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Why is alpha-gal clinically relevant and cross reacting carbohydrate determinants not? Thomas AE Platts-Mills FRS Oscar Swineford Jr Professor of Medicine University of Virginia. We are grateful to the NIH for continued generous support including AI-20565-31 (TPM) & K-O8 AI-085190 and R-56 AI113095 (SPC). these studies have also been supported by Phadia Thermo/Fisher in the form of unrestricted support for IgE and IgG4 assays. Introduction and History =Cetuximab induced anaphylaxis and IgE specific for galactose alpha-1, 3-galactose Chung, et al, N Engl J Med, 2008; 358: 1109-1117 =24 cases of delayed anaphylaxis to red meat in patients with IgE to alpha-gal Commins, et al, JACI, 2009; 123: 426-433 =Monitored challenges with red meat demonstrate delay in symptoms and basophil activation. Commins, et al, JACI, 2014; 134 (1): 108-115 =Tick bites are a(or the) major cause of IgE responses to alpha-gal Commins, et al, JACI, 2011, 127: 1286-1293 Delayed Anaphylaxis to Red Meat Masquerading as Idiopathic Anaphylaxis Tripathi et al JACI in practice, 2014; 2: 259-265. 2004,Dr Van Noonen reported cases of meat allergy following tick bites to the Sydney allergy society. 1991, Dr Antony Deutch reported cases of red meat allergy to the Georgia Allergy Society . 2006. Van Hage et al demonstrated that there was an oligosaccharide epitope on Cat IgA, which was subsequently shown to be alpha-gal.. IgE Antibodies Binding to Cetuximab in Serum from 76 Case Subjects and 462 Controls Chung CH et al. N Engl J Med 2008;358:1109-1117 Table 4. IgE antibodies to cetuximab (alpha-gal) as predictors of severe hypersensitivity reactions (SIR) during the first infusion of Cetuximab in all patients (n = 545)† SIR No SIR †Maier, #0.35 <0.10 kUA/l (n=506) 6 500 0.11-0.34 kUA/l (n=18) 1 17 ≥0.35 kUA/l# (n=21) 14 7 Chung, Morse, Platts-Mills et al., Cancer Medicine; 2014 . kUA/l is the cut-off used in the original report (Chung, Mirakhur…and Platts-Mills. Cetuximab-induced anaphylaxis and IgE specific for galactosealpha-1,3-galactose. NEJ Med 2008; 358.1109-1117) Glycosylation of cetuximab as shown in Chung et al ’08 and the true structure of the Fc fragment of IgG * Glycosylation Site Including α-gal and Sialic Acid N-88 Fab N-43 N-299 Glycosylation Site With Human Oligosaccharides Oligosaccharide Fc *Lammerts van Bueren, Rispens….. Platts-Mills, and Parren . IgE antibodies to galactose alpha-1,3galactose do not bind to alpha-galactosylated glycans attached to the Fc domain of intact therapeutic mAbs. Nat Biotechnol 2011. *Roy Jefferis . Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci, 30: 356-6 2 Case report: problems with the “other white meat” • Ms. I.C., age 79 – Non-atopic, employed at UVA for >40 years – Two episodes of hives in May 2012 – June 2012 – ate pork for lunch and 3 hours later began itching, which progressed to hives, shortness of breath, and tongue swelling before she collapsed in the hospital lobby with blood pressure of 60/45 – Received epinephrine, Benadryl, and Solu-Medrol – Admitted overnight – Serum tryptase: 36.5 (normal range <11.5 ng/ml) – IgE to galactose alpha-1,3-galactose 82.5 IU/ml. See Tripathi et al: .JACI In practice, 