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  • 1. Agianian, Bogos
    et al.
    Lesch, Christine
    Loseva, Olga
    Dushay, Mitchell S.
    Södertörn University, School of Life Sciences. Uppsala University.
    Preliminary characterization of hemolymph coagulation in Anopheles gambiae larvae2007In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 31, no 9, p. 879-888Article in journal (Refereed)
    Abstract [en]

    Hemolymph coagulation is a first response to injury, impeding infection, and ending bleeding. Little is known about its molecular basis in insects, but clotting factors have been identified in the fruit fly Drosophila melanogaster. Here, we have begun to study coagulation in the aquatic larvae of the malaria vector mosquito Anopheles gambiae using methods developed for Drosophila. A delicate clot was seen by light microscopy, and pullout and proteomic analysis identified phenoloxidase and apolipophorin-I as major candidate clotting factors. Electron microscopic analysis confirmed clot formation and revealed it contains fine molecular sheets, most likely a result of lipophorin assembly. Phenoloxidase appears to be more critical in clot formation in Anopheles than in Drosophila. The Anopheles larval clot thus differs in formation, structure, and composition from the clot in Drosophila, confirming the need to study coagulation in different insect species to learn more about its evolution and adaptation to different lifestyles.

  • 2. Backhed, F
    et al.
    Normark, S
    Schweda, Elke K H
    Södertörn University, Avdelning Naturvetenskap.
    Oscarson, S
    Richter-Dahlfors, A
    Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications2003In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 5, no 12, p. 1057-1063Article in journal (Refereed)
    Abstract [en]

    Cells of the mucosal lining are the first to encounter invading bacteria during infection, and as such, they have developed numerous ways of detecting microbial intruders. Recently, we showed that epithelial cells recognize lipopolysaccharide (LPS) through the CD14-Toll-like receptor (TLR)-4 complex. Here, we identify the substructures of LPS that are recognized by the TLR4 receptor complex. In contrast to lipid A, the O-antigen does not mediate an inflammatory response; rather it interferes with the lipid A recognition. An Escherichia coli strain genetically modified to express penta-acylated lipid A not only showed reduced immunogenicity, but was also found to inhibit proinflammatory signalling induced by wild-type E. coli (hexa-acylated lipid A) as well as LPS from other bacteria of the Enterobacteriaceae family. Furthermore, penta-acylated LPS from Pseudomonas aeruginosa acted as an antagonist to hexa-acylated E. coli LPS, as did E. coli, as shown by its inhibitory effect on IL-8 production in stimulated cells. Hypo-acylated lipidA, such as that of P. aeruginosa, is found in several species within the gut microflora as well as in several bacteria causing chronic infections. Thus, our results suggest that the composition of the microflora may be important in modulating pro-inflammatory signalling in epithelial cells under normal as well as pathologic conditions.

  • 3. Balogun, H. A.
    et al.
    Vasconcelos, N. -M
    Lindberg, Robert
    Södertörn University, School of Life Sciences.
    Haeggström, M.
    Moll, K.
    Chen, Q.
    Wahlgren, M.
    Berzins, K.
    Immunogenicity and antigenic properties of Pf332-C231, a fragment of a non-repeat region of the Plasmodium falciparum antigen Pf3322009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, no 1, p. 90-97Article in journal (Refereed)
    Abstract [en]

    Antigen Pf332, a megadalton protein has been shown to be associated with the membrane of infected erythrocytes Detailed functional studies on the antigen have remained hampered by the cross-reactive nature of antibodies generated to Pf332 PB32-C231, identified in the C-terminal region of Pf332 was cloned and antibodies against the C231 fragment were shown to react with intact Pf332 antigen by both immunofluorescence and immunoblotting analyses Antibodies to C231 inhibited in vitro Plasmodium falciparum growth efficiently In addition. human sera from malaria-exposed individuals reacted with recombinant C231 We show that Pf332-C231 represents a functional domain and is expected to facilitate further studies on Pf332 as a potential target for protective immune responses and the function of the antigen.

