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1.	AbdGawad, Mohamed, et al. (author) Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis 2012 In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:3 Journal article (peer-reviewed)abstract Background: ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues. Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV. less thanbrgreater than less thanbrgreater thanMethods: Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS. Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA. Expression of pro/anti-apoptotic factors, transcription factors C/EBP-alpha, C/EBP-beta and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR. less thanbrgreater than less thanbrgreater thanResults: AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50 +/- 14% vs. HBD 64 +/- 11%, p andlt; 0.0001). In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1. AASV patients had normal levels of G-CSF, GM-CSF and IL-3. Both C/EBP-alpha, C/EBP-beta were significantly higher in neutrophils from AASV patients than HBD. Levels of sFAS were significantly higher in AASV compared to HBD. less thanbrgreater than less thanbrgreater thanConclusion: Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ. Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV. Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.
2.	AbdGawad, Mohamed, et al. (author) Elevated neutrophil membrane expression of proteinase 3 is dependent upon CD177 expression 2010 In: Clinical and Experimental Immunology. - Chichester, West Sussex, United Kingdom : Wiley-Blackwell. - 0009-9104 .- 1365-2249. ; 161:1, s. 89-97 Journal article (peer-reviewed)abstract Proteinase 3 (PR3) is a major autoantigen in anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV), and the proportion of neutrophils expressing PR3 on their membrane (mPR3+) is increased in AASV. We have shown recently that mPR3 and CD177 are expressed on the same cells in healthy individuals. In this study we try to elucidate mechanisms behind the increased mPR3 expression in AASV and its relationship to CD177. All neutrophils in all individuals were either double-positive or double-negative for mPR3 and CD177. The proportion of double-positive neutrophils was increased significantly in AASV and systemic lupus erythematosus patients. The proportion of mPR3+/CD177+ cells was not correlated to general inflammation, renal function, age, sex, drug treatment and levels of circulating PR3. AASV patients had normal levels of granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor. Pro-PR3 was found to constitute 10% of circulating PR3 but none of the mPR3. We found increased mRNA levels of both PR3 and CD177 in AASV, but they did not correlate with the proportion of double-positive cells. In cells sorted based on membrane expression, CD177–mRNA was several-fold higher in mPR3+ cells. When exogenous PR3 was added to CD177-transfected U937 cells, only CD177+ cells bound PR3 to their membrane. In conclusion, the increased membrane expression of PR3 found in AASV is not linked directly to circulating PR3 or PR3 gene transcription, but is dependent upon CD177 expression and correlated with the transcription of the CD177 gene.
3.	AbdGawad, Mohamed, et al. (author) Increased neutrophil membrane expression and plasma level of proteinase 3 in systemic vasculitis are not a consequence of the - 564 A/G promotor polymorphism. 2006 In: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 145:1, s. 63-70 Journal article (peer-reviewed)abstract Several findings link proteinase 3 (PR3) to small vessel vasculitis. Besides being a major target of anti-neutrophil cytoplasm antibodies (ANCA), previous findings have shown increased circulating levels of PR3 in vasculitis patients, increased levels of neutrophil membrane-PR3 (mPR3) expression and a skewed distribution of the − 564 A/G polymorphism in the promotor region of the PR3 gene. In this study we elucidate how these three findings relate to each other. The plasma concentration of PR3 was measured by enzyme-linked immunosorbent assay (ELISA), mPR3 expression by fluorescence activated cell sorter (FACS) and the gene polymorphism by real-time polymerase chain reaction (PCR). We compared results from 63 patients with ANCA-associated systemic vasculitis (AASV) with 107 healthy blood donors. In accordance with previous reports, AASV patients had increased plasma concentrations of PR3 compared to healthy controls (mean 224 µg/l versus 155 µg/l, P < 0·0001). They also showed an increased number of mPR3-positive neutrophils (60% versus 42%, P < 0·001). However, contrary to a previous report, we found no skewed distribution of the polymorphism in PR3 gene. There was a weak correlation between mPR3 mean fluorescence intensity (MFI) and plasma PR3 among healthy controls and myeloperoxidase–ANCA (MPO–ANCA)-positive patients (r = 0·24, P = 0·015 and r = 0·52, P = 0·011, respectively). In conclusion, increased plasma PR3 and high expression of mPR3 are associated with small vessel vasculitis, but neither of them is a consequence of the − 564 A/G polymorphism of the PR3 gene promotor.
4.	AbdGawad, Mohamed, et al. (author) PR3 and CD177 are co-expressed on neutrophil plasma membranes in patients with ANCA associated systemic vasculitis 2007 In: Clinical and Experimental Rheumatology. - 1593-098X. ; 25:1 Suppl. 44, s. 82-82 Conference paper (peer-reviewed)
5.	AbdGawad, Mohamed, et al. (author) Studies of mechanisms underlying the prolonged neutrophil survival in ANCA-associated systemic vasculitis 2009 In: APMIS. - 1600-0463. ; 117, s. 125-125 Conference paper (peer-reviewed)
6.	Appelgren, Daniel, 1985-, et al. (author) Regulatory B cells are reduced in the blood in patients with granulomatosis with polyangiitis, and fail to regulate T-cell IFN-γproduction 2023 In: Clinical and Experimental Immunology. - : Oxford University Press. - 0009-9104 .- 1365-2249. ; 213:2, s. 190-201 Journal article (peer-reviewed)abstract Regulatory B (Breg) cells can dampen inflammation, autoreactivity, and transplant rejection. We investigated the frequencies, phenotypes, and function of Breg cells in granulomatosis with polyangiitis (GPA) to gain further knowledge as to whether there are numerical alterations or limitations of their ability to regulate T-cell function. Frequencies and phenotypes of CD24hiCD27+ and CD24hiCD38hi B-cells in the blood were determined with flow cytometry in 37 GPA patients (22 in remission and 15 with active disease) and 31 healthy controls (HC). A co-culture model was used to study the capacity of Breg cells to regulate T-cell activation and proliferation in cells from 10 GPA patients in remission and 12 HC. T-cell cytokine production in vitro and levels in plasma were determined with enzyme-linked immunosorbent assay. Frequencies of CD24hiCD27+ B-cells were reduced both during active disease and remission compared with HC (P = 0.005 and P = 0.010, respectively), whereas CD24hiCD38hi B-cells did not differ. Patient CD24hiCD27+ B-cells exhibited decreased expression of CD25 but increased expression of PD-L1 and PD-L2 during remission. B-cells from GPA patients regulated T-cell proliferation but failed to regulate interferon (IFN)-γproduction (median T-cells alone 222 ng/ml vs. T-cells + B-cells 207 ng/ml, P = 0.426). IFN-γwas also elevated in patient plasma samples (P = 0.016). In conclusion, GPA patients exhibit altered numbers and phenotypes of CD24hiCD27+ B-cells. This is accompanied by a disability to control T-cell production of Th1-type cytokines during remission, which might be of fundamental importance for the granulomatous inflammation that characterizes the chronic phase of this disease. © 2023 The Author(s). Published by Oxford University Press on behalf of the British Society for Immunology.
7.	Armstead, Sumiko I, et al. (author) A Case of Alport Syndrome with Posttransplant Antiglomerular Basement Membrane Disease despite Negative Antiglomerular Basement Membrane Antibodies by EIA Treated with Plasmapheresis and Intravenous Immunoglobulin. 2013 In: Case reports in transplantation. - : Hindawi Limited. - 2090-6943 .- 2090-6951. ; 2013:Dec 2 Journal article (peer-reviewed)abstract Posttransplant antiglomerular basement membrane (anti-GBM) disease occurs in approximately 5% of Alport patients and usually ends in irreversible graft failure. Recent research has focused on characterizing the structure of the anti-GBM alloepitope. Here we present a case of a 22-year-old male with end-stage renal disease secondary to Alport syndrome, with a previously failed renal allograft, who received a second deceased-donor kidney transplant. Six days after transplantation, he developed acute kidney injury. The serum anti-GBM IgG was negative by enzyme immunoassay (EIA). On biopsy, he had crescentic glomerulonephritis with linear GBM fixation of IgG. With further analysis by western blotting, we were able to detect antibodies to an unidentified protein from the basement membrane. This patient was treated with plasmapheresis twice per week and monthly intravenous immunoglobulin (IVIG) for a total of five months. At the end of treatment, these unknown antibodies were no longer detected. His renal function improved, and he has not required dialysis. We conclude that anti-GBM disease in patients with Alport Syndrome may be caused by circulating antibodies to other components of the basement membrane that are undetectable by routine anti-GBM EIA and may respond to treatment with plasmapheresis and IVIG.
