutrophil membrane.