  • 4.
    Bidla, Gawa
    et al.
    Stockolms universitet.
    Lindgren, Malin
    Södertörn University, School of Life Sciences.
    Theopold, Ulrich
    Stockholms universitet.
    Dushay, Mitchell S.
    Södertörn University, School of Life Sciences.
    Hemolymph coagulation and phenoloxidase in Drosophila larvae2005In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 29, no 8, p. 669-679Article in journal (Refereed)
    Abstract [en]

    Hemolymph coagulation is a first response to wounding in insects. Although studies have been performed in large-bodied insects such as the moth Galleria mellonella, less is known about clotting in Drosophila melanogaster, the insect most useful for genetic and molecular analyses of innate immunity. Here we show the similarities between clots in Drosophila and Galleria by light- and electron microscopy. Phenoloxidase changes the Drosophila clot's physical properties through cross-linking and melanization, but it is not necessary for preliminary soft clot formation. Bacteria associate with the clot, but this alone does not necessarily kill them. The stage is now set for rapid advances in our understanding of insect hemolymph coagulation, its roles in immune defense and wound healing, and for a more comprehensive grasp of the insect immune system in general.

  • 5. Brenden, N.
    et al.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Differential MHC expression requirements for positive selection of separate TCR Vb families1999In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 49, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Positive selection has been proposed to be involved in protection from diabetes. We examined positive selection by fluorescence-activated cell sorter analyses in thymocytes of protected and susceptible E-transgenic and non-transgenic NOD mice. Three Vb families showed positive selection in E-transgenic mice. Vb6+CD4+ and Vb10+CD4+ thymocytes were found at higher frequencies in both protected NOD-Ea and susceptible NOD-DY mice. The increased frequencies of Vb13+CD8+ thymocytes were found in protected NOD-Ea mice only, and not in susceptible NOD-DY transgenic mice. These three Vb families were further examined in bone-marrow chimeras between NOD-Ea and non-transgenic NOD mice, where we could examine the contribution of E-expressing bone-marrow-derived cells in positive selection. We find that NOD-Ea→NOD-Ea chimeras have an increased positive selection of Vb13+CD8+ cells and that positive selection is more efficient when both thymic epithelium and bone-marrow-derived cells express the E molecule. This was also seen for Vb6+CD4+ cells. However, for Vb6, bone-marrow-derived cells alone were also capable of positive selection. Positive selection of Vb10+CD4+ cells was restricted to E-expressing thymic epithelium only. For Vb13+CD8+ cells, we found that positive selection is most efficient with E-expression on both thymic epithelium and bone-marrow-derived cells, although positive selection also occurs with E-positive epithelium only. For Vb6+CD4+ cells, the dominating selecting cells are bone-marrow-derived cells, and Vb10+CD4+ cells seem to be selected exclusively by the thymic epithelium. Thus, the conditions for positive selection seem to vary considerably between different Vb families.

  • 6. Brenden, N.
    et al.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Disease-protected major histocompatibility complex Ea-transgenic non- obese diabetic (NOD) mice show interleukin-4 production not seen in susceptible Ea-transgenic and non-transgenic NOD mice1998In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 95, no 1, p. 1-7Article in journal (Refereed)
    Abstract [en]

    The non-obese diabetic (NOD) mouse is an animal model for insulin- dependent diabetes that has many similarities to the human disease. NOD mice transgenic for the Ea gene, allowing expression of the E molecule, are protected from diabetes and rarely develop insulitis. An Ea transgene mutated in the promoter region, (ΔY) lacks E expression on most B cells, thymic medullary epithelium and primary antigen-presenting cells, and confers no protection whatsoever. We have used these transgenic NOD mice, together with non-transgenic NOD mice, to study the correlation of E expression and production of interleukin-4 (IL-4) and interferon-γ (IFN-γ). We show that protected E-transgenic NOD mice have elevated levels of IL-4 compared with non-transgenic mice, both in the thymus and in the periphery. However, susceptible ΔY-transgenic mice have elevated thymic IL-4 levels, but express almost as little IL-4 as non-transgenic NOD mice in the periphery. This drop in peripheral IL-4 production seen in ΔY-transgenic mice thus correlates with the decreased E expression in the periphery of ΔY-transgenic NOD mice. In contrast, there were no differences in IFN-γ production between the three NOD lines. We suggest that Ea-transgenic NOD mice have E-selected regulatory T cells producing IL-4, which are subsequently activated by E-expressing primary antigen-presenting cells in the periphery. This activation would then be instrumental for the E-mediated protection from disease in NOD mice. Such a process would explain the total absence of protection in ΔY-transgenic NOD mice, despite their widespread E expression.