8.	Askman, Sandra, et al. (author) Decreased neutrophil function in newly diagnosed multiple myeloma patients is restored with lenalidomide therapy 2024 In: EUROPEAN JOURNAL OF HAEMATOLOGY. - 0902-4441 .- 1600-0609. Journal article (peer-reviewed)abstract ObjectivesBacterial infections are common and a major cause of morbidity and mortality in multiple myeloma (MM). We have investigated the function of polymorphonuclear leukocyte (PMN), the immune system's first line of defense against bacteria, in peripheral blood (PB) and bone marrow (BM) samples from patients with newly diagnosed MM (NDMM), smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS) and healthy controls.MethodsPhagocytosis and oxidative burst in PMN cells from patients and healthy donors were investigated using PhagoTest and PhagoBurst assay.ResultsPMN from NDMM, SMM, and MGUS patients had reduced phagocytosis and oxidative burst ability compared with healthy controls. The dysfunction was most prominent in BM samples from MM, SMM, and MGUS patients. Importantly the reduced phagocytosis in MM patients was restored in patients on lenalidomide therapy. Consistently the ability of Escherichia coli stimulated oxidative burst in BM was reduced for the MM, SMM, and MGUS cohort in contrast to the healthy controls and the patients on lenalidomide treatment.ConclusionOur results show that MM patients have neutrophil dysfunction that could contribute to susceptibility for bacterial infections and that lenalidomide therapy was associated with restored PMN function.
9.	Audard, Vincent, et al. (author) A 59-kd renal antigen as a new target for rapidly progressive glomerulonephritis 2007 In: American Journal of Kidney Diseases. - : Elsevier BV. - 1523-6838 .- 0272-6386. ; 49:5, s. 710-716 Journal article (peer-reviewed)abstract Anti-glomerular basement membrane (anti-GBM) antibodies are the hallmark of anti-GBM disease, which is characterized by rapidly progressive glomerulonephritis. We describe the case of a 58-year-old woman who presented with rapidly progressive glomerulonephritis with typical anti-GBM staining found by means of direct immunofluorescence microscopy, associated with linear immunoglobin G deposits on tubules. Serum analysis showed circulating anti-tubular basement membrane antibodies, but failed to detect anti-GBM antibodies. Immunoblotting showed that serum antibodies reacted with a 59-kd antigen found along both the GBM and tubular basement membrane.
10.	Bahnan, Wael, et al. (author) A human monoclonal antibody bivalently binding two different epitopes in streptococcal M protein mediates immune function 2023 In: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 15:2, s. 1-21 Journal article (peer-reviewed)abstract Group A streptococci have evolved multiple strategies to evade human antibodies, making it challenging to create effective vaccines or antibody treatments. Here, we have generated antibodies derived from the memory B cells of an individual who had successfully cleared a group A streptococcal infection. The antibodies bind with high affinity in the central region of the surface-bound M protein. Such antibodies are typically non-opsonic. However, one antibody could effectively promote vital immune functions, including phagocytosis and in vivo protection. Remarkably, this antibody primarily interacts through a bivalent dual-Fab cis mode, where the Fabs bind to two distinct epitopes in the M protein. The dual-Fab cis-binding phenomenon is conserved across different groups of M types. In contrast, other antibodies binding with normal single-Fab mode to the same region cannot bypass the M protein's virulent effects. A broadly binding, protective monoclonal antibody could be a candidate for anti-streptococcal therapy. Our findings highlight the concept of dual-Fab cis binding as a means to access conserved, and normally non-opsonic regions, regions for protective antibody targeting.
11.	Bahnan, Wael, et al. (author) Spike-Dependent Opsonization Indicates Both Dose-Dependent Inhibition of Phagocytosis and That Non-Neutralizing Antibodies Can Confer Protection to SARS-CoV-2 2022 In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12 Journal article (peer-reviewed)abstract Spike-specific antibodies are central to effective COVID19 immunity. Research efforts have focused on antibodies that neutralize the ACE2-Spike interaction but not on non-neutralizing antibodies. Antibody-dependent phagocytosis is an immune mechanism enhanced by opsonization, where typically, more bound antibodies trigger a stronger phagocyte response. Here, we show that Spike-specific antibodies, dependent on concentration, can either enhance or reduce Spike-bead phagocytosis by monocytes independently of the antibody neutralization potential. Surprisingly, we find that both convalescent patient plasma and patient-derived monoclonal antibodies lead to maximum opsonization already at low levels of bound antibodies and is reduced as antibody binding to Spike protein increases. Moreover, we show that this Spike-dependent modulation of opsonization correlate with the outcome in an experimental SARS-CoV-2 infection model. These results suggest that the levels of anti-Spike antibodies could influence monocyte-mediated immune functions and propose that non-neutralizing antibodies could confer protection to SARS-CoV-2 infection by mediating phagocytosis.
12.	Bauer, Susanne, et al. (author) Proteinase 3 and CD177 are expressed on the plasma membrane of the same subset of neutrophils. 2007 In: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 81, s. 458-464 Journal article (peer-reviewed)abstract Proteinase 3 (PR3) is found in granules of all nentrophils but also on the plasma membrane of a subset of nentrophils (mPR3). CD177, another neutrophil protein, also displays a bimodal surface expression. In this study, we have investigated the coexpression of these two molecules, as well as the effect of cell activation on their surface expression. We can show that CD177 is expressed on the same subset of nentrophils as mPR3. Experiments show that the expression of mPR3 and CD177 on the plasma membrane is increased or decreased in parallel during cell stimulation or spontaneous apoptosis. Furthermore, we observed a rapid internalization and recirculation of mPR3 and plasma membrane CD177, where A mPR3 is replaced within 30 min. Our findings suggest that the PR3 found on the plasma membrane has its origin in the same intracellular storage as CD177, i.e., secondary granules and secretory vesicles and not primary granules. PR3- and CD177-expressing neutrophils constitute a subpopulation of neutrophils with an unknown role in the innate immune system, which may play an important role in diseases such as Wegener's granulomatosis and polycythemia vera.
13.	Bengtsson, Anders, et al. (author) Low production of reactive oxygen species in granulocytes is associated with organ damage in systemic lupus erythematosus 2014 In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 16:3 Journal article (peer-reviewed)abstract Introduction: Polymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response. While the specific role of PMN in systemic lupus erythematosus (SLE) and autoimmunity is still unclear, their importance in chronic inflammation is gaining more attention. Here we investigate aspects of function, bone marrow release and activation of PMN in patients with SLE. Methods: The following PMN functions and subsets were evaluated using flow cytometry; (a) production of reactive oxygen species (ROS) after ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) or Escherichia coli (E. coli); (b) capacity to phagocytose antibody-coated necrotic cell material; (c) PMN recently released from bone marrow, defined as percentage of CD10(-)D16(low) in peripheral blood, and (d) PMN activation markers; CD11b, CD62L and C5aR. Results: SLE patients (n = 92) showed lower ROS production compared with healthy controls (n = 38) after activation ex vivo. The ROS production was not associated with corticosteroid dose or other immunotherapies. PMA induced ROS production was significantly reduced in patients with severe disease. In contrast, neither ROS levels after E. coli activation, nor the capacity to phagocytose were associated with disease severity. This suggests that decreased ROS production after PMA activation is a sign of changed PMN behaviour rather than generally impaired functions. The CD10(-)CD16(low) phenotype constitute 2% of PMN in peripheral blood of SLE patients compared with 6.4% in controls, indicating a decreased release of PMN from the bone marrow in SLE. A decreased expression of C5aR on PMN was observed in SLE patients, pointing towards in vivo activation. Conclusions: Our results indicate that PMN from SLE patients have altered function, are partly activated and are released abnormally from bone marrow. The association between low ROS formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor.
14.	Bolton, W K, et al. (author) Epitope spreading and autoimmune glomerulonephritis in rats induced by a T cell epitope of Goodpasture's antigen 2005 In: Journal of the American Society of Nephrology. - 1046-6673. ; 16:9, s. 2657-2666 Journal article (peer-reviewed)abstract An amino-terminal region of a, chain of type IV collagen noncollagenous domain [alpha(3)(IV)NC1] that induces experimental autoimmune glomerulortephritis (EAG) in rats has been identified. Only recombinant antigens that contain a nine-amino acid (AA) span of alpha(3)(IV)NC1, consistent with a T cell epitope, could induce EAG. It was hypothesized that synthetic peptides of this region should induce EAG. Human and rat peptides of this region were synthesized and rats were immunized to define the nephritogenic epitope. A 13-AA rat peptide induced EAG with proteinuria, decreased renal function, and glomerular basement membrane (GBM)-bound deposits in half of the rats. This peptide induces lymph node cell proliferation and development of antibodies to epitopes of alpha(3)(IV)NC1 external to the peptide immunogen. Carboxy-terminal extension to 21 amino acids results in all rats' demonstrating anti-GBM antibody and severe EAG. Asparagine at position 19 is critical for EAG induction. None of the 50 rats that were immunized with peptide that contained human sequence with isoleucine at position 19 developed EAG, whereas rat sequence with asparagine 19 induced EAG. Truncation of amino terminal AA of the peptide aborts EAG induction. These studies demonstrate that a T cell epitope of alpha(3)(IV)NC1 induces lymph node cell proliferation, EAG, and intramolecular epitope spreading; that the length of this peptide influences the formation of anti-GBM antibody; and that the presence of asparagine at position 19 of the peptide is critical to disease induction.
