Psychological and cognitive effects of laser printer emissions: A controlled exposure study.

The possible impact of ultrafine particles from laser printers on human health is controversially discussed although there are persons reporting substantial symptoms in relation to these emissions. A randomized, single-blinded, cross-over experimental design with two exposure conditions (high-level and low-level exposure) was conducted with 23 healthy subjects, 14 subjects with mild asthma, and 15 persons reporting symptoms associated with laser printer emissions. To separate physiological and psychological effects, a secondary physiologically based categorization of susceptibility to particle effects was used. In line with results from physiological and biochemical assessments, we found no coherent, differential, or clinically relevant effects of different exposure conditions on subjective complaints and cognitive performance in terms of attention, short-term memory, and psychomotor performance. However, results regarding the psychological characteristics of participants and their situational perception confirm differences between the participants groups: Subjects reporting symptoms associated with laser printer emissions showed a higher psychological susceptibility for adverse reactions in line with previous results on persons with multiple chemical sensitivity or idiopathic environmental intolerance. In conclusion, acute psychological and cognitive effects of laser printer emissions were small and could be attributed only to different participant groups but not to differences in exposure conditions in terms of particle number concentrations.

Health effects of laser printer emissions: a controlled exposure study.

Ultrafine particles emitted from laser printers are suspected to elicit adverse health effects. We performed 75-minute exposures to emissions of laser printing devices (LPDs) in a standardized, randomized, cross-over manner in 23 healthy subjects, 14 mild, stable asthmatics, and 15 persons reporting symptoms associated with LPD emissions. Low-level exposures (LLE) ranged at the particle background (3000 cm-3 ) and high-level exposures (HLE) at 100 000 cm-3 . Examinations before and after exposures included spirometry, body plethysmography, transfer factors for CO and NO (TLCO, TLNO), bronchial and alveolar NO, cytokines in serum and nasal secretions (IL-1ß, IL-5, IL-6, IL-8, GM-CSF, IFNγ, TNFα), serum ECP, and IgE. Across all participants, no statistically significant changes occurred for lung mechanics and NO. There was a decrease in volume-related TLNO that was more pronounced in HLE, but the difference to LLE was not significant. ECP and IgE increased in the same way after exposures. Nasal IL-6 showed a higher increase after LLE. There was no coherent pattern regarding the responses in the participant subgroups or single sets of variables. In conclusion, the experimental acute responses to short but very high-level LPD exposures were small and did not indicate clinically relevant effects compared to low particle number concentrations.

Development of a simplified urban water balance model (WABILA).

During the last decade, water sensitive urban design (WSUD) has become more and more accepted. However, there is not any simple tool or option available to evaluate the influence of these measures on the local water balance. To counteract the impact of new settlements, planners focus on mitigating increases in runoff through installation of infiltration systems. This leads to an increasing non-natural groundwater recharge and decreased evapotranspiration. Simple software tools which evaluate or simulate the effect of WSUD on the local water balance are still needed. The authors developed a tool named WABILA (Wasserbilanz) that could support planners for optimal WSUD. WABILA is an easy-to-use planning tool that is based on simplified regression functions for established measures and land covers. Results show that WSUD has to be site-specific, based on climate conditions and the natural water balance.

Influence and compensation of truncation artifacts in MR-based attenuation correction in PET/MR.

UNLABELLED: The goal of this article is to quantify the influence of truncation artifacts in the magnetic resonance (MR)-based attenuation map (MRMap) on reconstructed positron emission tomography (PET) image volumes and to propose a new method for minimizing this influence. METHODS: PET data sets of 20 patients investigated in a Philips Ingenuity PET/MR were reconstructed with and without applying two different methods for truncation compensation (TC1 vendor-provided, TC2 newly developed). In this patient group, the extent of truncation artifacts and quality of the truncation compensation (TC) was assessed visually in the MRMaps. In three additional patients MRMaps generated by algorithm TC2 could be compared to the ground truth of transmission-based attenuation maps obtained with a Siemens ECAT HR(+) scanner. The influence of truncation on regional SUVs in lesions, other hot structures (bladder, kidney, myocardium) and the arms was assessed in suitable volume of interests (VOI). RESULTS: Truncation compensated MRMaps exhibited residual artifacts in the arms in 16 patients for algorithm TC1 and to a lesser extent in eight patients for algorithm TC2. Compared to the transmission-based attenuation maps algorithm TC2 slightly overestimated the size of the truncated arms by 0.3 cm in the radial direction. Without truncation compensation, VOIs located in the trunk showed an average SUVmax underestimation of less than 5.4% relative to the results obtained with TC2. Inside the patients' arms underestimations up to 46.5% were found. CONCLUSION: In the trunk, standardized uptake values (SUV) underestimations due to truncation artifacts in the MRMap are rather small. Inside the arms, severe SUV underestimations can occur. Therefore, reliable TC is mandatory and can be achieved by applying the newly developed algorithm TC2 which has yielded promising results so far. Implementation of the proposed method is straightforward and should be easily adaptable to other PET/MR systems.