  • 7. Fox, Kate L.
    et al.
    Li, Jianjun
    Schweda, Elke K. H.
    Södertörn University, School of Life Sciences.
    Vitiazeva, Arvara
    Makepeace, Katherine
    Jennings, Michael P.
    Moxon, E. Richard
    Hood, Derek W.
    Duplicate copies of lic1 direct the addition of multiple phosphocholine residues in the lipopolysaccharide of Haemophilus influenzae2008In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 2, p. 588-600Article in journal (Refereed)
    Abstract [en]

    The genes of the lic1 operon (lic1A to lic1D) are responsible for incorporation of phosphocholine (PCho) into the lipopolysaccharide (LPS) of Haemophilus influenzae. PCho plays a multifaceted role in the commensal and pathogenic lifestyles of a range of mucosal pathogens, including H. influenzae. Structural studies of the LPS of nontypeable H. influenzae (NTHI) have revealed that PCho can be linked to a hexose on any one of the oligosaccharide chain extensions from the conserved inner core triheptosyl backbone. In a collection of NTHI strains we found several strains in which there were two distinct but variant lic1D DNA sequences, genes predicted to encode the transferase responsible for directing the addition of PCho to LPS. The same isolates were also found to express concomitantly two PCho residues at distinct positions in their LPS. In one such NTHI isolate, isolate 1158, structural analysis of LPS from lic1 mutants confirmed that each of the two copies of lic1D directs the addition of PCho to a distinct location on the LPS. One position for PCho addition is a novel heptose, which is part of the oligosaccharide extension from the proximal heptose of the LPS inner core. Modification of the LPS by addition of two PCho residues resulted in increased binding of C-reactive protein and had consequential effects on the resistance of the organism to the killing effects of normal human serum compared to the effects of glycoforms containing one or no PCho. When bound, C-reactive protein leads to complement-mediated killing, indicating the potential biological significance of multiple PCho residues.

  • 8. Hamsten, C.
    et al.
    Starkhammar, M.
    Tran, T. A. T.
    Johansson, Magnus
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Biology. Örebro University.
    Bengtsson, U.
    Ahlen, G.
    Sallberg, M.
    Gronlund, H.
    van Hage, M.
    Identification of galactose-alpha-1,3-galactose in the gastrointestinal tract of the tick Ixode sricinus; possible relationship with red meat allergy2013In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, no 4, p. 549-552Article in journal (Refereed)
    Abstract [en]

    Patients with IgE antibodies against the carbohydrate epitope galactose--1,3-galactose (-Gal) have reported severe allergic reactions after consumption of red meat. Investigations have revealed associations between IgE to -Gal and tick bites. We provide the first direct evidence that -Gal is present within ticks thus potentially explaining the relationship between tick exposure and sensitization to -Gal, with development of red meat allergy as a secondary phenomena. Serum from Swedish patients with delayed severe reactions to red meat was included in the study. A dose-dependent inhibition of IgE responses to -Gal by the tick Ixodesricinus is demonstrated. Furthermore, using cryostat-cut sections of I.ricinus, we show that both a monoclonal and a polyclonal antibody against -Gal stains the gastrointestinal tract of the tick. The same pattern is seen when staining with patient sera IgE positive to -Gal. These results confirm that the -Gal epitope is present in I.ricinus and imply host exposure to -Gal during a tick bite. This provides further evidence that tick bites are associated with IgE responses to -Gal and red meat allergy.

  • 9.
    Havervall, Carolina
    Södertörn University College, School of Life Sciences.
    CXCL13: A Prognostic Marker in Multiple Sclerosis2010Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    In the demyelinating autoimmune disease multiple sclerosis (MS) there is a great need for validated prognostic biomarkers that can give information about both prognosis and disease course. So far only clinical parameters have been shown to predict future outcome. CXCL13 is a potent B cell chemoattractant that has been suggested to be a potential biomarker candidate. The aim of this study was to investigate the usefulness of CXCL13 as a prognostic biomarker for MS.