15.	Bolton, W Kline, et al. (author) Molecular mapping of the Goodpasture's epitope for glomerulonephritis 2005 In: Transactions of the American Clinical and Climatological Association. - 0065-7778. ; 116, s. 229-238 Journal article (peer-reviewed)abstract Goodpasture's syndrome is an autoimmune disease characterized by pulmonary hemorrhage, glomerulonephritis, and antiglomerular basement membrane (GBM) antibodies. We have studied a rat model with chimeric proteins (CPs) consisting of portions of the nephritogenic non-collagenous domain of alpha3 type IV collagen (alpha3(IV)NC1) and non-nephritogenic alpha1(IV)NC1. CPs with aminoterminal alpha3 that contains the major epitope for Goodpasture antibody binding induced EAG. We next immunized with D3, an alpha1(IV)NC1 CP with 69AA of alpha3(IV)NC1 (binds Goodpasture sera), D4, the D3 construct shortened by 4 AA (nonbinding), P9 and P10, single AA mutants (nonbinding) and S2, an alpha1(IV)NC1 with nine AA of alpha3(IV)NC1 (binding). GBM, S2 and D3 induced EAG. GBM immunized rats had intense IgG deposits but S2 and D3 rats had minimal deposits. A 13 mer rat peptide encompassing the aminoterminal site induced EAG sans antibody, while peptides not encompassing the region failed to induce GN. Asparagine at position 19 rather than isoleucine was essential for disease induction. These studies define critical limited AA sequences of alpha3(IV)NC1 associated with glomerulonephritis without antibody, and demonstrate that this region contains a T-cell epitope responsible for induction of glomerulonephritis.
16.	Borza, Corina M., et al. (author) Integrin alpha 3 beta 1, a Novel Receptor for alpha 3(IV) noncollagenous domain and a trans-dominant inhibitor for integrin alpha v beta 3 2006 In: Journal of Biological Chemistry. - 1083-351X. ; 281:30, s. 20932-20939 Journal article (peer-reviewed)abstract Exogenous soluble human alpha 3 noncollagenous (NC1) domain of collagen IV inhibits angiogenesis and tumor growth. These biological functions are attributed to the binding of alpha 3NC1 to integrin alpha v beta 3. However, in some tumor cells that express integrin alpha v beta 3, the alpha 3NC1 domain does not inhibit proliferation, suggesting that integrin alpha v beta 3 expression is not sufficient to mediate the anti-tumorigenic activity of this domain. Therefore, in the present study, we searched for novel binding receptors for the soluble alpha 3NC1 domain in cells lacking alpha v beta 3 integrin. In these cells, soluble alpha 3NC1 bound integrin alpha 3 beta 1; however, unlike alpha v beta 3, alpha 3 beta 1 integrin did not mediate cell adhesion to immobilized alpha 3NC1 domain. Interestingly, in cells lacking integrin alpha 3 beta 1, adhesion to the alpha 3NC1 domain was enhanced due to activation of integrin alpha v beta 3. These findings indicate that integrin alpha 3 beta 1 is a receptor for the alpha 3NC1 domain and transdominantly inhibits integrin alpha v beta 3 activation. Thus integrin alpha 3 beta 1, in conjunction with integrin alpha v beta 3, modulates cellular responses to the alpha 3NC1 domain, which may be pivotal in the mechanism underpinning its anti-angiogenic and anti-tumorigenic activities.
17.	Bryland, Anna, et al. (author) Citrate treatment reduces endothelial death and inflammation under hyperglycaemic conditions. 2012 In: Diabetes & Vascular Disease Research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 9:1, s. 42-51 Journal article (peer-reviewed)abstract Hyperglycaemia and glucose degradation products (GDPs) are closely associated with oxidative stress and inflammation in diabetic patients, a condition that leads to endothelial dysfunction and cardiovascular problems. We evaluated the effect of citrate and gluconate on glucose- and GDP-induced endothelial inflammation by measuring changes in viability, inflammation and function in primary human umbilical vein endothelial cells (HUVECs). The extent of apoptosis/necrosis was measured by flow cytometry and visualised with confocal microscopy by staining with annexin V or propidium iodide, respectively. Protein kinase C-βII (PKC-βII) activation was evaluated with Western blotting. Incubation with glucose (30 mM) and GDP (50 µM) significantly increased PKC-βII expression, endothelial cell death and inflammation. The addition of citrate decreased hyperglycaemia-induced apoptosis (p = 0.021), necrosis (p = 0.04) and reduced PKC-βII expression (p = 0.021) down to background levels. Citrate improved endothelial function by reducing the inflammatory markers(p = 0.01) and by decreasing neutrophil diapedesis (p = 0.012). These results suggest that citrate may have therapeutic potential by reducing hyperglycaemia-induced endothelial inflammation and abolishing endothelial dysfunction.
18.	Carlsson, Michael, et al. (author) Different fractions of human serum glycoproteins bind galectin-1 or galectin-8, and their ratio may provide a refined biomarker for pathophysiological conditions in cancer and inflammatory disease 2012 In: Biochimica et Biophysica Acta - General Subjects. - : Elsevier. - 0304-4165 .- 1872-8006 .- 0006-3002. ; 1820:9, s. 1366-1372 Journal article (peer-reviewed)abstract Background: Changes in glycosylation of serum proteins are common, and various glycoforms are being explored as biomarkers in cancer and inflammation. We recently showed that glycoforms detected by endogenous galectins not only provide potential biomarkers, but also have different functions when they encounter galectins in tissue cells. Now we have explored the use of a combination of two galectins with different specificities, to further increase biomarker sensitivity and specificity. less thanbrgreater than less thanbrgreater thanMethods: Sera from 14 women with metastatic breast cancer, 12 healthy controls, 14 patients with IgA-nephritis (IgAN), and 12 patients with other glomerulonephritis were fractionated by affinity chromatography on immobilized human galectin-1 or galectin-8N, and the protein amounts of the bound and unbound fractions for each galectin were determined. less thanbrgreater than less thanbrgreater thanResults: Each galectin bound largely different fractions of the serum glycoproteins, including different glycoforms of haptoglobin. In the cancer sera, the level of galectin-1 bound glycoproteins was higher and galectin-8N bound glycoproteins lower compared to the other patients groups, whereas in IgAN sera the level of galectin-8N bound glycoproteins were higher. less thanbrgreater than less thanbrgreater thanConclusion: The ratio of galectin-1 bound/galectin-8N bound glycoproteins showed high discriminatory power between cancer patients and healthy, with AUC of 0.98 in ROC analysis, and thus provides an interesting novel cancer biomarker candidate. less thanbrgreater than less thanbrgreater thanGeneral significance: The galectin-binding ability of a glycoprotein is not only a promising biomarker candidate but may also have a specific function when the glycoprotein encounters the galectin in tissue cells, and thus be related to the pathophysiological state of the patient. This article is part of a Special Issue entitled Glycoproteomics.
19.	Carlsson, Michael, et al. (author) Galectin-8 in IgA Nephritis: Decreased Binding of IgA by Galectin-8 Affinity Chromatography and Associated Increased Binding in Non-IgA Serum Glycoproteins 2012 In: Journal of Clinical Immunology. - : Springer Verlag (Germany). - 0271-9142 .- 1573-2592. ; 32:2, s. 246-255 Journal article (peer-reviewed)abstract Background Immunoglobulin A nephritis (IgAN) is the most common primary glomerulonephritis worldwide. It is caused by accumulation of IgA1-containing immune complexes in the kidney resulting in renal failure, which is thought to be due to altered glycosylation of IgA with a decrease of 2-3-sialylated galactosides (NeuAc alpha 2-3Gal). less thanbrgreater than less thanbrgreater thanPurpose The purpose of this study was to analyze whether altered glycosylation of IgA would lead to an altered binding to galectin-8, an endogenous lectin with strong affinity for 2-3-sialylated galactosides. Galectins are a family of beta-galactoside-binding proteins; by binding various glycoproteins, they play important roles in the regulation of cellular functions in inflammation and immunity. Hence, an altered binding of IgA to galectin-8 could lead to pathologic immune functions, such as glomerulonephritis. less thanbrgreater than less thanbrgreater thanMethods Affinity chromatography of serum glycoproteins on the human sialogalactoside-binding lectin galectin-8N permitted quantitation of bound and unbound fractions, including IgA. less thanbrgreater than less thanbrgreater thanResults Analysis of similar to 100 IgA nephritis sera showed that the galectin-8N unbound fraction of IgA increased compared to similar to 100 controls, consistent with the known loss of galactosylation. A subgroup of similar to 15% of the IgAN patients had a ratio of galectin-8 bound/unbound IgA andlt;0.09, not found for any of the controls. Unexpectedly, the galectin-8N-binding fraction of serum glycoproteins other than IgA increased in the sera of IgAN patients but not in controls, suggesting a previously unrecognized change in this disease. less thanbrgreater than less thanbrgreater thanConclusion This is the first study that relates a galectin, an endogenous lectin family, to IgA nephritis and thus should stimulate new avenues of research into the pathophysiology of the disease.