An automatic method for accurate volume delineation of heterogeneous tumors in PET.

PURPOSE: Accurate volumetric tumor delineation is of increasing importance in radiation treatment planning. Many tumors exhibit only moderate tracer uptake heterogeneity and delineation methods using an adaptive threshold lead to robust results. These methods use a tumor reference value R (e.g., ROI maximum) and the tumor background Bg to compute the volume reproducing threshold. This threshold corresponds to an isocontour which defines the tumor boundary. However, the boundaries of strongly heterogeneous tumors can not be described by an isocontour anymore and therefore conventional threshold methods are not suitable for accurate delineation. The aim of this work is the development and validation of a delineation method for heterogeneous tumors. METHODS: The new method (voxel-specific threshold method, VTM) can be considered as an extension of an adaptive threshold method (lesion-specific threshold method, LTM), where instead of a lesion-specific threshold for the whole ROI, a voxel-specific threshold is computed by determining for each voxel Bg and R in the close vicinity of the voxel. The absolute threshold for the considered voxel is then given by Tabs=T×(R-Bg)+Bg, where T=0.39 was determined with phantom measurements. VALIDATION: 30 clinical datasets from patients with non-small-cell lung cancer were used to generate 30 realistic anthropomorphic software phantoms of tumors with different heterogeneities and well-known volumes and boundaries. Volume delineation was performed with VTM and LTM and compared with the known lesion volumes and boundaries. RESULTS: In contrast to LTM, VTM was able to reproduce the true tumor boundaries accurately, independent of the heterogeneity. The deviation of the determined volume from the true volume was (0.8±4.2)% for VTM and (11.0±16.4)% for LTM. CONCLUSIONS: In anthropomorphic software phantoms, the new method leads to promising results and to a clear improvement of volume delineation in comparison to conventional background-corrected thresholding. In the next step, the suitability for clinical routine will be further investigated.

RGD-mutants of B-lymphotropic polyomavirus capsids specifically bind to alpha(v)beta3 integrin.

Integrins are a family of cell surface proteins that function as receptors for extracellular matrix ligands and for some viruses. A subset of integrins recognises peptide sequences containing arginine-glycine-aspartic acid (RGD) motifs as ligands. The B-lymphotropic polyomavirus (LPV) has a non-enveloped capsid that recognises a sialylated cell surface receptor. To change the receptor binding specificity we have replaced sets of three amino acids in three predicted surface loops of the major capsid protein VP1 of the B-lymphotropic polyomavirus LPV by RGD. Ten mutants gave rise to the expected 40 kDa VP1 protein upon expression from a baculovirus vector in insect cells. Five of the VP1 mutants representing all three surface loops have retained the ability to spontaneously assemble to capsids in the nuclei of the insect cells. Structural changes of the mutant capsid surface were shown by differential reactivity with a set of 7 neutralising monoclonal antibodies that recognise conformational surface epitopes of wildtype LPV virions. In addition all mutant capsids had lost specific binding to the LPV receptor. Three mutant capsids of one loop (BC) showed specific binding to alpha(v)beta3 integrin but not to integrins alpha(v)beta5, alpha(v)beta6, or to alpha(IIb)beta3 known also to recognise RGD containing peptide sequences. This selective binding of the mutant capsids could be inhibited by synthetic peptides that specifically bind to alpha(v)beta3 integrin with IC50 values between 10 and 40 nM.

IL-10 and TGF-beta differ in their regulation of aminopeptidase N/CD13 expression in monocytes.