    Clinical, paraclinical, laboratory and MRI data about a large group of MS patients and controls were collected. CXCL13 levels in cerebrospinal fluid (CSF) samples from these patients were determined by standard enzymelinked immunosorbent assay (ELISA).

    In general CXCL13 were increased in CSF in MS, especially in relapsing-remitting MS during relapses, i.e. with ongoing inflammations in the central nervous system. CXCL13 is a good candidate prognostic marker for MS, since newly diagnosed MS with high CXCL13 levels showed worsened disease course within five years. Most importantly, MS conversion occurred in higher rate in possible MS patients with high concentrations of CXCL13 in CSF, and in a shorter time point. This observation may support an early treatment decision in these patients.

    In conclusion, this study provides support for an association between CXCL13 levels in the CSF and later development of disease severity in MS.

  • 10. Högstrand, K.
    et al.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Gene conversion of major histocompatibility complex genes is associated with CpG-rich regions1999In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 49, no 5, p. 446-455Article in journal (Refereed)
    Abstract [en]

    We examined 32 DNA sequences of mouse and human major histocompatibility complex (MHC) genes believed to have been subjected to gene conversion events. All regions of the mouse H2 genes as well as the human HLA genes which have been implied to be involved in gene conversion events had elevated levels of CpG dinucleotides, whereas the rest of the genes showed extensive CpG suppression. Mouse MHC genes which have been suspected but not directly implied to be involved in gene conversion events also showed elevated levels of CpG dinucleotides. Moreover, both mouse and human MHC genes which have never been suspected of undergoing gene conversion had low levels of CpG throughout the genes. These results indicate that high CpG levels are correlated with gene conversion rather than with polymorphism, as non-polymorphic genes that have been implicated as gene conversion donors also have elevated levels of CpG dimers in the involved regions whereas polymorphic genes which have never been considered to undergo gene conversion events have a low level of CpG dinucleotides. We also studied the methylation pattern of CpG dimers in the Abk gene by restriction enzyme digestion of mouse testis DNA followed by Southern blot and hybridization to an Abk-specific probe. The examined CpG dimers in prepubescent mice, where the latest germline stages are spermatogonia, leptene, or pachytene, are respectively non-methylated. Accordingly, the CpG dimers appear to be non-methylated in germline DNA from the testis of prepubescent mice, where gene conversions have been reported to occur.

  • 11.
    Lesch, Christine
    et al.
    Stockholms universitet.
    Goto, Akira
    UPR9022 du CNRS, IBMC, Strasbourg, France.
    Lindgren, Malin
    Södertörn University, School of Life Sciences.
    Bidla, Gawa
    Stockholms universitet.
    Dushay, Mitchell S.
    Södertörn University, School of Life Sciences. Uppsala University.
    Theopold, Ulrich
    Stockholms universitet.
    A role for Hemolectin in coagulation and immunity in Drosophila melanogaster2007In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 31, no 12, p. 1255-1263Article in journal (Refereed)
    Abstract [en]

    Hemolectin has been identified as a candidate clotting factor in Drosophila. We reassessed the domain structure of Hemolectin (Hml) and propose that instead of C-type lectin domains, the two discoidin domains are most likely responsible for the protein's lectin activity. We also tested Hml's role in coagulation and immunity in Drosophila. Here we describe the isolation of a new hml allele in a forward screen for coagulation mutants, and our characterization of this and two other hml alleles, one of which is a functional null. While loss of Hml had strong effects on larval hemolymph coagulation ex vivo, mutant larvae survived wounding. Drosophila thus possesses redundant hemostatic mechanisms. We also found that loss of Hml in immune-handicapped adults rendered them more sensitive to Gram(-) bacteria infection. This demonstrates an immunological role of this clotting protein and reinforces the importance of the clot in insect immunity.

