Immunoglobulin G4: an odd antibody Aalberse, R. C.; Stapel, S. O.; Schuurman, J. ...
Clinical and experimental allergy,
April 2009, Letnik:
39, Številka:
4
Journal Article
Recenzirano
Summary
Despite its well‐known association with IgE‐mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved ...in a continuous process of half‐molecules (i.e. a heavy and attached light‐chain) exchange. This process, also referred to as ‘Fab‐arm exchange’, results usually in asymmetric antibodies with two different antigen‐combining sites. While these antibodies are hetero‐ bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T‐helper type 2 (Th2) cells, the IgG4 response is largely restricted to non‐microbial antigens. This Th2‐dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE‐mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen‐blocking effect at the mast cell level and/or at the level of the antigen‐presenting cell (preventing IgE‐facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL‐10 and other anti‐inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non‐activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti‐inflammatory cytokines triggering an overwhelming expansion of IgG4‐producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen‐specific IgG4 indicates that anti‐inflammatory, tolerance‐inducing mechanisms have been activated. The existence of the IgG4 subclass, its up‐regulation by anti‐inflammatory factors and its own anti‐inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.
Background
Replacement of peanut extracts by recombinant peanut components is an important step in allergy serologic testing. Criteria are needed for the unbiased inclusion of patients into a study ...to validate such a replacement.
Methods
Plasma samples from 64 peanut‐positive children (42 reactors, 22 nonreactors in a double‐blind, placebo‐controlled food challenge) were used to compare IgE reactivity to six recombinant peanut allergens with reactivity to natural peanut proteins extracted at neutral or low pH. We tested the hypothesis that poor extractability of Ara h 9 and other basic allergens at neutral pH leads to under‐representation of patients with such sensitization.
Results
IgE reactivity to the components did not fully explain IgE reactivity to peanut extract in 5 of 32 reactors with IgE to peanut extract ≤100 kUA/l. IgE reactivity to components was stronger than to the extract in 11 plasma samples, which was largely due to a low Ara h 8 reactivity of the extract. IgE reactivity to Ara h 9 was much lower than reactivity to other basic proteins, some of which bound IgE well in the RAST, but lost IgE reactivity upon immunoblotting.
Conclusions
Conventional peanut extracts are deficient in significant IgE‐binding components. The inclusion of patients for a validation study should be based on serology performed with improved peanut reagents to avoid a bias against these under‐represented, potentially important allergens. To judge clinical relevance of an allergen, the reagent used for inclusion of patients needs to be efficient in detecting IgE to this component.
Structural biology of allergens Aalberse, Rob C.
Journal of allergy and clinical immunology,
08/2000, Letnik:
106, Številka:
2
Journal Article
Recenzirano
One of the major challenges of molecular allergy is to predict the allergenic potential of a protein, particularly in novel foods. Two aspects have to be distinguished: immunogenicity and ...cross-reactivity. Immunogenicity reflects the potential of a protein to induce IgE antibodies, whereas cross-reactivity is the reactivity of (usually preexisting) IgE antibodies with the target protein. In addition to these two issues, the relation between IgE-binding potential and clinical symptoms is of interest. This is influenced by physical properties (eg, stability and size) and immunologic properties (affinity and epitope valence). Discussions on immunogenicity and cross-reactivity of allergens rely on the establishment of structural similarities and differences among allergens and between allergens and nonallergens. For comparisons between the 3-dimensional protein folds, the representation as 2-dimensional proximity plots provides a convenient visual aid. Analysis of approximately 40 allergenic proteins (or parts of these proteins), of which the protein folds are either known or can be predicted on the basis of homology, indicates that most of these can be classified into 4 structural families: (1) antiparallel β-strands: the immunoglobulin-fold family (grass group 2, mite group 2), serine proteases (mite group 3, 6, and 9), and soybean-type trypsin inhibitor (Ole e 1, grass group 11); (2) antiparallel β-sheets intimately associated with one or more α-helices: tree group 1, lipocalin, profilin, aspartate protease (cockroach group 2); (3) (α+β) structures, in which the α- and β-structural elements are not intimately associated: mite group 1, lysozyme/lactalbumin, vespid group 5; and (4) α-helical: nonspecific lipid transfer protein, seed 2S protein, insect hemoglobin, fish parvalbumin, pollen calmodulin, mellitin from bee venom, Fel d 1 chain 1, serum albumin. Allergens with parallel β-strands (in combination with an α-helix linking the two strands, a motif commonly found in, for example, nucleotide-binding proteins) seem to be underrepresented. The conclusion is that allergens have no characteristic structural features other than that they need to be able to reach (and stimulate) immune cells and mast cells. Within this constraint, any antigen may be allergenic, particularly if it avoids activation of TH2-suppressive mechanisms (CD8 cells and TH1 cells). (J Allergy Clin Immunol 2000;106:228-38.)