Human monocytic cells express considerable amounts of aminopeptidase N (APN)/CD13, a transmembrane protein proposed to play a role in the modulation of kinins, neuropeptides and chemotactic mediators as well as in adhesion and cell-cell interactions. Previous studies have shown that APN/CD13 participates in antigen processing and presentation, trimming peptides protruding out of MHC class II molecules. In several inflammatory processes, macrophages have been shown to express especially high amounts of MHC class II molecules and of this peptidase. To learn more about the regulation of APN/CD13 on monocytes we investigated its expression under the influence of cytokines. Here, we report a dose- and time-dependent up-regulation of APN/CD13 mRNA and protein expression by transforming growth factor (TGF)-beta on human monocytes. To the contrary, we found IL-10 down-regulating the expression of APN/CD13 mRNA and protein. Both the regulation of the APN/CD13 protein assessed by immunofluorescence and the gene expression assessed by real-time PCR were highly correlated. Using the Dual-Luciferase reporter assay, we demonstrate that TGF-beta treatment of monocytes results in a higher activity of the APN/CD13 myeloid promoter. Our results implicate differences in the expression of the membrane peptidase APN/CD13 and therefore in the peptide-modulating ability of monocytes after exposure to these two immunosuppressive cytokines, TGF-beta and IL-10.

Model simulations of NOx and ultrafine particles close to a Swedish highway.

Based on the results from a 6-week monitoring campaign in an area close to a major highway north of Stockholm, Sweden, NOx emission factors representative for vehicle speeds of 100-120 km per h were determined to 0.61 g/veh,km for light duty and to 7.1 g/veh,km for heavy duty vehicles. The corresponding factors for particle number were 1.4 x 10(14) and 52 x 10(14) particles/veh,km, determined for an ambient temperature interval of +7 to +17 degrees C. The removal effects of coagulation and dry deposition on total number concentrations were assessed by numerical model simulations. Velocity and turbulence fields, including those produced by the vehicles, were simulated in a Computational Fluid Dynamics (CFD) model. Coagulation was found to be of little importance over the first 100 m downwind of the highway. The high friction velocities over the road surface created by vehicle movements enhanced deposition locally, contributing to the removal of approximately 10% of the particles originally emitted. Beyond a point 10 m downwind of the highway the removal rate was low and the ultrafine particles were almost inert while being advected over the next hundred meters. As a consequence, it seems reasonable to use monitored data from stations close to highways to estimate emission factors for particle number, assuming that the particles are inert. Those "effective" emission factors should be applicable for urban models with a larger spatial resolution.

Gene expression induced by interleukin-17 in fibroblast-like synoviocytes of patients with rheumatoid arthritis: upregulation of hyaluronan-binding protein TSG-6.

Interleukin-17 (IL-17) has been characterized as a proinflammatory cytokine produced by CD4+ CD45RO+ memory T cells. Overproduction of IL-17 was detected in the synovium of patients with rheumatoid arthritis (RA) compared with patients with osteoarthritis. This study examines differentially expressed genes after the stimulation of fibroblast-like synoviocytes of RA patients by IL-17. Among these genes we identified the following: tumor necrosis factor-stimulated gene-6 (TSG-6), IL-6, IL-8, GRO-beta, and bone morphogenetic protein-6 with an expression 3.6-10.6-fold that in the unstimulated control. IL-17 augmented the expression of TSG-6, a hyaluronan-binding protein, in a time- and dose-dependent manner. IL-17 showed additive effects with IL-1beta and tumour necrosis factor-alpha on the expression of TSG-6, IL-6 and IL-8. The mitogen-activated protein kinase p38 seems to be necessary for the regulation of TSG-6 expression by IL-17, as shown by inhibition with SB203580. Our results support the hypothesis that IL-17 is important in the pathogenesis of RA, contributing to an unbalanced production of cytokines as well as participating in connective tissue remodeling.

HLA-A, B, Cw, DRB1, DRB3/4/5, DQB1 in German patients suffering from rapidly progressive periodontitis (RPP) and adult periodontitis (AP).

