Miller MJ, Price C, Shields TC, Zarpak R, Lee P, et al.
Systematic reviews •
Tick bites may expose individuals to a carbohydrate not found in humans, galactose-alpha-1,3-galactose (alpha-gal). A spectrum of disorders may result from IgE-mediated hypersensitivity reactions to alpha-gal, including alpha-gal syndrome (AGS), an allergy to meat or meat-derived products usually presenting 2-6 h after consuming the product plus positive alpha-gal specific IgE testing for the oligosaccharide. Reports of anaphylaxis in group O recipients of group B plasma in the absence of other risk factors for severe allergic reactions to blood transfusion could be alpha-gal sensitization; the allergen galactose-alpha-1,3-galactose (Gal-alpha-1-3Galβ1-(3)4GlcNAc-R) is antigenically similar to the B blood group antigen (Gal-alpha-1-3(Fuc-alpha-1,2)Gal). The potential cross-reactivity of alpha-gal specific IgE to B type red blood cells may pose a safety consideration for blood donation and transfusion. This scoping review protocol will be used to research all publications on alpha-gal sensitization to (1) describe characteristics of all known cases of transfusion-related alpha-Gal syndrome (TRAGS) and hypersensitivity reactions to infusions of mammalian red meat-derived medical products besides blood components that may resemble TRAGS; (2) identify studies that explore possible relationships between alpha-gal sensitization and blood group that may be relevant to understanding TRAGS; (3) describe which clinical, laboratory, and epidemiologic parameters used to diagnose AGS food allergy are also appropriate to diagnose TRAGS; and (4) identify which diagnostic assays exist for AGS and how they are used for AGS and/or TRAGS. Using peer-reviewed search strategies, our study team will perform a scoping review with no date or language limit of all literature relevant to the research objectives in PubMed, Scopus, Embase, Web of Science, and Cochrane Central Register of Controlled Trials, including title, abstract, full-text screening, and data collection using Covidence. This study involves published data predominantly from humans (and, rarely, animal) studies of diagnostic assays in development for use in humans. It does not require institutional review board or ethics approval. We intend to disseminate our findings to specialists in allergy, immunology, hematology, and blood banking and to patients or blood donors experiencing symptoms of alpha-gal sensitization. Open Science Framework (osf.io) (DOI: https://doi.org/10.17605/OSF.IO/WDZT6 ).
Miller MJ, Zarpak R, Lee P, Osterwind Z, Lenz M, et al.
Journal of translational medicine •
BACKGROUND: Tick bites may expose individuals to a carbohydrate not found in humans, galactose-alpha-1,3-galactose (alpha-gal), including allergy to mammalian red meat or red meat-derived products presenting 2–6 hours after consuming the product plus positive alpha-gal specific IgE testing that may indicate alpha-gal syndrome (AGS). Anaphylaxis in group O recipients of group B blood products in the absence of other risk factors for allergic transfusion reactions could be transfusion-related alpha-gal syndrome (TRAGS); galactose-alpha-1,3-galactose (Gal-alpha1-3 Galβ1-(3)4GlcNAc-R) is similar to the B blood group antigen (Gal-alpha1-3(Fuc-alpha-1,2)Gal). OBJECTIVES: To review scientific and grey literature with no date or language limit to: 1) describe characteristics of all known cases of transfusion-related alpha-gal syndrome (TRAGS) and hypersensitivity reactions to infusions of mammalian red meat-derived medical products besides blood components that may resemble TRAGS; 2) identify studies that explore possible relationships between alpha-gal sensitization and blood group that may be relevant to understanding TRAGS; 3) describe which clinical, laboratory, and epidemiologic parameters used to diagnose AGS food allergy are also appropriate to diagnose TRAGS; and 4) identify which diagnostic assays exist for AGS and how they are used for AGS and/or TRAGS. METHODS: Using search strategies peer-reviewed by biomedical librarians we performed a scoping review of literature in five medical databases, charted in Microsoft Excel and Covidence software. RESULTS: Of 11732 studies imported for screening, 3858 duplicates were removed and 7874 papers were screened. Title and abstract screening excluded 7383 papers. Full-text screening excluded 380 papers. Of the included papers, 20/111 (18%) addressed risk for alpha-gal allergy by blood group and 18/111 diagnostics (16%). CONCLUSION: A comprehensive literature review showed a possible association between alpha-gal allergy and blood group. Further guidance is needed regarding potential clinical implications.