20.	Carlsson, Malin, et al. (author) Pseudomonas aeruginosa in cystic fibrosis: Pyocyanin negative strains are associated with BPI-ANCA and progressive lung disease 2011 In: Journal of Cystic Fibrosis. - : Elsevier Science B.V., Amsterdam.. - 1569-1993 .- 1873-5010. ; 10:4, s. 265-271 Journal article (peer-reviewed)abstract The clinical consequence of chronic Pseudomonas aeruginosa colonization in cystic fibrosis (CF) varies between individuals for unknown reasons. Auto-antibodies against bactericidal/permeability increasing protein (BPI-ANCA) are associated with poor prognosis in CF. We hypothesize that there is a correlation between the presence of BPI-ANCA, the properties of the colonizing bacteria and the clinical conditions of the host. We compared isolates of P. aeruginosa from BPI-ANCA positive CF patients who have deteriorating lung disease with BPI-ANCA negative CF patients who are in stable clinical conditions. Epithelial cells (A549) and isolated polymorphonuclear granulocytes (PMNs) were stimulated with the isolates and cell death was analyzed with flow cytometry. We found that the ANCA associated strains in most cases showed pyocyanin negative phenotypes. These strains also induced less inflammatory response than the non-ANCA associated strains as shown by apoptosis and necrosis of epithelial cells and neutrophils. Our results suggest that colonization with strains of P. aeruginosa that induce a weak inflammatory response is associated with unfavorable outcome in CF. We speculate that inadequate control of pathogen proliferation through an insufficient inflammatory response results in a slowly increasing number of bacteria and accumulation of dying PMNs in the airways, contributing to progression in CF lung disease.
21.	Chauveau, Bertrand, et al. (author) Atypical Anti-Glomerular Basement Membrane Nephritis : A Case Series From the French Nephropathology Group In: American Journal of Kidney Diseases. - 1523-6838. Journal article (peer-reviewed)abstract RATIONALE & OBJECTIVE: Atypical anti-glomerular basement membrane (GBM) nephritis is characterized by a bright linear immunoglobulin staining along the GBM by immunofluorescence without a diffuse crescentic glomerulonephritis nor serum anti-GBM antibodies by conventional ELISA. We characterized a series of patients with atypical anti-GBM disease.STUDY DESIGN: Case series.SETTING & PARTICIPANTS: Patients were identified by the French Nephropathology Group as having atypical anti-GBM nephritis between 2003 and 2022.FINDINGS: Among 38 potential cases, 25 were included. 14 (56%) were female and 23 (92%) had hematuria. Median [interquartile range (IQR)] serum creatinine at diagnosis was 150 [102-203] μmol/L and median [IQR] urine protein to creatinine ratio was 2.4 [1.3-5.2] g/g. 9 (36%) patients had endocapillary proliferative glomerulonephritis (GN), 4 (16%) had mesangial proliferative GN, 4 (16%) had membranoproliferative GN, 2 (8%) had pure and focal crescentic GN, 1 (4%) had focal segmental glomerulosclerosis, and 5 had glomeruli that were unremarkable on histopathology. Nine patients (36%) had crescents, involving a median of 9% of glomeruli. Bright linear staining for IgG was seen in 22 cases (88%) and for IgA in 3 cases (12%). The nine patients (38%) who had a monotypic staining pattern tended to be older with less proteinuria and rarely had crescents. Kidney survival rate at one year was 83% and did not appear to be associated with the light chain restriction.LIMITATIONS: Retrospective case series with a limited number of biopsies including electron microscopy.CONCLUSIONS: Compared to typical anti-GBM disease, atypical anti-GBM nephritis frequently presents with endocapillary or mesangial proliferative glomerulonephritis pattern and appears to have slower disease progression. Further studies are needed to fully characterize its pathophysiology and associated clinical outcomes.
22.	Chen, Lanlin, et al. (author) A nephritogenic peptide induces intermolecular epitope spreading on collagen IV in experimental autoimmune glomerulonephritis 2006 In: Journal of the American Society of Nephrology. - 1046-6673. ; 17:11, s. 3076-3081 Journal article (peer-reviewed)abstract This group previously identified a peptide p13 of alpha 3(IV)NC1 domain of type IV collagen that induces experimental autoimmune glomerulonephritis (EAG) in rats with generation of antibodies to sites on alpha 3(IV)NC1 external to the peptide as a result of intramolecular epitope spreading. It was hypothesized that intermolecular epitope spreading to other collagen IV chains also was induced. Rats were immunized with nephritogenic peptide that was derived from the amino terminal part of rat alpha 3(IV)NC1 domain, and serum and kidney eluate were examined for antibodies to both native and recombinant NC1 domains of collagen IV. Peptide induced EAG with proteinuria and decreased renal function and glomerular basement membrane IgG deposits. Sera from these rats were examined by ELISA, which revealed reactivity not only to immunizing peptide but also to human and rat alpha 3(IV)NC1 and to human alpha 4(IV)NC1 domains. Kidney eluate that was depleted of alpha 3(IV)NC1 antibodies still reacted to alpha 4(IV)NC1, and alpha 3(IV)NC1 column-bound antibody reacted with alpha 3(IV)NC1. There was minimal reactivity to other collagen chains. Eluate that was adsorbed to NC1 hexamer from rat glonterular basement membrane lost all reactivity to glomerular constituents, and the eluted antibodies reacted to alpha 3(IV)NC1 and alpha 4(IV)NC1 domains. These studies show that a T cell epitope of alpha 3(IV)NC1 induces EAG, intramolecular epitope spreading along alpha 3(IV)NC1, and intermolecular epitope spreading to alpha 4(IV)NC1 domain with minimal or no reactivity to other collagen chains or glomerular constituents. This is the first demonstration in EAG of intermolecular epitope spreading and identification of the spread epitopes.
23.	Chen, Lanlin, et al. (author) Immunodominant epitopes of alpha3(IV)NC1 induce autoimmune glomerulonephritis in rats. 2003 In: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 64:6, s. 2108-2120 Journal article (peer-reviewed)
24.	Clavarino, Giovanna, et al. (author) Letter: Routinely used immunoassays do not detect circulating anti-GBM antibodies against native NC1 hexamer and EA epitope of the 3 chain of type IV collagen in EUROPEAN JOURNAL OF IMMUNOLOGY, vol 48, issue 6, pp 1082-1084 2018 In: European Journal of Immunology. - : WILEY. - 0014-2980 .- 1521-4141. ; 48:6, s. 1082-1084 Journal article (other academic/artistic)abstract n/a
25.	Clavarino, Giovanna, et al. (author) Routinely used immunoassays do not detect circulating anti-GBM antibodies against native NC1 hexamer and EA epitope of the α3 chain of type IV collagen 2018 In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 48:6, s. 1082-1084 Journal article (peer-reviewed)
26.	Cui, Zhao, et al. (author) Natural autoantibodies against myeloperoxidase, protease 3 and glomerular basement membrane in normal healthy individuals 2009 In: APMIS. - 1600-0463. ; 117, s. 171-171 Conference paper (peer-reviewed)
27.	Cui, Zhao, et al. (author) Natural autoantibodies to myeloperoxidase, proteinase 3, and the glomerular basement membrane are present in normal individuals 2010 In: Kidney International. - London, UK : Elsevier BV. - 1523-1755 .- 0085-2538. ; 78:6, s. 590-597 Journal article (peer-reviewed)abstract Anti-neutrophil cytoplasmic antibodies (ANCAs) have a pathogenic role in ANCA-associated vasculitis. The origin of ANCAs and anti-glomerular basement membrane (GBM) antibodies, however, is unknown. In this study, we determined whether natural autoantibodies against myeloperoxidase (MPO), proteinase 3 (PR3), and GBM were present in each of 10 healthy Chinese and Swedish individuals, negative for all three antigens by routine ELISA. Antibodies were purified from isolated IgG by antigen-specific affinity columns. Natural anti-GBM autoantibodies gave a linear staining pattern along the GBM of human renal sections. On ethanol-fixed granulocytes, both natural anti-MPO and anti-PR3 autoantibodies gave cytoplasmic staining. The titers of natural anti-MPO/PR3 autoantibodies were significantly lower than those from patients with vasculitis. In competition ELISA, the binding of natural anti-MPO autoantibodies could be inhibited by MPO, but not by PR3 or noncollagenous domains from type IV collagen. The same specificity results were found for natural anti-PR3 and anti-GBM autoantibodies. Overall, individuals of the Chinese origin had more natural autoantibodies than did those of the Swedish origin, but no other differences were found. Hence, our study shows that healthy individuals have masked circulating, noncross-reactive, antigen-specific natural autoantibodies against MPO, PR3, and GBM in their serum and IgG fractions. Further studies are needed to determine their role if any in the etiology of ANCA-associated vasculitis and anti-GBM disease. Kidney International (2010) 78, 590-597; doi:10.1038/ki.2010.198; published online 30 June 2010
28.	Elmér, Evelina, et al. (author) Increased Frequencies of Switched Memory B Cells and Plasmablasts in Peripheral Blood from Patients with ANCA-Associated Vasculitis 2020 In: Journal of Immunology Research. - : Hindawi Limited. - 2314-7156 .- 2314-8861. ; 2020 Journal article (peer-reviewed)abstract B cells are thought to play a central role in the pathogenesis of antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV). ANCAs have been proposed to cause vasculitis by activating primed neutrophils to damage small blood vessels. We studied a cohort of AAV patients of which a majority were in remission and diagnosed with granulomatosis with polyangiitis (GPA). Using flow cytometry, the frequencies of CD19+ B cells and subsets in peripheral blood from 106 patients with AAV and 134 healthy controls were assessed. B cells were divided into naive, preswitch memory, switched memory, and exhausted memory cells. Naive and switched memory cells were further subdivided into transitional cells and plasmablasts, respectively. In addition, serum concentrations of immunoglobulin A, G, and M were measured and clinical data were retrieved. AAV patients displayed, in relation to healthy controls, a decreased frequency of B cells of lymphocytes (5.1% vs. 8.3%) and total B cell number. For the subsets, a decrease in percentage of transitional B cells (0.7% vs. 4.4%) and expansions of switched memory B cells (22.3% vs. 16.5%) and plasmablasts (0.9% vs. 0.3%) were seen. A higher proportion of B cells was activated (CD95+) in patients (20.6% vs. 10.3%), and immunoglobulin levels were largely unaltered. No differences in B cell frequencies between patients in active disease and remission were observed. Patients in remission with a tendency to relapse had, compared to nonrelapsing patients, decreased frequencies of B cells (3.5% vs. 6.5%) and transitional B cells (0.1% vs. 1.1%) and an increased frequency of activated exhausted memory B cells (30.8% vs. 22.3%). AAV patients exhibit specific changes in frequencies of CD19+ B cells and their subsets in peripheral blood. These alterations could contribute to the autoantibody-driven inflammatory process in AAV.