IgE‐binding epitopes: a reappraisal Aalberse, R. C.; Crameri, R.
Allergy (Copenhagen),
October 2011, Letnik:
66, Številka:
10
Journal Article
Recenzirano
Odprti dostop
To cite this article: Aalberse RC, Crameri R. IgE‐binding epitopes: a reappraisal. Allergy 2011; 66: 1261–1274.
Here, we discuss various questions related to IgE epitopes: What are the technical ...possibilities and pitfalls, what is currently known, how can we put this information into hypothetical frameworks and the unavoidable question: how useful is this information for patient care or allergenicity prediction? We discuss the information obtained by (i) 3D structures of allergen–antibody complexes; (ii) analysis of allergen analogues; (iii) mimics without obvious structural similarity; (iv) mAbs competing with IgE; (v) repertoire analysis of cloned IgEs, and other developments. Based on limited data, four suggestions are presented in the literature: (i) IgE might be more cross‐reactive than IgG; (ii) IgE might be more often directed to immunologically ‘uninviting’ surfaces; (iii) IgE epitopes may tend to cluster and (iv) IgE paratopes might have a higher intrinsic flexibility. While these are not proven facts, they still can generate hypotheses for future research. The hypothesis is put forward that the IgE repertoire of switched B‐cells is less influenced by positive selection, because positive selection might not be able to rescue IgE‐switched B cells. While this might be of interest for the discussion about mechanisms leading to allergen‐sensitization, we need to be modest in answering the ‘clinical relevance’ question. Current evidence indicates the IgE‐epitope repertoire is too big to make specific IgE epitopes a realistic target for diagnosis, treatment or allergenicity prediction. In‐depth analysis of a few selected IgE epitope‐peptides or mimitopes derived from allergen‐sequences and from random peptide libraries, respectively, might well prove rewarding in relation to diagnosis and prognosis of allergy, particularly food allergy.
T regulatory cells and IL-10 have been implicated in the mechanism of immunotherapy in patients with systemic anaphylaxis following bee stings. We studied the role of IL-10 in the induction of ...clinical, cellular, and humoral tolerance during immunotherapy for local mucosal allergy in subjects with seasonal pollinosis. Local and systemic IL-10 responses and serum Ab concentrations were measured before/after a double-blind trial of grass pollen (Phleum pratense, Phl P) immunotherapy. We observed local increases in IL-10 mRNA-positive cells in the nasal mucosa after 2 years of immunotherapy, but only during the pollen season. IL-10 protein-positive cells were also increased and correlated with IL-10 mRNA(+) cells. These changes were not observed in placebo-treated subjects or in healthy controls. Fifteen and 35% of IL-10 mRNA signals were colocalized to CD3(+) T cells and CD68(+) macrophages, respectively, whereas only 1-2% of total CD3(+) cells and 4% of macrophages expressed IL-10. Following immunotherapy, peripheral T cells cultured in the presence of grass pollen extract also produced IL-10. Immunotherapy resulted in blunting of seasonal increases in serum allergen Phl p 5-specific IgE, 60- to 80-fold increases in Phl p 5-specific IgG, and 100-fold increases in Phl p 5-specific IgG4. Post-immunotherapy serum exhibited inhibitory activity, which coeluted with IgG4, and blocked IgE-facilitated binding of allergen-IgE complexes to B cells. Both the increases in IgG and the IgG "blocking" activity correlated with the patients' overall assessment of improvement. Thus, grass pollen immunotherapy may induce allergen-specific, IL-10-dependent "protective" IgG4 responses.
EAACI Molecular Allergology User's Guide Matricardi, P. M.; Kleine-Tebbe, J.; Hoffmann, H. J. ...
Pediatric allergy and immunology,
20/May , Letnik:
27, Številka:
S23
Journal Article
Recenzirano
Odprti dostop
The availability of allergen molecules (‘components’) from several protein families has advanced our understanding of immunoglobulin E (IgE)‐mediated responses and enabled ‘component‐resolved ...diagnosis’ (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology User's Guide (MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low‐abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross‐reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE‐mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross‐reactive panallergens from plant (lipid transfer proteins, polcalcins, PR‐10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE‐mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients.