2014 Exam. five hours after reaction and eight hours after eating pork Further Features of Acute Episodes in Patients with IgE to Galactose-alpha-1,3-galactose Urticaria Only (n=87) Anaphylaxis (n=249) 0 – 2 hours# 18% 20% 2 – 6 hours 61% 68% >6 hours 22% 12% 28% 75% 6:00 – 12:00 4% 19% 12:00 – 18:00 21% 23% 18:00 – 0:00 42% 38% 0:00 – 6:00 21% 33% Variable IV. Time to Reaction V. Received acute/emergency care VI. Timing of individual episodes of care: #Some of this group had reactions involving other antigens, exercise, or alcohol FACS Detection of CD63, a marker of Basophil Activation CD63 -PE Histamine nuclear membrane Basophil activation ex vivo following challenges with pork . Delayed clinical and ex-vivo response to mammalian meat in patients with IgE to galactose alpha-1, 3-galactose. Commins SP, James HR, Pochan S,…, and Platts-Mills. JACI E Pub March 2014 Hypothesis: Alpha-gal may enter the circulation as a glycophospholipid α1,3 α1,3 = = β1,4 β1,4 P Alpha-gal moieties P Galactose N-acetylglucosamine Chylomicron HDL LDL IDL VLDL Absorption of eicosanpentaenoic acid (EPA)* following ingestion of oils derived from algae or krill *EPA is an omega-3 fatty acid that is a carboxylic acid with a 20-carbon aliphatic chain and 5 cis double bonds A Meat Status-time Amino Acids Peptide Carbohydrate Lipid Nucleotide Xenobiotic Total=32 metabolites B alpha-glutamyltryptophan C dodecanedioate A B Mean Decrease in Model Accuracy (6hr) Confusion Matrix for Random Forest Analysis Predicted group: baseline MA Class Error Ctrl 6 2 25% MA 5 3 62.5% Predictive accuracy = 56.25% Predicted group: 6 hour Actual group Ctrl MA Class Error Ctrl 5 3 37.5% amino acid MA 3 5 37.5% carbohydrate Predictive accuracy = 62.5% lipid nucleotide xenobiotics Increasing Importance to Group Separation Actual group Ctrl IgE Antibodies to Oligosaccharides are Well-Recognized as Part of the Human Immune Response Antigen Source Nematodes (Parasite) Schistosomiasis Anisakiasis Ticks (Parasite) Ambylomma americanum (USA) Ixodes ricinus (Europe) Ixodes holocyclus (Australia) Haemaphysalis longicornis (Japan) Alpha-gal* Venoms MMXF3 (CCD) Pollen Allergens* HUXF3 (CCD) Natural Rubber Latex *For both pollen allergens and alpha-gal there is very little evidence for immediate symptoms following natural exposure and many investigators have tried to explain why. Conclusions • Neither CCD nor alpha-gal give rise to immediate symptoms when consumed orally: • ie. No rapid onset of oral or abdominal symptoms: • After eating red meat patients with IgE to alpha-gal may develop delayed urticaria, abdominal pain or frank anaphylaxis. • The only coherent explanation for this phenomenon is that glyco-lipids can be absorbed and can take part in lipid particles such as LDL, and that these particles are responsible for the release of histamine and tryptase at the time of the symptoms. Colleagues: 2006-2015 University of Virginia Scott Commins Alexander Schuyler Peter Heymann Anubha Tripathi Jake Hosen Sharma Satinover Hayley James Lisa Workman Josh Kennedy Elizabeth Erwin/Ohio Matt Perzanowski/Columbia Gus Litonjua, Harvard Diane Gold, Harvard Africa and Europe Eva Ronmark, Sweden Bo Lundback, Sweden Lucy N’Ganga, Kenya Joseph Odiambo, Kenya