29.	Elmér, Evelina, et al. (author) Methotrexate Treatment Suppresses Monocytes in Nonresponders to Pneumococcal Conjugate Vaccine in Rheumatoid Arthritis Patients 2022 In: Journal of Immunology Research. - : Hindawi Limited. - 2314-8861 .- 2314-7156. ; 2022 Journal article (peer-reviewed)abstract Patients with rheumatoid arthritis (RA) have an increased risk of infections; therefore, immunization against vaccine-preventable diseases is important. Methotrexate (MTX) impairs the antibody response to pneumococcal conjugate vaccine (PCV) in patients with arthritis, and the underlying mechanism is largely unknown. Here, we investigate the potential role of the innate immune system in the faltering antibody response following PCV vaccination in RA patients treated with MTX. Phenotypes of circulating granulocytes and monocytes were analyzed in 11 RA patients treated with MTX, 13 RA patients without disease-modifying antirheumatic drug treatment (0DMARD), and 13 healthy controls (HC). Peripheral blood samples were collected before and 7 days after vaccination. In addition, the MTX group was sampled before initiating treatment. Frequencies of granulocyte and monocyte subsets were determined using flow cytometry. Serotype-specific IgG were quantified using a multiplex bead assay, pre- and 4-6 weeks after vaccination. At baseline, no differences in granulocyte and monocyte frequencies were observed between the groups. Within the MTX group, the frequency of basophils increased during treatment and was higher compared to the HC and 0DMARD groups at the prevaccination time point. MTX patients were categorized into responders and nonresponders according to the antibody response. Before initiation of MTX, there were no differences in granulocyte and monocyte frequencies between the two subgroups. However, following 6-12 weeks of MTX treatment, both the frequency and concentration of monocytes were lower in PCV nonresponders compared to responders, and the difference in monocyte frequency remained after vaccination. In conclusion, the suppressive effect of MTX on monocyte concentration and frequency could act as a biomarker to identify nonresponders to PCV vaccination.
30.	Erdbrugger, U, et al. (author) Mapping of myeloperoxidase epitopes recognized by MPO-ANCA using human-mouse MPO chimers 2006 In: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 69:10, s. 1799-1805 Journal article (peer-reviewed)abstract Myeloperoxidase ( MPO) is one of the major target antigens of antineutrophil cytoplasmic autoantibodies ( ANCA) found in patients with small-vessel vasculitis and pauci-immune necrotizing glomerulonephritis. To date, the target epitopes of MPO-ANCA remain poorly defined. Human MPO-ANCA do not typically bind mouse MPO. We utilized the differences between human and mouse MPO to identify the target regions of MPO-ANCA. We generated five chimeric MPO molecules in which we replaced different segments of the human or mouse molecules with their homologous counterpart from the other species. Of serum samples from 28 patients screened for this study, 43 samples from 14 patients with MPO-ANCA-associated vasculitis were tested against recombinant human and mouse MPO and the panel of chimeric molecules. Sera from 64 and 71% of patients bound to the carboxy-terminus of the heavy chain, in the regions of amino acids 517-667 or 668-745, respectively. No patient serum bound the MPO light chain or the amino-terminus of the heavy chain. All sera bound to only one or two regions of MPO. Although the pattern of MPO-ANCA binding changed over time ( 4-27 months) in 6 of 10 patients with several serum samples, such changes were infrequent. Other target regions of MPO-ANCA may not have been detected due to conformational differences between the native and recombinant forms of MPO. MPO-ANCA do not target a single epitope, but rather a small number of regions of MPO, primarily in the carboxy-terminus of the heavy chain.
31.	Garwicz, Daniel, et al. (author) Characterization of the processing and granular targeting of human proteinase 3 after transfection to the rat RBL or the murine 32D leukemic cell lines. 1997 In: J Leukoc Biol. - 0741-5400. ; 61:1, s. 113-123 Journal article (peer-reviewed)
32.	Gummesson, Christina, et al. (author) A Centre for Teaching and Learning ”Moving in from the Margins” 2017 In: ; , s. 1-77 Conference paper (peer-reviewed)abstract Background: Faculty development roles are changing within organizations (Gibbs 2013). In previous research the expanding role in organizations as “Coming in from the margins” was described (Schroeder 2011). We studied how different levels of participation evolved within a research intense faculty with a complex organization and various educational programs.Summary of Work: The Centre was established in 1982 in a medical school and re-established 2006 to also support health sciences education. The Faculty’s mission included mainly courses and teacher support whereas the Center’s vision was to interact at all levels in the organization and to establish Scholarship of Teaching and Learning.Summary of Results: The Centre has continued to give courses and workshops but has also established itself in a new role: it is represented in the education board and in all curriculum and assessment committees; the number of conference presentations and published articles has increased and authors include Centre staff and teaching faculty.Discussion: The emerging position of the Centre has given opportunities to support development at different system levels based on educational theory and evidence. Courses and workshops are used to increase the Centre’s credibility and to network through contacts with teachers has been important in establishing the new role.Conclusion: The competence of the staff at the Centre has been a key in the development. Staff with diverse expert educational competence as well as experienced teachers from the faculty has been recruited. Small grants have enabled research, often in collaboration with teachers, to be published and presented at conferences.Take-home Message: A clear vision and alignedstrategies to guide the development was important. Strategies included networking opportunities and competence development within the Centre. Shared experiences with staff such as projects and conferences created opportunities to build trust and collaboration. Faculty leaders were key players and change of leaders can impede development.4A2
33.	Gunnarsson, Andreas, et al. (author) Molecular properties of the Goodpasture epitope 2000 In: Journal of Biological Chemistry. - 1083-351X. ; 275:40, s. 30844-30848 Journal article (peer-reviewed)abstract Goodpasture disease fulfils all criteria for a classical autoimmune disease, where autoantibodies targeted against the non-collagenous domain of the alpha3-chain of collagen IV initiates an inflammatory destruction of the basement membrane in kidney glomeruli and lung alveoli. This leads to a rapidly progressive glomerulonephritis and severe pulmonary hemorrhage. Previous studies have indicated a limited epitope for the toxic antibodies in the N-terminal part of the non-collagenous domain. The epitope has been partially characterized by recreating the epitope in the non-reactive alpha1-chain by exchanging nine residues to the corresponding ones of alpha3. In this study we have investigated to what extent each of these amino acids contribute to the antibody binding in different patient sera. The results show that seven of the nine substitutions are enough to get an epitope that is recognized equally well as the native alpha3-chain by all sera from 20 clinically verified Goodpasture patients. Furthermore, the patient sera reactivity against the different recombinant chains used in the study are very similar, with some minor exceptions, strongly supporting a highly defined and restricted epitope. We are convinced that the restriction of the epitope is of significant importance for the understanding of the etiology of the disease. Thereby also making every step on the way to characterization of the epitope a crucial step on the way to specific therapy for the disease.