The journal of allergy and clinical immunology. In practice •
The severity of anaphylaxis is determined by many factors. The allergenic source as well as the age of the affected individual and the route of allergen exposure encompass the major contributors of the clinical outcome. Moreover, the severity can be modulated further by intrinsic and extrinsic factors. Among these, the genetic predisposition, certain comorbidities such as uncontrolled asthma, and hormonal fluctuations have been proposed as intrinsic and antihypertensive medications or physical activity as extrinsic factors. Recent advances have highlighted immunologic pathways that may exacerbate the response to allergens through receptors on mast cells, basophils, platelets, and other granulocytes. Atopy, platelet-activating factor acetylhydrolase deficiency, hereditary alpha tryptasemia, and clonal mast cell disorders are examples associated with genetic alterations that may predispose to severe anaphylaxis. Identifying risk factors that lower the threshold of reactivity or increase the severity of multisystem reactions is important in the management of this patient population.
The journal of allergy and clinical immunology. In practice •
Insect sting anaphylaxis and mast cell disorders are intertwined in a specific and unusual way. There may be specific subsets of clonal mast cell disorders that are predisposed to sting anaphylaxis. The clinical characteristics of the sting reactions should raise suspicion of underlying mastocytosis (eg, hypotension without hives especially in a male). A baseline serum tryptase level is helpful in the evaluation of patients with insect sting anaphylaxis because it correlates with important risks for these patients, and they have a high frequency of abnormally elevated baseline levels. Elevated baseline serum tryptase level has been reported to correlate with clonal mast cell disease in patients with insect sting anaphylaxis but may also indicate one of several possible underlying syndromes, including mast cell activation syndrome (MCAS), familial hypertryptasemia, and idiopathic anaphylaxis. There is some overlap in these conditions, so it is important to evaluate the clinical pattern at presentation as well as laboratory markers, and to consider bone marrow biopsy to make a final and specific diagnosis of clonal mast cell disease. The presence of venom-IgE does not prove that the patient's previous sting reactions were IgE-mediated, but even low levels of venom-IgE in patients with mastocytosis predispose to severe sting anaphylaxis. Evaluation of all these possible factors will affect the recommendation for venom immunotherapy.
Luke T, Bennett RS, Gerhardt DM, Burdette T, Postnikova E, et al.
The Journal of infectious diseases •
Transchromosomic bovines (Tc-bovines) adaptively produce fully human polyclonal immunoglobulin (Ig)G antibodies after exposure to immunogenic antigen(s). The National Interagency Confederation for Biological Research and collaborators rapidly produced and then evaluated anti-Ebola virus IgG immunoglobulins (collectively termed SAB-139) purified from Tc-bovine plasma after sequential hyperimmunization with an Ebola virus Makona isolate glycoprotein nanoparticle vaccine. SAB-139 was characterized by several in vitro production, research, and clinical level assays using wild-type Makona-C05 or recombinant virus/antigens from different Ebola virus variants. SAB-139 potently activates natural killer cells, monocytes, and peripheral blood mononuclear cells and has high-binding avidity demonstrated by surface plasmon resonance. SAB-139 has similar concentrations of galactose-α-1,3-galactose carbohydrates compared with human-derived intravenous Ig, and the IgG1 subclass antibody is predominant. All rhesus macaques infected with Ebola virus/H.sapiens-tc/GIN/2014/Makona-C05 and treated with sufficient SAB-139 at 1 day (n = 6) or 3 days (n = 6) postinfection survived versus 0% of controls. This study demonstrates that Tc-bovines can produce pathogen-specific human Ig to prevent and/or treat patients when an emerging infectious disease either threatens to or becomes an epidemic.