Adnan Custovic, Manchester Alpha-Gal Research Christine Chung, Nashville Beloo Mirakhur, BMS Qinwei Zhou; ImClone Tina Hatley, Bentonville. Louis Matos. Tilo Biederman And the many other colleagues who have enrolled or referred adult and pediatric . cases with the alpha-gal syndrome. * Connecting the dots: alpha-gal allergy leading to delayed anaphylaxis. Steinke J , Platts-Mills TA & Commins SP *Reindeer are mammals! Structure and Mechanism of an active lipid-linked Oligosaccharide Flippase. In vitro LLO flipping assay. C Perez, Gerber….& Locker. Nature 524: 433, August 2015 Proposed LLO flipping mechanism including five states . Perez et al, Nature 524: 433, August 2015 Delayed Anaphylaxis, Atopic (n=130) 10000 IgE to Alpha-gal, inhalant, food and venom allergens in patients with a history of anaphylaxis IgE Antibodies (IU/mL) 1000 100 10 Delayed Anaphylaxis, Atopic (n=130) 0 12 A lp ha -g al B ee f 1 28 24 54 64 68 76 89 89 78 57 W as p p H on ey be e C om m on Sh rim nu t t Pe a W he a d ra gw ee gr as s in us ot hy Ti m 100 10 1 0 6 B ee f 36 43 115 115 115 112 113 111 104 87 om m W as p H on ey be e p Sh rim nu t Pe a t W he a d on ra gw ee gr as s in us ot hy Ti m on ys s da nd er D .p te r D og 's m ilk 0.1 C ow IgE Antibodies (IU/mL) 1000 A lp ha -g al IgE to galactose alpha-1,3 galactose (alpha-gal) induced by bites of the lone star tick. D .p te r D og C ow 's Delayed Anaphylaxis, Non-atopic (n=115) 10000 Delayed Anaphylaxis, Non-atopic (n=115) : IgE neg to mite, grass and ragweed on ys s da nd er m ilk 0.1 Convergent IgE CDR3 Amino Acid Sequences Table2: Convergent CDR3 Amino Acid Sequences found in Samples A and I cdr3aa cdr3_length isotype AGGISIFGVGSGFGDY 16 IgE AKGISIFGVGSGFGDY 16 IgE ARGIANFGVGSGFGDY 16 IgE ARGILIFGVGSGFGDY 16 IgE ARGIPIFGVGSGFGDY 16 IgE ARGISICGVGSGFGDY 16 IgE ARGISIFEVGSGFGDY 16 IgE ARGISIFGAGSGFGDY 16 IgE ARGISIFGIGSGFGDY 16 IgE ARGISIFGVGGGFGDY 16 IgE ARGISIFGVGIGFGDY 16 IgE ARGISIFGVGRGFGDY 16 IgE ARGISIFGVGSECGDY 16 IgE ARGISIFGVGSEFGDY 16 IgE ARGISIFGVGSGCGDY 16 IgE ARGISIFGVGSGCGYY 16 IgE ARGISIFGVGSGFGAY 16 IgE ARGISIFGVGSGFGDC 16 IgE ARGISIFGVGSGFGDD 16 IgE ARGISIFGVGSGFGDY 16 IgE ARGISIFGVGSGFGEY 16 IgE ARGISIFGVGSGFGGY 16 IgE ARGISIFGVGSGFGND 16 IgE ARGISIFGVGSGFGNY 16 IgE ARGISIFGVGSGLGDY 16 IgE ARGISIFGVGSGSGDY 16 IgE ARGISIFGVGSGSGYY 16 IgE ARGISIFGVGSGVGDY 16 IgE ARGISIFGVGSRFGDY 16 IgE ARGISIFGVSSGFGDY 16 IgE ARGISIFRVGSGFGDY 16 IgE ARGISIFVVGSGFGDY 16 IgE ARGISISGVGSGFGDY 16 IgE ARGISIVGVGSGFGDY 16 IgE ARGISMFGVGSGCGDY 16 IgE ARGISMFGVGSGFGDY 16 IgE ARGISNFGVGSGFGDY 16 IgE ARGISTFGVGSGFGDY 16 IgE ARGIWIFGVGSGFGDY 16 IgE ARGMSIFGVGRGFGDY 16 IgE found_in_sample alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-I,alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A alpha-gal-A Conclusions • Synthesis of glycoprotein and glycolipids in mammals: • Oligosaccharide synthesis occurs in the endoplasmic reticulum and in the Golgi. These are the primary sites for the relevant transferases, including alpha-1,3-galactosyl transferase • There is a specific transfer mechanism for the transfer of oligosaccharides to the “outside” of the cell: Flippases • Thus, there is the potential for the presence of large numbers of mol.ecules