34.	Hellmark, Thomas, et al. (author) Anti-GBM antibodies in Goodpasture syndrome; anatomy of an epitope 1997 In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 12:4, s. 646-648 Journal article (peer-reviewed)
35.	Hellmark, Thomas, et al. (author) Autoantibodies against components of renal basement membrane 1997 In: Advances in nephrology from the Necker Hospital. - 0084-5957. ; 26, s. 291-302 Journal article (peer-reviewed)
36.	Hellmark, Thomas, et al. (author) Biomedicinsk utbildning vid Medicinska fakulteten, Lunds universitet. Utbildning och arbetsliv – en alumnundersökning 2010 Reports (other academic/artistic)abstract Strax under 100 alumner som avslutat biomedicinsk utbildning vid Lunds universitet mellan 2005-vt 2007 har tillfrågats om utbildningens mål och arbetsmarknad. Svarsfrekvensen är 67%. Frågorna har ställts till biomedicinare som varit ute på arbetsmarknaden några år. Syftet är att utnyttja alumnernas erfarenheter för att få kunskap om utbildningen och krav i yrkeslivet särskilt med inriktning mot de allmänna målen för grundläggande högskoleutbildning. Alumnerna bedömer i hög utsträckning att de mål som framgår av Högskolelagen uppnåtts. Undantag är beredskap att möta förändringar i arbetslivet som enligt svaren tränats i mindre omfattning under utbildningen än övriga färdigheter. Cirka 70% av respondenterna är nöjda med sitt val av utbildning. Intresset för forskarutbildning är stort och den vanligaste sysselsättningen är också att vara doktorand. Graden av sysselsättning är hög även om någon anser sig arbeta inom områden som inte kräver biomedicinsk examen. 80% av respondenterna har arbeten inom det biomedicinska området. Då är doktoranderna inkluderade. Alumnerna anger den starka forskningsinriktningen, de problembaserade studieupplägget och bra föreläsare som styrkor i utbildningen. Svagheter som anges är bristen på laborativ träning och svag kontakt med och ställning på arbetsmarknaden. Arbetsmarknadsanknytningen har förbättrats sedan respondenterna gick utbildningen. Bland annat har kurser i professionell utveckling lagts in som en röd tråd genom utbildningen. En särskild enkät med fokus på arbetsmarknad har gått ut till samtliga biomedicinare som disputerat vid Lunds universitet före ht 2009. Även några som disputerat vid annat universitet har fått enkäten. Sammanlagt har 70 doktorer tillfrågats. Svarsfrekvens är 87%. Disputerade biomedicinare har arbete. Bland de 50 biomedicinare som disputerat före 2009 har 49 arbeten. De flesta inom akademin. 15% av de disputerade biomedicinarna har dock en period av sammanhängande arbetslöshet bakom sig. Arbetsmarknaden för biomedicinare från Lund, oavsett om de har utbildning på grund- och anvancerad nivå eller forskarnivå, tycks vara bättre än sitt rykte.
37.	Hellmark, Thomas, et al. (author) Characterization of anti-GBM antibodies involved in Goodpasture's syndrome 1994 In: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 46:3, s. 823-829 Journal article (peer-reviewed)abstract Characterization of anti-GBM antibodies involved in Goodpasture's syndrome. Goodpasture's syndrome is a life threatening autoimmune kidney disease. The patients have autoantibodies to the glomerular basement membrane, which are specific for the C-terminal domain of type IV collagen (NC1). The major antigen has been localized to the alpha3(IV)-chain. We have investigated sera from 44 patients with anti-NC1 antibodies. The quantity of antibodies to four different alpha(IV)-chains of type IV collagen was measured with direct ELISA. We used affinity chromatography to separate the antibodies and their specificities were studied with ELISA. The results show that about 1% of the patients total IgG are anti-NC1 antibodies and that 90% of these antibodies are specific for the alpha3(IV)-chain. Antibodies to the other alpha(IV)-chains were found in 80% of the patients. Furthermore, affinity purified anti-alpha3(IV) antibodies from one patient were inhibited by antibodies from the other patients, from 4 to 72%. The antibodies, from 39 of the patients, were inhibited by a monoclonal antibody against the alpha3(IV)-chain. The results indicate that patients with Goodpasture's syndrome can have antibodies to most of the alpha(IV)-chains, while the majority of anti-NC1 antibodies are restricted to the alpha3(IV)-chain. Moreover the number of epitopes seems to be limited and the majority of the antibodies from most patients are against one single epitope on the alpha3(IV)-chain.
38.	Hellmark, Thomas, et al. (author) Comparison of anti-GBM antibodies in sera with or without ANCA 1997 In: Journal of the American Society of Nephrology. - 1046-6673. ; 8:3, s. 376-385 Journal article (peer-reviewed)abstract An appreciable percentage of patients with serum anti-glomerular basement membrane (anti-GBM) antibodies also have antineutrophil cytoplasmic antibodies (ANCA), against either myeloperoxidase (MPO-ANCA), or proteinase 3 (PR3-ANCA). In sera without ANCA, the anti-GBM antibodies have been shown to react mainly with the noncollagenous domain (NC1) of Type IV collagen, and especially with its alpha 3 chain, alpha 3(IV)NC1. In most sera, the antibodies can be partially blocked by a monoclonal antibody (Mab17) against alpha 3(IV)NC1, suggesting that a limited region is recognized. Although there is evidence that some anti-GBM antibodies that coexist with ANCA react with alpha 3(IV)NC1, extensive analysis of the specificity of such anti-GBM antibodies has not been reported. In the study presented here, sera were analyzed from 332 patients tested both for anti-GBM antibodies and ANCA (MPO or PR3-ANCA) and found to have one or more positive tests. Of the 100 sera with anti-GBM antibodies, 38 also had ANCA-25 with MPO-ANCA (66%), 12 with PR3-ANCA (32%), and one with both (2%). Of the 232 sera with ANCA only, 153 had MPO-ANCA (66%), 75 had PR3-ANCA (32%), and four had both (2%). Sera was also analyzed from 259 other patients who had positive ANCA tests and were not tested for anti-GBM antibodies: 138 had MPO-ANCA (54%), and 121 had PR3-ANCA (46%). The relative frequencies of MPO or PR3-ANCA in patients with coexisting anti-GBM antibodies did not differ significantly from those in all patients with ANCA (P = 0.35). Seventeen sera with anti-GBM antibodies only and 16 sera with anti-GBM antibodies plus ANCA were selected for further studies to compare the specificity of anti-GBM antibodies in sera with or without ANCA. Using enzyme-linked immunosorbent assays (ELISA), all sera in both groups were found to react with the NC1 domain (as a hexamer) of bovine Type IV collagen and with alpha 3 (IV)NC1 monomers. Furthermore, all but six sera also reacted with one or more of the alpha 1, 2, and 4 (IV)NC1 monomers, generally with considerably lower titers. Reactivity to alpha 3(IV)NC1 was partially blocked by Mab17, with comparable degrees of inhibition in both groups. Western blot analysis with the human NC1 domains revealed no differences in reactivity between the two groups. Thus, differences in antigen specificities of anti-GBM antibodies in sera with or without ANCA were not detected. The anti-GBM response in both situations is hypothesized to be driven by the same immunogen, which is probably derived from NC1 domains of endogenous Type IV collagen.
39.	Hellmark, Thomas, et al. (author) Diagnosis and classification of Goodpastures disease (anti-GBM) 2014 In: Journal of Autoimmunity. - : Elsevier. - 0896-8411 .- 1095-9157. ; 48-49, s. 108-112 Journal article (peer-reviewed)abstract Goodpastures disease or anti-glomerular basement membrane disease (anti-GBM-disease) is included among immune complex small vessel vasculitides. The definition of anti-GBM disease is a vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM auto-antibodies. The disease is a prototype of autoimmune disease, where the patients develop auto-antibodies that bind to the basement membranes and activate the classical pathway of the complement system, which start a neutrophil dependent inflammation. The diagnosis of anti-GBM disease relies on the detection of anti-GBM antibodies in conjunction with glomerulonephritis and/or alveolitis. Overt clinical symptoms are most prominent in the glomeruli where the inflammation usually results in a severe rapidly progressive glomerulonephritis. Despite modern treatment less than one third of the patients survive with a preserved kidney function after 6 months follow-up. Frequencies vary from 0.5 to 1 cases per million inhabitants per year and there is a strong genetic linkage to HLA-DRB11501 and DRB11502. Essentially, anti-GBM disease is now a preferred term for what was earlier called Goodpastures syndrome or Goodpastures disease; anti-GBM disease is now classified as small vessel vasculitis caused by in situ immune complex formation; the diagnosis relies on the detection of anti-GBM in tissues or circulation in conjunction with alveolar or glomerular disease; therapy is effective only when detected at an early stage, making a high degree of awareness necessary to find these rare cases; 20-35% have anti-GBM and MPO-ANCA simultaneously, which necessitates testing for anti-GBM whenever acute test for ANCA is ordered in patients with renal disease.