Carter MC, Ruiz-Esteves KN, Workman L, Lieberman P, Platts-Mills TAE, et al.
Allergy •
IgE antibodies (Ab) specific to galactose-α-1,3-galactose (alpha-gal) are responsible for a delayed form of anaphylaxis that occurs 3-6 hours after red meat ingestion. In a unique prospective study of seventy participants referred with a diagnosis of idiopathic anaphylaxis (IA), six (9%) were found to have IgE to alpha-gal. Upon institution of a diet free of red meat, all patients had no further episodes of anaphylaxis. Two of these individuals had indolent systemic mastocytosis (ISM). Those with ISM had more severe clinical reactions but lower specific IgE to alpha-gal and higher serum tryptase levels, reflective of the mast cell burden. The identification of alpha-gal syndrome in patients with IA supports the need for routine screening for this sensitivity as a cause of anaphylaxis, where reactions to alpha-gal are delayed and thus may be overlooked.
Whole-cell cancer vaccines are a promising strategy for treating cancer, but the characteristics of a favorable immune response are not fully understood. New insights could enable development of better vaccines, discovery of new antigens, and identification of biomarkers of efficacy. Using glyco-antigen microarrays, we demonstrate that GVAX Pancreas (a granulocyte macrophage colony-stimulating factor-modified whole-cell tumor vaccine) induces large immunoglobulin G and immunoglobulin M responses to many antigens, including tumor-associated carbohydrates, blood group antigens, α-Gal, and bovine fetuin. Antibody responses to α-Gal, a glycan found in fetal bovine serum (FBS) used to produce the vaccine, correlated inversely with overall survival and appear to compete with productive responses to the vaccine. H1299 lysate vaccine, produced with FBS, also induced responses to α-Gal and fetuin but not K562-GM, which is produced in serum-free medium. Our results provide new potential biomarkers to evaluate productive/unproductive immune responses and suggest that removal/reduction of FBS could improve the efficacy of whole-cell vaccines.
Yilmaz B, Portugal S, Tran TM, Gozzelino R, Ramos S, et al.
Cell •
Glycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the UDP-galactose:β-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galβ1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans.
Yoshida Y, Yang J, Peaker PE, Kato H, Bush CA, et al.
The Journal of biological chemistry •
The coaggregation receptor polysaccharides (RPS) of Streptococcus oralis and related species are recognized by lectin-like adhesins on other members of the oral biofilm community and by RPS-specific antibodies. The former interactions involve beta-GalNAc or beta-Gal containing host-like motifs in the oligosaccharide repeating units of these polysaccharides, whereas the latter involves features of these molecules that are immunogenic. In the present investigation, the molecular and corresponding structural basis for the serotype specificity of S. oralis ATCC 10557 RPS was determined by engineering the production of this polysaccharide in transformable Streptococcus gordonii 38. This involved the systematic replacement of genes in the rps cluster of strain 38 with different but related genes from S. oralis 10557 and structural characterization of the resulting polysaccharides. The results identify four unique genes in the rps cluster of strain 10557. These include wefI for an alpha-Gal transferase, wefJ for a GalNAc-1-phosphotransferase that has a unique acceptor specificity, wefK for an acetyl transferase that acts at two positions in the hexasaccharide repeating unit, and a novel wzy associated with the beta1-3 linkage between these units. The serotype specificity of engineered polysaccharides correlated with the wefI-dependent presence of alpha-Gal in these molecules rather than with partial O-acetylation or with the linkage between repeating units. The findings illustrate a direct approach for defining the molecular basis of polysaccharide structure and antigenicity.