such as the blood group substances on the outside of red blood cells Changes Following Red Meat Challenge Circulation: Basophils and Serum Markers N = nucleus (basophils are polymorphonuclear and mast cells are mononuclear) Mast Cells in the Tissues N N N Allergics (n=12) CD63 ↑ Histamine Tryptase 9/12 5/9 3/12 Controls (n=12) CD63 ↑ Histamine Tryptase 6/12 3/11 0/12 Symptoms and Urticaria Symptoms and Urticaria 8/12 (neg to ++) 0/12 (neg) A Reactions to Cetuximab B Rocky mountain spotted fever Incidence rates (per 1,000,000 persons) 0 0.1-0.9 1.0-9.9 10.0-14.9 15.0+ C D Delayed anaphylaxis to beef Spread of the lone star tick Convergent IgE Sequences Vary in Mutations Ctrl_4h Color by Group Ctrl_2h 20 20 * 20 MA_4h Ctrl 6h Ctrl_6h MA_6h MA bsl Ctrl_Bsl MA_Bsl 10 MA 2h MA_2h MA_2h MA_4h * 5 MA 4h MA 6h 5 MA_6h MA_Bsl * 0 0 -5 -5 -10 MA bsl Ctrl_Bsl MA_Bsl MA 2h MA_2h Ctrl 4h MA_4h Ctrl_4h 10 Comp.2 [8.96%] Principal component 2 (8.96%) 15 Ctrl_4h MA_4h Ctrl_6h MA_6h 20 MA 4h MA_4h 15 15 MA 6h MA_6h Principal component 2 (8.96%) 15 PCA: Meat Allergic Ctrl_4h Ctrl_6h Ctrl bsl Color byCtrl_Bsl Group Ctrl 2h Ctrl_2h MA_2h MA_Bsl 10 10 5 5 0 0 Comp.2 [8.96%] PCA: All Samples Ctrl_6h Color byCtrl_Bsl Group Ctrl_2h MA_2h -5 -5 -10 -10 -10 -15 -20 -15 -20 -15 -15 -15 -10 0 10 20 30 -10 0 Comp.110 20 30 [17.82%] Principal component 1 (17.82%) 40 40 -15 -10 -5 0 5 10 -10 -5 Comp.10[17.82%] 5 10 Principal component 1 (17.82%) 15 15 H h • Patients presenting with anaphylaxis, or recurrent urticaria who have IgE specific for alpha-gal have normal lung function no increase in asthma symptoms and normal FeNO. • This ectoparasite induced IgE response cross reacts with cat, can make major contributions to total IgE, and appears to be a model for IgE responses to parasites that do not create or increase the risk for asthma. • The results explain previous enigmatic IgE antibodies to cat in a Kenyan village and in the ED in Virginia. AJRCCM June 2012 Features Associated with Delayed Urticaria and Anaphylaxis in Patients with IgE to Galactose-alpha-1,3-galactose Urticaria Only (n=87) Anaphylaxis# (n=249) 0 – 20 years 20% 16% 21 – 40 years 20% 25% 41 – 50 years 22% 24% >50 years 39% 35% 46% 52% Mild 44% 0% Moderate 45% 75% Severe 12% 25% Variable I. Age of Onset II. Atopy III. Severity of Reaction #Anaphylaxis was based primarily on patient reports, many cases were improved by the time they reached the emergency facility August 29th, 2014 (Charlottesville, VA) – 43 year old man with metastatic colon cancer developed anaphylaxis within 2 minutes of starting his first infusion of Cetuximab* – Prolonged circulatory collapse-resuscitation – Transferred to ICU at local hospital – Generalized organ failure including ARDS and hepato-renal syndrome September 3rd, 2014 – Support withdrawn Serum IgE to alpha-gal Total IgE 3.1 IU/mL 149 IU/mL *Information from Kevin Lawrence, MD Mount Washington Resort at Bretton Woods, NH Site of the 1st International Monetary Fund conference, July 1944 Bretton Woods was recognized in the early 1900s as a hay fever resort by the United States Hay Fever Association (founded in 1873), and also in the 1930s through the 1950s, along with other areas in the White Mountains, as a retreat