  • 12. Lundström, Susanna L.
    et al.
    Li, Jianjun
    Månsson, Martin
    Södertörn University, School of Life Sciences.
    Figueira, Marisol
    Leroy, Magali
    Goldstein, Richard
    Hood, Derek W.
    Moxon, E. Richard
    Richards, James C.
    Schweda, Elke K. H.
    Södertörn University, School of Life Sciences.
    Application of capillary electrophoresis mass spectrometry and liquid chromatography multiple-step tandem electrospray mass spectrometry to profile glycoform expression during Haemophilus influenzae pathogenesis in the chinchilla model of experimental otitis media2008In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 7, p. 3255-3267Article in journal (Refereed)
    Abstract [en]

    Otitis media caused by nontypeable Haemophilus influenzae (NTHi) is a common and recurrent bacterial infection of childhood. The structural variability and diversity of H. influenzae lipopolysaccharide (LPS) glycoforms are known to play a significant role in the commensal and disease-causing behavior of this pathogen. In this study, we determined LPS glycoform populations from NTHi strain 1003 during the course of experimental otitis media in the chinchilla model of infection by mass spectrometric techniques. Building on an established structural model of the major LPS glycoforms expressed by this NTHi strain in vitro (M. Mansson, W. Hood, J. Li, J. C. Richards, E. R. Moxon, and E. K. Schweda, Eur. J. Biochem. 269:808-818, 2002), minor isomeric glycoform populations were determined by liquid chromatography multiple-step tandem electrospray mass spectrometry (LC-ESI-MSn). Using capillary electrophoresis ESI-MS (CE-ESI-MS), we determined glycoform profiles for bacteria from direct middle ear fluid (MEF) samples. The LPS glycan profiles were essentially the same when the MEF samples of 7 of 10 animals were passaged on solid medium (chocolate agar). LC-ESI-MSn provided a sensitive method for determining the isomeric distribution of LPS glycoforms in MEF and passaged specimens. To investigate changes in LPS glycoform distribution during the course of infection, MEF samples were analyzed at 2, 5, and 9 days postinfection by CE-ESI-MS following minimal passage on chocolate agar. As previously observed, sialic acid-containing glycoforms were detected during the early stages of infection, but a trend toward more-truncated and less-complex LPS glycoforms that lacked sialic acid was found as disease progressed.

  • 13. Rietz, C.
    et al.
    Pilström, B.
    Brenden, N.
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap. Karolinska Institute.
    Minute defects in the expression of MHC E molecules lead to impaired protection from autoimmunity in NOD mice1999In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 50, no 4, p. 405-410Article in journal (Refereed)
    Abstract [en]

    The E complex of the major histocompatibility complex (MHC) can prevent the spontaneous development of diabetes in nonobese diabetic (NOD) mice transgenic for the Ea gene. None of three promoter-mutated Ea constructs with Ea expression directed to different subsets of immunocompetent cells exerts full protection in NOD mice. The promoter-mutated constructs are all capable of mediating intrathymic elimination of I-E-restricted T cells. Thus, thymic negative selection is not responsible for the protective effect but a more complex effect is likely. Here we show that combinations of two or three different mutated Ea constructs do not protect against intra-islet insulitis either. We also show that spleen cells from protected animals are sufficient to protect NOD mice in adoptive transfer experiments. The only detectable expression defects in splenic cells or cells influencing the repertoire of splenic cells are in the B-cell compartment. Furthermore, in three construct combinations, the differences to wild-type expression are extremely small. Thus, we conclude that even minute disturbances of the E expression pattern might reduce the protection of NOD mice from insulitis.

  • 14. Rietz, C
    et al.
    Screpanti, V
    Brenden, N
    Böhme, Jan
    Södertörn University, Avdelning Naturvetenskap.
    Fernandez, C
    Overexpression of Bcl-2 in T cells affects insulitis in the nonobese diabetic mouse2003In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 57, no 4, p. 342-349Article in journal (Refereed)
    Abstract [en]

    The nonobese diabetic (NOD) mouse is a useful model for human autoimmune diabetes. The gene for the anti-apoptotic protein Bcl-2 has previously been suggested as a probable susceptibility candidate for the NOD mouse disease. In this study, we investigated how overexpression of Bcl-2 in lymphocytes might affect insulitis in NOD mice. A bcl-2 transgene expressed constitutively under the SV40-promoter and the 5'Igh enhancer, Emu, was bred onto NOD background. Two bcl-2 transgenic NOD strains were produced and analysed, one with overexpression of Bcl-2 on only B cells and the other with overexpression of Bcl-2 on both B and T cells. Subsequent to verification of expression pattern and functionality of the transgene, insulitis intensity was investigated in different backcross generations of the two transgenic strains. Overexpression of Bcl-2 on both B and T cells leads to a statistically significant protection of the mice from insulitis compared with normal littermates. Overexpression of Bcl-2 on only B cells, on the other hand, does not have any statistically significant effect on insulitis. Possible mechanisms for the effect of Bcl-2 on insulitis in NOD mice are discussed.