BACKGROUND/AIM: There is growing indication that differences in host response determine susceptibility and resistance to periodontal disease. Particularly, the effect of histocompatibility antigens (HLA) on early onset periodontitis (EOP) has been studied. As most of the results are not conclusive and to date no report has been done on German patients, the aim of this study was to investigate the distribution of HLA alleles in a group of 50 German RPP patients and 102 German AP patients and to compare them to 102 control probands without periodontitis. METHODS: Diagnosis was established according to standardised clinical criteria. HLA typing was performed using serologic and molecular biologic (PCR-SSP) techniques. RESULTS: Compared to the controls, RPP patients had a significantly higher frequency of HLA-DRB1*13 and a significantly lower frequency of HLA-DRBblank*(non-DRB3/4/5). AP patients showed a significantly increased occurrence of HLA-B*14 and -Cw*08 as well as a significantly decreased frequency of HLA-A*03. In both patient groups HLA-A*11 and -A*29 had an increased frequency and HLA-A*31 and -A*30/31 were decreased. These differences were statistical significant in the whole patient group (RPP + AP). CONCLUSIONS: Based on modern DNA techniques the present study shows an association of HLA to both RPP and AP. Certain HLA alleles seem to be associated with susceptibility or resistance to periodontitis in general. However, before this knowledge can be used for differential diagnosis or prognosis, further investigations are necessary.

Expression, modulation and signalling of IL-17 receptor in fibroblast-like synoviocytes of patients with rheumatoid arthritis.

Interleukin-17 (IL-17) has been characterized as a proinflammatory cytokine produced by CD4+ CD45RO+ memory T cells. Overproduction of IL-17 was detected in the synovium of patients with rheumatoid arthritis (RA) compared to patients with osteoarthritis. In contrast to the restricted expression of IL-17, the IL-17 receptor (IL-17R/CDw217) is expressed ubiquitously. Using a real-time RT-PCR assay, we detected similar absolute levels of IL-17R mRNA expression in fibroblast-like synoviocytes (SFC) from patients with RA (mean 9 pg/microg total RNA; ranged from 0.1 pg to 96 pg IL-17R mRNA/microg total RNA) compared to synoviocytes of non-RA patients. Analysis of the IL-17R surface expression confirmed the results obtained for IL-17R mRNA expression. Exposure of SFC to IL-17 led to a mRNA induction of CXC chemokines IL-8, GRO-alpha and GRO-beta. An anti-IL-17 antibody blocked these effects of IL-17. The MAPK p38 appears necessary for the regulation of IL-8, GRO-alpha and GRO-beta expression as shown by inhibition with SB203580. The inhibitors genistein (tyrosine kinase inhibitor) and calphostin C (inhibitor of protein kinase C) reduced significantly the IL-17-stimulated mRNA expression of IL-8, GRO-alpha and GRO-beta in SFC, whereas PD98059 (inhibitor of MEK-1/2) was without effect. Pharmacological drugs used in therapy of RA, such as cyclosporin and methotrexate, induced a fourfold increase of IL-17R mRNA expression and augmented the IL-17-stimulated IL-8 expression. Our results support the hypothesis that IL-17/IL-17R may play a significant role in the pathogenesis of RA contributing to an unbalanced production of cytokines as well as participating in connective tissue remodelling.

Increased expression of interleukin-8 and aminopeptidase N by cell-cell contact: interleukin-8 is resistant to degradation by aminopeptidase N/CD13.

In rheumatic joints, high concentrations of interleukin-8 (IL-8) have been measured in synovial fluid and in pannus tissue. In both locations aminopeptidase N (APN)/CD13, an exopeptidase with reported activity towards IL-8 is also present. The surprising stability of IL-8 in the presence of an alleged IL-8-degrading peptidase prompted us to undertake the present study. Cocultivation of fibroblast-like synoviocytes (SFC) with T cells or with T lymphocytic cell membranes, or of T cells with SFC cell membranes, all resulted in increased IL-8 mRNA expression and IL-8 secretion into the medium, and an increase of APN expression on lymphocytes. IL-8 degradation was monitored by Western blots and HPLC. IL-8(72), as a partially processed form, was used throughout this study since it is abundant in tissues and has increased biological activity in comparison to IL-8(77). Thus its degradation/inactivation is considered of high biological significance. Whereas trypsin as a positive control rapidly degraded IL-8, we did not see any IL-8 degradation, either by a variety of soluble APNs, by leucine aminopeptidase or by APN expressed on the surface of SFC, or on ECV304 cells transfected with an APN expression vector. The much more sensitive HPLC technique resulted in negative results as well.

Association of chronic lymphocytic leukemia with specific alleles of the HLA-DR4:DR53:DQ8 haplotype in German patients.