We had shown previously that all major glycoproteins of pigeon egg white contain Galalpha1-4Gal epitopes (Suzuki, N., Khoo, K. H., Chen, H. C., Johnson, J. R., and Lee, Y. C. (2001) J. Biol. Chem. 276, 23221-23229). We now report that Galalpha1-4Gal-bearing glycoproteins are also present in pigeon serum, lymphocytes, and liver, as probed by Western blot with Griffonia simplicifolia-I lectin (specific for terminal alpha-Gal) and anti-P1 (specific for Galalpha1-4Galbeta1-4GlcNAcbeta1-) monoclonal antibody. One of the major glycoproteins from pigeon plasma was identified as IgG (also known as IgY), which has Galalpha1-4Gal in its heavy chains. High pressure liquid chromatography, mass spectrometric (MS), and MS/MS analyses revealed that N-glycans of pigeon serum IgG included (i) high mannose-type (33.3%), (ii) disialylated biantennary complex-type (19.2%), and (iii) alpha-galactosylated complex-type N-glycans (47.5%). Bi- and tri-antennary oligosaccharides with bisecting GlcNAc and alpha1-6 Fuc on the Asn-linked GlcNAc were abundant among N-glycans possessing terminal Galalpha1-4Gal sequences. Moreover, MS/MS analysis identified Galalpha1-4Galbeta1-4Galbeta1-4GlcNAc branch terminals, which are not found in pigeon egg white glycoproteins. An additional interesting aspect is that about two-thirds of high mannose-type N-glycans from pigeon IgG were monoglucosylated. Comparison of the N-glycan structures with chicken and quail IgG indicated that the presence of high mannose-type oligosaccharides may be a characteristic of these avian IgG.
Ovotransferrin (POT), two ovalbumins (POA(hi) and POA(lo)), and ovomucoid (POM) were isolated from pigeon egg white (PEW). Unlike their chicken egg white counterparts, PEW glycoproteins contain terminal Galalpha1-4Gal, as evidenced by GS-I lectin (specific for terminal alpha-Gal), anti-P(1) (Galalpha1-4Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glcbeta1-1Cer) monoclonal antibody, and P fimbriae on uropathogenic Escherichia coli (specific for Galalpha1-4Gal). Galalpha1-4Gal on PEW glycoproteins were found in N-glycans releasable by treatment with glycoamidase F. The respective contents of N-glycans in each glycoprotein were 3.5%, POT; 17%, POA(hi); and 31-37%, POM. POA(hi) has four N-glycosylation sites, in contrast to chicken ovalbumin, which has only one. High performance liquid chromatography analysis showed that N-glycans on POA(hi) were highly heterogeneous. Mass spectrometric analysis revealed that the major N-glycans were monosialylated tri-, tetra-, and penta-antennary oligosaccharides containing terminal Galalpha1-4Gal with or without bisecting N-acetylglucosamine. Oligosaccharide chains terminating in Galalpha1-4Gal are rare among N-glycans from the mammals and avians that have been studied, and our finding is the first predominant presence of (Galalpha1-4Gal)-terminated N-glycans.
The teratocarcinoma-derived F9 cells respond to retinoic acid (RA) and RA plus dibutyrylcyclic adenosine monophosphate (dcAMP) by differentiating into endoderm cells, which elaborate a laminin and type IV collagen-rich matrix. We found that the induction of differentiation is accompanied by a small but consistent increase in cell adhesiveness to a variety of substrates, including laminin. Therefore we investigated biochemical mechanisms involved in this phenomenon. Endoglycosidase treatment showed that laminin contains complex and hybrid oligosaccharide structures. RA enhanced general biosynthesis of laminin without a specific increase in galactose incorporation: this sugar was mainly in polylactosamine structures in the A chain of laminin and as terminal galactose alpha 1,3 galactose in the B chain. Laminin receptor analysis showed that RA decreased laminin binding protein-37 (LBP-37) but increased the amount of beta 1 integrin, suggesting the involvement of beta 1 integrin in the attachment process. Northern blot analysis showed increased expression of retinoid receptors within hours of RA exposure. These studies demonstrate that RA increases cell to substrate interactions by increasing the biosynthesis of laminin and beta 1 integrin. These effects are most likely subsequent to the RA-induced biosynthesis of the retinoid receptors.