for ragweed hay fever sufferers Anaphylaxis to cetuximab is regional. States with high prevalence of Hypersensitivity reactions to Cetuximab during first infusion:* •Tennessee Virginia •North Carolina Arkansas •Missouri Martha Stewart : Sold stock in ImClone on the day before the FDA delayed marketing of Cetuximab. Bert O’Neil’ UNC Oncology Bentonville *O’Neil et al JClin Oncology Aug ’07,, Chung et al NEJM March 13th ‘08 In 2006, we knew about four things including two forms of anaphylaxis that didn’t make sense. • A patient with carcinoma of the colon died of anaphylaxis within 20 minutes of starting his first infusion of cetuximab*. • A 43-year-old hunter who reported three episodes of anaphylaxis, each starting four hours after eating beef. • A village in Kenya where 70% of the children had IgE antibodies to cat without exposure or symptoms. and: You cant grow Azaleas in Central Virginia. *. Bert O’Neil, UNC Delayed anaphylaxis to red meat and the nature of the IgE responses to galactose-alpha 1, 3-galactose (Alpha-gal) =Severe immediate reactions to cetuximab in patients with IgE to alpha-gal (>0.35 IU/ml) Chung, et al, N Engl J Med, 2008; 358: 1109-1117 =24 cases of delayed anaphylaxis to red meat in patients with IgE to alpha-gal Commins, et al, JACI, 2009; 123: 426-433 =Monitored challenges with red meat demonstrate delay in symptoms and basophil activation. Commins, et al, JACI, 2014; 134 (1): 108-115 =Tick bites are a(or the) major cause of IgE responses to alpha-gal Commins, et al, JACI, 2011, 127: 1286-1293 = IgG and IgE antibody responses to the oligosaccharide galactose alpha1, 3-galactose: potential for distinct/unrelated control mechanisms IgM & IgG2 to alpha-gal from gut organisms: Mesenteric Lymph Nodes IgE & IgG1 response to tick bites: Draining lymph node Local inflammation with query local switch due to multiple seed tick bites IgG2 is common in antibody responses to sugars and may be T-independent IgE responses are generally considered to be T-dependent, but the specificity of T cells related to tick bites is not known Current Opinion in Immunology 2013 Rispens et al Plos one 2013 Bites of Amblyomma americanum can be Extremely Pruritic . Bites of adult or larval ticks have been associated with rapid rises in IgE ab and total IgE. Rash at 48 hours Koike et al. Proc Nat Acad Sci 2006;104(2):559564. Karl Landsteiner Defined the ABO system and recognized the presence of other closely related “B like” oligosaccharides on mammalian cells which also gave rise to antibody responses in humans. But also established the concept of a hapten. Macher BA and Galili U. The AlphaGal epitope:a carbohydrate of unique evolutionary and clinical relevance, Biochim. Biophys. Acta, 1780:75-88. ’08 Platts-Mills TA and Isizaka K. Activation of the alternative pathway of human complement by rabbit red cells, J.Immunol 1974. Commins et al. Galactose-α-1,3-galactose-specific IgE is associated with anaphylaxis but not asthma. AJRCCM. 