The etiology of chronic lymphocytic leukemia (CLL) remains unknown, though a genetic susceptibility has been suggested. Results of complete DNA typing of HLA alleles in CLL patients are lacking. We compared HLA class I and class II frequencies in 101 German CLL patients and 157 healthy German controls as determined by PCR-SSP/SSO DNA analysis and serologic typing. The most striking difference was the increased frequency of HLA-DRB4*0103 [relative risk (RR) = 2.74, p < 0.0025] among patients. The presence of alleles HLA-DRB1*0401, HLA-DQB1*0302 and HLA-DPB1*0301 as well as of homozygosity for HLA-DQB1 was also associated with a higher risk for CLL, though none of these differences remained significant after correction for multiple comparisons. No association was found for any HLA class I allele. Haplotype analysis revealed a CLL-specific linkage disequilibrium for HLA-DRB1*0401:DRB4*0103 and HLA-DRB4*0103:DQB1*0302. Our results suggest that CLL could be associated with distinct class II alleles of the Caucasian haplotype HLA-DR4:DR53:DQ8, which has also been related to a susceptibility for several auto-immune diseases. The positive, though weak, association of CLL with HLA-DPB1*0301 might represent an independent susceptibility factor since no linkage disequilibrium existed with any of the other CLL-associated alleles. None of the previously reported associations with HLA class I antigens was confirmed. Our results suggest that factors within or close to the human MHC class II region confer susceptibility to CLL.

IL-1 beta- and IL-4-induced down-regulation of autotaxin mRNA and PC-1 in fibroblast-like synoviocytes of patients with rheumatoid arthritis (RA).

Autotaxin (ATX) is a 125-kD ectonucleotide pyrophosphate/phosphodiesterase, which was initially isolated and cloned from human melanoma cells as a potent stimulator of tumour cell motility. ATX shows 44% identity to the plasma cell membrane marker PC-1. Recently, we described the decreased expression of ATX mRNA in cultured fibroblast-like synoviocytes (SFC) of patients with RA by interferon-gamma. In this study using a competitive reverse transcriptase-polymerase chain reaction, we show an increased ATX mRNA expression in SFC from patients with RA in comparison with synoviocytes from non-RA patients. The median ATX mRNA amount in SFC of RA patients (440 pg/microg total RNA) was five-fold higher than the expression in synoviocytes from non-RA patients (80 pg/microg total RNA) or foreskin fibroblasts (MRHF cells, 90 pg/microg total RNA). In contrast to the elevated ATX mRNA expression in SFC of patients with RA, we did not measure increased mRNA amounts of PC-1 in these cells. Both the ATX mRNA amount and the 5'-nucleotide phosphodiesterase (PDE) activity of SFC lysate were reduced after treatment of SFC with the cytokines IL-1beta or IL-4. IL-1beta and IL-4 induced a down-regulation of PC-1 mRNA and protein expression in SFC. In SFC treated with transforming growth factor-beta the expression of PC-1 mRNA and protein was increased, whereas no significant effect on ATX mRNA expression was detectable. Pharmacological drugs used in therapy for RA, such as dexamethasone, cyclosporin, methotrexate and indomethacin, did not show a statistically significant effect on either ATX mRNA or PC-1 mRNA expression. Only pentoxifylline suppressed ATX mRNA as well as PC-1 mRNA expression. In conclusion, we show a tight regulation of ATX and PC-1 gene expression by cytokines detectable in the inflamed tissue of RA. Further investigations will deal with the regulation of ATX protein expression as well as with the function of ATX in RA.

Caveolae/lipid rafts in fibroblast-like synoviocytes: ectopeptidase-rich membrane microdomains.

Membrane peptidases play important roles in cell activation, proliferation and communication. Human fibroblast-like synoviocytes express considerable amounts of aminopeptidase N/CD13, dipeptidyl peptidase IV/CD26, and neprilysin/CD10, transmembrane proteins previously proposed to be involved in the regulation of intra-articular levels of neuropeptides and chemotactic mediators as well as in adhesion and cell-cell interactions. Here, we report these peptidases in synoviocytes to be localized predominantly in glycolipid- and cholesterol-rich membrane microdomains known as 'rafts'. At the ultrastructural level, aminopeptidase N/CD13 and dipeptidyl peptidase IV/CD26 were found in caveolae, in particular in intracellular yet surface-connected vesicle-like structures and 'rosettes' made up of several caveolae. In addition, clusters of peptidases were seen at the cell surface in flat patches ranging in size from about 60 to 160 nm. Cholesterol depletion of synoviocytes by methyl-beta-cyclodextrin disrupted >90% of the caveolae and reduced the raft localization of aminopeptidase N/CD13 without affecting Ala-p-nitroanilide-cleaving activity of confluent cell cultures. In co-culture experiments with T-lymphocytes, cholesterol depletion of synoviocytes greatly reduced their capability to induce an early lymphocytic expression of aminopeptidase N/CD13. We propose caveolae/rafts to be peptidase-rich 'hot-spot' regions of the synoviocyte plasma membrane required for functional cell-cell interactions with lymphocytes. The peptidases may act in concert with other types of proteins such as receptors and signal transducers localized in these specialized membrane domains.