IgG4 breaking the rules Aalberse, Rob C.; Schuurman, Janine
Immunology,
January 2002, 2002-Jan, 2002-01-00, 20020101, Letnik:
105, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Summary
Immunoglobulin G4 (IgG4) antibodies have been known for some time to be functionally monovalent. Recently, the structural basis for this monovalency has been elucidated: the in vivo exchange ...of IgG half‐molecules (one H‐plus one L‐chain) among IgG4. This process results in bispecific antibodies that in most situations will behave as functionally monovalent antibodies. The structural basis for the abnormal behaviour of IgG4 seems to be largely the result of a single amino acid change relative to human IgG1: the change of a proline in core hinge of IgG1 to serine. This results in a marked shift in the equilibrium between interchain disulphide bridges and intrachain disulphide bridges, which for IgG4 results in 25–75% absence of a covalent interaction between the H‐chains. Because of strong non‐covalent interactions between the CH3 domains (and possibly also between the CH1 domain and the trans‐CH2 domain) IgG4 is a stable four‐chain molecule and does not easily exchange half‐molecules under standard physiological conditions in vitro. We postulate that the exchange is catalysed in vivo by protein disulphide isomerase (PDI) and/or FcRn (the major histocompatibility complex (MHC)‐related Fc receptor) during transit of IgG4 in the endosomal pathway in endothelial cells. Because IgG4 is predominantly expressed under conditions of chronic antigen exposure, the biological relevance of this exchange of half‐molecules is that it generates antibodies that are unable to form large immune complexes and therefore have a low potential for inducing immune inflammation. In contrast to monovalent immunoglobulin fragments, these scrambled immunoglobulins have a normal half‐life. The significance of the ensuing bispecificity needs further evaluation, because this will be relevant only in situations where high IgG4 responses are found to two unrelated antigens that happen to be present in the body at the same time and place. In this context the significance of IgG4 autoreactivity might have to be re‐evaluated. The main function of IgG4, however, is presumably to interfere with immune inflammation induced by complement‐fixing antibodies, or, in the case of helminth infection or allergy, by IgE antibodies.
The cross‐reactivity of IgE antibodies is of interest for various reasons, three of which are discussed. Firstly, from the clinical view, it is important to know the patterns of cross‐reactivity, ...because they often (but not always) reflect the pattern of clinical sensitivities. We discuss the cross‐reactivities associated with sensitization to pollen and vegetable foods: PR‐10 (Bet v 1‐related), profilin, the cross‐reactive carbohydrate determinant (CCD), the recently described isoflavone reductase, and the (still elusive) mugwort allergen that is associated with celery anaphylaxis; cross‐reactivities between allergens from invertebrates, particularly tropomyosin, paramyosin, and glutathione S‐transferase (GST); and latex‐associated cross‐reactivities. Clustering cross‐reactive allergens may simplify diagnostic procedures and therapeutic regimens. Secondly, IgE cross‐reactivity is of interest for its immunologic basis, particularly in relation to the regulation of allergic sensitization: are IgE antibodies to allergens more often cross‐reactive than IgG antibodies to “normal” antigens? If so, why? For this discussion, it is relevant to compare not only the structural relation between the two allergens in question, but also the relatedness to the human equivalent (if any) and how the latter influences the immune repertoire. Thirdly, prediction of IgE cross‐reactivity is of interest in relation to allergic reactivity to novel foods. Cross‐reactivity is a property defined by individual antibodies to individual allergens. Quantitative information (including relative affinity) is required on cross‐reactivity in the allergic population and with specific allergens (rather than with whole extracts). Such information is still scarce, but with the increasing availability of purified (usually recombinant) allergens, such quantitative information will soon start to accumulate. It is expected that similarity in short stretches of the linear amino‐acid sequence is unlikely to result in relevant cross‐reactivity between two proteins unless there is similarity in the protein fold.
Until recently, glycan epitopes have not been documented by the WHO/IUIS Allergen Nomenclature Sub‐Committee. This was in part due to scarce or incomplete information on these oligosaccharides, but ...also due to the widely held opinion that IgE to these epitopes had little or no relevance to allergic symptoms. Most IgE‐binding glycans recognized up to 2008 were considered to be “classical” cross‐reactive carbohydrate determinants (CCD) that occur in insects, some helminths and throughout the plant kingdom. Since 2008, the prevailing opinion on lack of clinical relevance of IgE‐binding glycans has been subject to a reevaluation. This was because IgE specific for the mammalian disaccharide galactose‐alpha‐1,3‐galactose (alpha‐gal) was identified as a cause of delayed anaphylaxis to mammalian meat in the United States, an observation that has been confirmed by allergists in many parts of the world. Several experimental studies have shown that oligosaccharides with one or more terminal alpha‐gal epitopes can be attached as a hapten to many different mammalian proteins or lipids. The classical CCDs also behave like haptens since they can be expressed on proteins from multiple species. This is the explanation for extensive in vitro cross‐reactivity related to CCDs. Because of these developments, the Allergen Nomenclature Sub‐Committee recently decided to include glycans as potentially allergenic epitopes in an adjunct section of its website (www.allergen.org). In this article, the features of the main glycan groups known to be involved in IgE recognition are revisited, and their characteristic structural, functional, and clinical features are discussed.
IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological ...appearance; and—often but not always—elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4–7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4+ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.
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