2012;185:723. Norrbotten, Sweden 1000 199/219 9/127 r =0.92; p<0.001 100 10 Association with asthma p<0.001 1 Fel d 1 (IU/ml) Fel d 1 (IU/ml) 1000 Kabati, Kenya 0.1 100 10 1 0.1 0.1 1 10 100 0.1 1000 1 100 1000 Cat Epithelium (IU/ml) Cat Epithelium (IU/ml) 1000 IgE to Alpha-Gal (IU/ml) 1000 1/233 Alpha Gal (IU/ml) 10 100 10 1 0.1 97/127 100 r =0.77; p<0.001 10 No relationship to asthma 1 0.1 0.1 1 10 100 Cat Epithelium (IU/ml) 1000 0.1 1 10 100 Cat Epithelium (IU/ml) 1000 The Allergy Epidemics: 1870-2010: Conclusions. Relevant Changes Epidemic ~ 1880-1950 a) Clean water, Shoes, and Helminth eradication. b) Increase in dairy herds and in the pollen of grass and ragweed Hay Fever (Catarrhus aestivus) ~ 1955-2000 Onset of Indoor Life Style: • Decreased physical activity • Changes indoors: increased sensitization to mite, cat, etc. Pediatric Asthma ~1995 a) b) c) d) Peanut Allergy in children ~2007 Increase in tick bites secondary to the rising population of deer. Changes in Peanut products Delayed exposure Changes in the skin (eczema) Vaccination policy Late night anaphylaxis (due to red meat) The Allergy Epidemics: 1870-2010. JACI July 2015 Multiple bites from the first hatching of Amblyomma ticks and IgE ab to alpha-gal. Photograph: August 23, 2007. Test 10/26/06 5/21/07 10/9/07 11/6/07 Cetuximab (alphaGal) 0.49 16.9 48.3 130 Total IgE 127 199 350 532 •Female ticks can lay up to 1,000 eggs and the first hatching of a tick is called a ‘seed tick’; approximate size: 1.0-1.5 mm. •Multiple bites by seed ticks are not uncommon in the Southeast. Aalberse and Platts-Mills JACI 2004 Lymph Node or Bone Marrow Bone Marrow The enigma of IgE B-cell memory in human subjects: J.Davies, T.Platts-Mills and R.Aalberse, JACI 2013 Deep sequencing data from Scott Boyd , Stanford , on B cells from Virginia. Alpha-gal cases have now been reported from: -Australia -Sweden -France -Germany -Spain -Japan -China -Zimbabwe -South Africa -England Stockholm, Sweden: Marianne van Hage Borstel, Germany: Uta Jappe Biedermann IgE ab to alpha-gal have been Reported from Kenya & Ecuador. Nancy, France: Moneret-Vautrin, And Morisset Berlin, Germany: Jorg KleineTebbe Sequential class switching is required for the generation of high affinity IgE antibodies. Huizhong Xiong , ..Maria de Lafaille, and Juan Lafaille. Journal of Experimental Medicine: Jan 16th 2012 i. IgE B cells are rare in germinal centers (GC). ii. IgE plasma cells can be derived by direct switch from IgM or via IgG B cells which have undergone maturation in germinal centers . iii. They suggest that only IgE antibodies made via the germinal center route are relevant to allergic disease and even that low affinity antibodies are protective. NB Deficiency of Bcl6 impairs GC but allows normal IgE in patients with DOCK8 mutations and immunodeficiency. See Zhang et al NEJMed 2009 August 29th, 2014 (Charlottesville, VA) – 43 year old man with metastatic colon cancer developed anaphylaxis within 2 minutes of starting his first infusion of Cetuximab* – Prolonged circulatory collapse-resuscitation – Transferred to ICU at local hospital – Generalized organ failure including ARDS and hepato-renal syndrome September 3rd, 2014 – Support withdrawn Serum IgE to alpha-gal Total IgE 3.1 IU/mL 149 IU/mL *Information from Kevin Lawrence, MD A Meat Status-basal differences Amino Acids Peptide Carbohydrate Lipid Xenobiotic Co-factor/vitamin Total=20 metabolites B aspartyl phenylalanine leucylglycine C taurocholate 10-undecenoate