Systematic mutational analysis of the active-site threonine of HIV-1 proteinase: rethinking the "fireman's grip" hypothesis.

Aspartic proteinases share a conserved network of hydrogen bonds (termed "fireman's grip"), which involves the hydroxyl groups of two threonine residues in the active site Asp-Thr-Gly triplets (Thr26 in the case of human immunodeficiency virus type 1 (HIV-1) PR). In the case of retroviral proteinases (PRs), which are active as symmetrical homodimers, these interactions occur at the dimer interface. For a systematic analysis of the "fireman's grip," Thr26 of HIV-1 PR was changed to either Ser, Cys, or Ala. The variant enzymes were tested for cleavage of HIV-1 derived peptide and polyprotein substrates. PR(T26S) and PR(T26C) showed similar or slightly reduced activity compared to wild-type HIV-1 PR, indicating that the sulfhydryl group of cysteine can substitute for the hydroxyl of the conserved threonine in this position. PR(T26A), which lacks the "fireman's grip" interaction, was virtually inactive and was monomeric in solution at conditions where wild-type PR exhibited a monomer-dimer equilibrium. All three mutations had little effect when introduced into only one chain of a linked dimer of HIV-1 PR. In this case, even changing both Thr residues to Ala yielded residual activity suggesting that the "fireman's grip" is not essential for activity but contributes significantly to dimer formation. Taken together, these results indicate that the "fireman's grip" is crucial for stabilization of the retroviral PR dimer and for overall stability of the enzyme.

Increased lymphocytic aminopeptidase N/CD13 promoter activity after cell-cell contact.

Aminopeptidase N (APN)/CD13 is a transmembrane ectoenzyme expressed on a wide variety of cells. With respect to haematopoietic cells, APN/CD13 has been considered specific for the myeloid lineage, because granulocytes and monocytes/macrophages, but not lymphocytes of peripheral blood, show a surface expression of CD13 antigen. However, we could recently show that cell-cell contact of lymphocytes with endothelial cells, monocytes, and fibroblast-like synoviocytes (SFCs) results in an increase of steady-state APN/CD13 mRNA and a rapid expression of cell-surface protein on the lymphocytes. In this study using the Dual-Luciferase reporter assay, we demonstrate that interaction of the T-cell line Jurkat with SFCs results in a higher activity of the APN/CD13 myeloid promoter in T cells. An enhancer located between the myeloid and epithelial APN/CD13 promoter increases the response of the promoter to the cell-cell contact-induced expression of APN/CD13 in lymphocytes. Adhesion of lymphocytes to extracellular matrix did not result in increased promoter activity. The lymphocytic promoter response induced by direct cell-cell contact with SFCs is not affected by mutations of a proximal promoter element (nucleotides -48 to -35), which has a possible functional role in the basal APN/CD13 gene expression in lymphocytes. Upregulated peptidase-promoter activity via cell-cell contact shown in this study for the first time is discussed as a general mechanism in peptidase induction.

HLA-A, B, Cw and DRB1, DRB3/4/5, DQB1, DPB1 frequencies in German immunoglobulin A-deficient individuals.

HLA class I and II frequencies and haplotype frequencies were determined in 80 German immunoglobulin (Ig)A-deficient individuals and 157 healthy controls with normal IgA levels using serological and DNA typing methods. For several alleles, significant associations were found, which could be explained mainly in the context of a positive association with three different extended haplotypes (HLA-B*08:DRB1*0301: DQB1*0201, HLA-B*14:DRB1*0102:DQB1*0501 and HLA-B*44:DRB1*0701:DQB1*0202) and a negative association with a fourth haplotype (HLA-B*07:DRB1*1501:DQB1*0602). Furthermore, for the first time this study reports a positive association of IgA deficiency with DPB1 alleles. Homozygosity rate for the gene loci DRB1 and DQB1 was increased in IgA deficiency. Further analysis suggested a different pattern of HLA associations depending on the degree of IgA deficiency and the gender of the IgA-deficient individuals.