  • 15. Theopold, U
    et al.
    Schmidt, O
    Söderhäll, K
    Dushay, Mitchell S
    Södertörn University, School of Chemistry, Biology, Geography and Environmental Science.
    Coagulation in arthropods: defence, wound closure and healing2004In: Trends in immunology, ISSN 1471-4906, E-ISSN 1471-4981, Vol. 25, no 6, p. 289-294Article in journal (Refereed)
    Abstract [en]

    Arthropods have open circulatory systems and must seal wounds and keep bacteria from entering the hemocoel using efficient clotting systems. Enzymes that crosslink the clot include transglutaminase, which is phylogenetically conserved, and phenoloxidase, which is not found in vertebrates. Prophenoloxidase is usually activated through a proteolytic cascade similar to the vertebrate clotting cascade. The well-characterized clotting cascade in horseshoe crabs is strongly activated by bacterial elicitors, in contrast to vertebrate clotting where induction relies more on endogenous signals. Many arthropod clotting factors are not orthologues of blood clotting factors, but show novel architectures assembled from domains that are also found in their vertebrate counterparts. The cellular mechanisms that lead to coagulation of blood and hemolymph appear to be similar. Recent findings in Drosophila reveal parallels between developmental processes that involve epithelial fusion and wound healing, enabling genetic dissection of the signal pathways involved. This Review is the first in a series on interactions between haemostasis and inflammation.

  • 16. Vilhelmsson, Monica
    et al.
    Glaser, Andreas G.
    Martinez, Daniel Badia
    Schmidt, Margit
    Johansson, Catharina
    Rhyner, Claudio
    Berndt, Kurt D.
    Södertörn University, School of Life Sciences. Karolinska Institutet.
    Scheynius, Annika
    Crameri, Reto
    Achour, Adnane
    Zargari, Arezou
    Mutational analysis of amino acid residues involved in IgE-binding to the Malassezia sympodialis allergen Mala s 112008In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, no 2, p. 294-303Article in journal (Refereed)
    Abstract [en]

    The yeast Malassezia sympodialis, which is an integral part of the normal cutaneous flora, has been shown to elicit specific IgE- and T-cell reactivity in atopic eczema (AE) patients. The M. sympodialis allergen Mala s 11 has a high degree of amino acid sequence homology to manganese superoxide dismutase (MnSOD) from Homo sapiens (50%) and Aspergillus fumigatus (56%). Humoral and cell-mediated cross-reactivity between MnSOD from H. sapiens and A. fumigatus has been demonstrated. Taken together with the recent finding that human MnSOD (hMnSOD) can act as an autoallergen in AE patients sensitised to M. sympodialis, we hypothesized that cross-reactivity could also occur between hMnSOD and Mala s 11, endogenous hMnSOD thus being capable of stimulating an immune response through molecular mimicry. Herein we demonstrate that recombinant Mala s 11 (rMala s 11) is able to inhibit IgE-binding to recombinant hMnSOD and vice versa, indicating that these two homologues share common IgE-binding epitopes and providing an explanation at a molecular level for the autoreactivity to hMnSOD observed in AE patients sensitised to Mala s 11. Using molecular modelling and mapping of identical amino acids exposed on the surface of both Mala s 11 and hMnSCE) we identified four regions each composed of 4-5 residues which are potentially involved in IgE-mediated cross-reactivity. Mutated rMala s 11 molecules were produced in which these residues were altered. Native-like folding was verified by enzymatic activity tests and circular dichroism. The rMala s 11 mutants displayed lower IgE-binding in comparison to wild-type rMala s 11 using plasma from AE patients. In particular, mutation of the residues E29, P30, E122 and K125 lowered the IgE-binding to Mala s 11. The results of this study provide new insights in the molecular basis underlying the cross-reactivity between Mala s 11 and hMnSOD.

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