40.	Hellmark, Thomas, et al. (author) Eosinophils in anti-neutrophil cytoplasmic antibody associated vasculitis 2019 In: BMC Rheumatology. - : Springer Science and Business Media LLC. - 2520-1026. ; 3:9 Journal article (peer-reviewed)abstract Background: Anti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) are characterized by autoimmune small vessel inflammation. Eosinophils are multifunctional cells with both pro-inflammatory and immunoregulatory properties. Tissue activated eosinophils secrete cyto- and chemokines and form extracellular traps (EETs), they release free granules and produce reactive oxygen species. The role of eosinophils is well established in eosinophilic granulomatosis with polyangiitis (EGPA) but very little is known about their role in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).Methods: The expression of surface markers CD11c, CD11b, CD16, CD35, CD62L, CD64, CD88, Siglec-8 and CD193 and reactive oxygen species production by peripheral blood eosinophils were studied using flow cytometry. Fluorescence microscopy was used to visualize the release of eosinophil extracellular DNA traps (EETs). 98 GPA and MPA patients and 121 healthy controls were included in the study.Results: Both GPA and MPA patients had decreased frequency of eosinophils in peripheral blood compared with healthy controls (p < 0.0001), which could not solely be explained by corticosteroid treatment. The patient's eosinophils showed increased surface expression of the Fc receptors CD16 (p < 0.0001) and CD64 (p = 0.0035) as well as CCR3 (CD193) (p = 0.0022). Decreased expression was found of the complement receptors CD35 (p = 0.0022), CD88 (p < 0,0001) as well as CD11c (p < 0,0001), CD11b (p = 0.0061) and Siglec-8 (p = 0,0015). Moreover, GPA and MPA eosinophils, showed decreased capacity to produce ROS (p < 0.0001). ANCA stimulation of eosinophils from GPA and MPA patients after C5a priming enhanced EETosis (p = 0,0088).Conclusions: The percentage of eosinophils were decreased in peripheral blood in GPA and MPA patients and showed altered surface marker expression and function. The enhanced EETosis after ANCA stimulation, suggests that eosinophil can contribute to the autoantibody driven inflammatory process.
41.	Hellmark, Thomas, et al. (author) Epitope mapping of anti-glomerular basement membrane (GBM) antibodies with synthetic peptides 1996 In: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 105:3, s. 504-510 Journal article (peer-reviewed)abstract Autoantibodies to the non-collagenous (NC1) domain of the alpha 3(IV)-chain of type IV collagen are found in sera from patients with anti-GBM nephritis. These antibodies have been shown to be pathogenic. In this study the antibody specificity has been investigated in patients with Goodpasture's syndrome and from a patient with atypical anti-GBM antibodies, recognizing the alpha 1(IV)-chain only. Overlapping synthetic peptides, covering the complete NC1 domains of the alpha 1(IV)- and alpha 3(IV)-chains were used in sandwich ELISA and competitive ELISA. None of the Goodpasture sera showed reactivity to the synthetic peptides. However, antibodies from the patient with atypical anti-GBM antibodies recognized a 20 amino acid peptide from the alpha 1(IV)-chain. The reactive peptide was further narrowed down with glycine substitution of the different amino acids. We have localized the epitope to the four last C-terminal amino acids of the alpha 1(IV)-chain, with the sequence 1754-MRRT. The two arginine residues were found to be essential for antibody binding. Threonine is important, while methionine is of less importance. These four amino acids are also determined to be the smallest peptide that could inhibit the binding of the autoantibodies to the native alpha 1(IV)-chain. This study shows that overlapping peptides can be used to map linear epitopes. However, for conformational epitopes such as the Goodpasture epitope, other methods must be used. It would be prognostically important to know the fine specificity of anti-GBM antibodies, since the patient with anti-alpha 1(IV) antibodies had a mild disease, while the Goodpasture patients with anti-alpha 3(IV) antibodies had a rapidly progressive disease.
42.	Hellmark, Thomas, et al. (author) Glomerular basement membrane autoantibodies 2007 In: Autoantibodies. - 9780444527639 ; , s. 553-559 Book chapter (peer-reviewed)abstract Anti-glomerular basement membrane (anti-GBM) disease is a prototype of autoimmune disease. The disease can be transferred with the antibodies and there is a strong correlation with certain human leukocyte antigen (HLA) genes. The pathogenic epitope on the NC1 domain of the 3-chain of type IV collagen is well characterized and only antibodies against this epitope correlate with disease. The diagnosis is made on the combination of rapidly progressive renal failure and the demonstration of anti-GBM antibodies. The course is sometimes complicated by severe lung haemorrhage, and untreated anti-GBM disease has a poor prognosis. Early diagnosis and treatment with immunosuppression and plasma exchange leads to improved prognosis. Because of its clinical significance and high predictive value, anti-GBM antibody analysis is indicated in most cases of unknown renal failure with microhaematuria, especially if progression is rapid. Circulating anti-GBM antibodies can be detected with indirect immunofluorescence (IF) or enzyme-linked immunosorbent assay (ELISA). In indirect IF, serum from the patient is overlaid with a section of normal kidney. A good substrate and a good pathologist are needed because unspecific staining can be difficult to distinguish from the true linear staining pattern. Low levels of circulating autoantibodies cannot usually be detected with indirect IF. There are several ELISA kits available on the market. The performances of these assays depend on the purity of the antigen preparation, but are generally good.
43.	Hellmark, Thomas, et al. (author) Goodpasture disease. Characterization of a single conformational epitope as the target of pathogenic autoantibodies 1999 In: Journal of Biological Chemistry. - 1083-351X. ; 274:36, s. 25862-25868 Journal article (peer-reviewed)abstract Goodpasture disease is a prototype autoimmune disease characterized by the formation of autoantibodies against the heterotrimeric basement membrane collagen type IV, which causes a rapidly progressive glomerulonephritis. The pathogenic antibody response is directed to the non-collagenous (NC1) domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1), but not to the homologous region of the alpha1(IV)NC1. To identify the conformation-dependent immunodominant epitope on the alpha3(IV)NC1, a variety of recombinant NC1 domains were constructed by replacing single residues of alpha3(IV) with the corresponding amino acids from the nonreactive alpha1(IV) chain. Replacement mutations were identified that completely destroyed the Goodpasture epitope in the alpha3(IV) chain. Based on the identification of these critical positions, the epitope was finally reconstructed within the frame of the alpha1(IV) chain. The substitution of nine discontinuous positions in the alpha1(IV)NC1 with amino acid residues from the alpha3 chain resulted in a recombinant construct that was recognized by all patients' sera (n = 20) but by none of the sera from healthy controls (n = 10). This provides, for the first time, the molecular characterization of a single immunodominant conformational epitope recognized by pathogenic autoantibodies in a human autoimmune disease, representing the basis for the development of new epitope-specific strategies in the treatment of Goodpasture disease.
44.	Hellmark, Thomas, et al. (author) Identification of a clinically relevant immunodominant region of collagen IV in Goodpasture disease 1999 In: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 55:3, s. 936-944 Journal article (peer-reviewed)abstract BACKGROUND: The characteristic feature of Goodpasture disease is the occurrence of an autoantibody response to the noncollagenous domain of the alpha3 chain of type IV collagen [alpha3(IV)NC1] in the alveolar and glomerular basement membrane. These antibodies are associated with the development of a rapidly progressive glomerulonephritis, with or without lung hemorrhage, whereas autoantibodies specific for the other alpha chains of the heterotrimeric type IV collagen probably do not cause disease. In this study, we have investigated whether differences in fine specificity of autoimmune recognition of the alpha3(IV)NC1 correlate with clinical outcome. METHODS: For mapping of antibody binding to type IV collagen, chimeric collagen constructs were generated in which parts of the alpha3(IV)NC1 domain were replaced by the corresponding sequences of homologous nonreactive alpha1(IV). The different recombinant collagen chimeras allowed the analysis of antibody specificities in 77 sera from well-documented patients. RESULTS: One construct that harbors the aminoterminal third of the alpha3(IV)NC1 was recognized by all sera, indicating that it represents the dominant target of the B-cell response in Goodpasture disease. Seventy percent of the samples recognized other parts of the molecule as well. However, only reactivity to the N-terminus of the alpha3(IV)NC1 correlated with prognosis, that is, kidney survival after six months of follow-up. CONCLUSION: The results indicate the crucial importance of antibody recognition of this particular domain for the pathogenesis of Goodpasture disease, thereby opening new avenues for the development of better diagnostic and therapeutic procedures.
45.	Hellmark, Thomas (author) Molecular dissection of the Goodpasture epitope 1999 Doctoral thesis (other academic/artistic)abstract Goodpasture disease is a prototype autoimmune disease that is characterized by a rapidly progressive glomerulonephritis, with or without lung haemorrhage, associated with autoantibodies against the glomerular basement membrane. The major antigen has previously been shown to be the non-collagenous domain of the a3 chain of type IV collagen, one of the six known a chains of type IV collagen. On average, one percent of the total IgG fraction from the patients is comprised of anti-type IV collagen autoantibodies. Ninety percent of these antibodies are a3(IV)-specific and the remaining ten percent are low-affinity antibodies, showing cross-reactivity with the other a(IV) chains. Furthermore, the epitope specificity seems to be limited, as shown by monoclonal antibody inhibition. To test the hypothesis that only antibodies against certain epitopes are nephrotoxic, clinical and serological data from 77 anti-GBM positive patients were retrieved. The results showed that the anti-a3(IV) titre, and especially the antibodies that can be blocked using a monoclonal antibody, correlated with the outcome, in terms of kidney survival. Thus, the study strongly indicates the pathogenic role of the circulating autoantibodies. Epitope mapping of the anti-GBM antibodies has been done using overlapping synthetic peptides. The epitope specificity of the autoantibodies from one patient with anti-a1(IV) antibodies was revealed, and reactivity in ELISA was successfully blocked using a four-amino-acid-long peptide from the a1(IV) sequence. The same approach did not show any reactivity with the anti-a3(IV) autoantibodies. By using recombinant antigens expressed in a human cell line as chimeric proteins, where the a3(IV) sequence was exchanged for the corresponding sequence from the a1(IV) chain, we could show that only autoantibodies against the N-terminal third of the a3(IV) chain correlated with disease. The reactive sequence was further narrowed down to nine discontinuous amino acid residues. A chimeric protein comprised of a1(IV), but with these nine positions expressed as a3(IV), bound the toxic autoantibodies with approximately the same affinity as native a3(IV). These studies provide evidence that only autoantibodies against a very limited region of the a3(IV) chain carry a toxic potential. Furthermore, epitope spreading is relatively limited, thus indicating a possibility for new forms of therapy, including epitope immunomodulatory treatment. In the future, therapy might be adjusted for each individual patient, on the basis of diagnostic tests, e.g., regarding the fine specificity and titre of the autoantibodies, thereby minimising unnecessary discomfort caused by the side effects of immunosuppressive treatment.
46.	Hellmark, Thomas, et al. (author) Point mutations of single amino acids abolish ability of alpha(3) NC1 domain to elicit experimental autoimmune glomerulonephritis in rats 2003 In: Journal of Biological Chemistry. - 1083-351X. ; 278:47, s. 46516-46522 Journal article (peer-reviewed)abstract We previously showed concordance between Goodpasture syndrome antibody binding and production of experimental glomerulonephritis using human chimeric proteins. We now examine a more limited aminoterminal region of alpha(3)( IV) non- collagenous domain ( NC1) and the impact of single amino acid ( AA) mutations of this region on glomerulonephritis induction. Rats were immunized with collagenase- solubilized glomerular basement membrane ( csGBM), D3, an alpha(1)( IV) NC1 chimeric protein with 69 AA of alpha(3)( IV) NC1 ( binds Goodpasture sera), D4, the D3 construct shortened by 4 AA ( nonbinding), P9, P10, single AA mutants ( non- binding), and S2, alpha(1)( IV) NC1 with 9 AA of alpha(3)( IV) NC1 ( binding). All rats immunized with csGBM and S2 and 50% of D3 rats developed glomerulonephritis. csGBM rats had intense GBM- bound IgG deposits, but S2 and D3 rats had minimal deposits. None of the D4, P9, or P10 rats developed glomerulonephritis. Lymphocytes from nephritic rats proliferated with csGBM, S2, and D3, but not with D4, P9, or P10. Discrete segments of alpha(3)( IV) NC1 within the alpha(1)( IV) NC1 backbone can induce glomerulonephritis. Single AA mutations within that epitope render the antigen unresponsive to Goodpasture sera and incapable of inducing glomerulonephritis. These studies support the concordance of glomerulonephritis inductivity and Goodpasture serum binding. Further, they define a critical limited AA sequence within alpha(3)( IV) NC1 of nine or fewer AA, which confers nephritogenicity to the non-nephritogenic alpha(1)( IV) NC1 without in vivo antibody binding. This region may be a T- cell epitope responsible for induction of glomerulonephritis in this model in rats and Goodpasture syndrome in man.
47.	Ishchuk, Olena, 1980, et al. (author) RNAi as a Tool to Study Virulence in the Pathogenic Yeast Candida glabrata 2019 In: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 10 Journal article (peer-reviewed)abstract The yeast Candida glabrata is a major opportunistic pathogen causing mucosal and systemic infections in humans. Systemic infections caused by this yeast have high mortality rates and are difficult to treat due to this yeast's intrinsic and frequently adapting antifungal resistance. To understand and treat C. glabrata infections, it is essential to investigate the molecular basis of C. glabrata virulence and resistance. We established an RNA interference (RNAi) system in C. glabrata by expressing the Dicer and Argonaute genes from Saccharomyces castellii (a budding yeast with natural RNAi). Our experiments with reporter genes and putative virulence genes showed that the introduction of RNAi resulted in 30 and 70% gene-knockdown for the construct-types antisense and hairpin, respectively. The resulting C. glabrata RNAi strain was used for the screening of a gene library for new virulence-related genes. Phenotypic profiling with a high-resolution quantification of growth identified genes involved in the maintenance of cell integrity, antifungal drugs, and ROS resistance. The genes identified by this approach are promising targets for the treatment of C. glabrata infections.
48.	Johansson, Charlott, et al. (author) Anti-type IV collagen antibodies in Goodpasture syndrome 1994 In: Contributions to Nephrology. - 0302-5144. ; 107, s. 188-193 Journal article (peer-reviewed)
49.	Johansson, Åsa Cm, et al. (author) Impaired phagocytosis and reactive oxygen species production in phagocytes is associated with systemic vasculitis 2016 In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 18 Journal article (peer-reviewed)abstract BACKGROUND: Anti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) is a group of autoimmune diseases, characterized by small vessel inflammation. Phagocytes such as neutrophils and monocytes are the main effector cells found around the inflamed vessel wall. Therefore, we wanted to investigate aspects of function and activation of these cells in patients with AAV.METHODS: Flow cytometry was used to evaluate: the expression of activation markers (CD11c, CD62L, CD177 and C5aR); the number of recently released neutrophils from bone marrow, defined as CD10(-)D16(low) cells in peripheral blood; and the capacity of peripheral blood monocytes and polymorphonuclear leukocytes (PMN) to produce reactive oxygen species and to phagocytose opsonized bacteria.RESULTS: AAV patients (n = 104) showed an increase of CD10(-)CD16(low) neutrophils and total PMN in peripheral blood, suggesting a combination of increased bone marrow release and prolonged survival. An increased percentage of AAV PMN expressed CD177 but no other signs of activation were seen. A decreased production of reactive oxygen species was observed in AAV phagocytes, which was associated with disease activity. Moreover, granulocytes from patients with microscopic polyangiitis showed lower oxidative burst capacity compared to patients with granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis. In addition, decreased phagocytosis capacity was seen in PMN and monocytes.CONCLUSION: Our results indicate that phagocytes from AAV patients have impaired function, are easily mobilized from bone marrow but are not particularly activated. The association between low reactive oxygen species formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor.
50.	Jönsson, Anneli, et al. (author) Causes of nephrotic syndrome in Sweden: The relevance of clinical presentation and demographics 2023 In: Frontiers in Nephrology. - : Frontiers Media SA. - 2813-0626. ; 3, s. 1-9 Journal article (peer-reviewed)abstract Background: Many pathological processes can disrupt the integrity of the glomerular capillary wall and cause a massive leakage of protein, resulting in nephrotic syndrome (NS). Clinical parameters such as age, sex, renal function, presence of diabetes, and how NS is defined influence the spectrum of underlying diseases. In this study, we examine how these parameters interact.Methods: Age, sex, hematuria, proteinuria, plasma creatinine plasma albumin levels, and final diagnosis were retrieved for all adult patients with NS as an indication for biopsy and/or massive albuminuria in conjunction with low plasma albumin from the biopsy module of the Swedish Renal Registry (SRR) between 2014 and 2019. A basic calculator was developed to demonstrate the importance of clinical presentation in relation to the likelihood of having a specific diagnosis.Results: A total of 913 unique patients were included in the study. Diabetic nephropathy (DN) and membranous nephropathy (MN) (both found in 17% of patients) were the most common diagnoses. With a stringent definition of NS, MN and minimal change nephropathy (MCN) increased in proportion. Among the cohort as a whole, MCN was the most frequent diagnosis in women and those < 50 years of age (found in 21% and 17%, respectively). In the case of patients aged between 50 and 70 years, those with chronic kidney disease stage 4, and those with negative dipstick tests for hematuria, the most common underlying disease was DN (in 23%, 30%, and 21% of cases, respectively). Among those with high-grade hematuria (dipstick grade 3 or 4), membranoproliferative glomerulonephritis was the most common diagnosis (14%), closely followed by IgA nephropathy (13%). Focal segmental glomerulosclerosis (9.7%) was less common than in many comparable studies.Conclusion: Clinical parameters have a profound impact on the likelihood of different diagnoses in adult patients with NS. Differences in clinical practice and study inclusion criteria may be more important than genetic background and environmental factors when explaining differences between studies in different parts of the world

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