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IgE antibodies to the mammalian oligosaccharide galactose-alpha-1, 3-galactose (alpha-gal): immunology, epidemiology and relevance to allergic and inflammatory disease

Award Number: R37AI020565
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY The syndrome of delayed anaphylaxis to red meat, i.e. the alpha-gal syndrome (AS), is found exclusively in patients who have serum IgE antibody (ab) to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). This form of sensitization is related to bites of the tick Amblyomma americanum, however other ticks appear to be relevant in other countries. The objective of the studies proposed here is to investigate the epidemiology, etiology, immunology and clinical features of AS which is now known to be common in a large area of the USA. The studies focus on three aspects of the syndrome. Firstly we will use a detailed map of the cases of AS to compare with maps of tick-related diseases and the distribution of ticks. The serologic response to alpha-gal will be compared from AS cases in participating sites from different parts of the country. Additionally, to investigate the possibility that the Rickettsiae group of obligate intracellular bacteria, such as Rickettsia amblyommii or Ehrlichia chaffeensis, could be relevant to AS sensitization we will carry out assays for specific IgG ab. Secondly, in the area where there is a high prevalence of IgE to alpha-gal there are many individuals who are sensitized but either do not report symptoms or report delayed symptoms that are not recognized as allergic. These include patients with repeated episodes of abdominal pain. Our primary hypothesis about the 3- 5 hour delay in the onset of symptoms is that this reflects the time taken to process dietary mammalian glycoprotein and/or glycolipids lipids to a size that readily penetrates into tissue, for example the size of LDL (~20 nm). Another disease not traditionally considered to be related to allergy is coronary artery disease. In a preliminary investigation we have found that the presence of detectable levels of IgE to alpha-gal is significantly associated with the burden of atherosclerosis in a cohort of subjects in central Virginia. This study, which utilized intravascular ultrasound (IVUS), also demonstrated an association with coronary plaques which had unstable, i.e. high risk, features. We will further investigate this association in a larger cohort at our institution and extend the investigation to subjects in other regions with high prevalence of alpha-gal sensitization. The primary objective of the third aim is to obtain better information about the B cells that relate to the antibody response to alpha-gal. Preliminary data using mass cytometry suggests that subjects with AS have a population of plasmablasts that can respond to alpha-gal. The proposed studies will further investigate these cells with an expanded mass cytometry bead panel and use multiple samples in a single batch. In conjunction with parallel studies employing antibody deep sequencing, collective results are expected to shed insight into the B cell populations that produce `natural' antibodies to alpha-gal, i.e. IgM and IgG2 antibody, as well as those B cells that produce IgE and IgG1. Finally, we will compare the response in AS with that in eosinophilic esophagitis (EoE) which is another form of food allergy with a delayed response and a dramatically different antigen-specific IgE and IgG4 response.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $1,245,603 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	002	40	8/21/2024	SUPPLEMENT FOR EXPANSION	$262,801
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	40	5/29/2024	NON-COMPETING CONTINUATION	$622,802
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	40	6/24/2024	SUPPLEMENT FOR EXPANSION	$360,000
														Subtotal = $1,245,603

Issue Date FY: 2023 ( Subtotal = $622,802 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	39	3/6/2023	EXTENSION WITH OR WITHOUT FUNDS	$622,802
														Subtotal = $622,802

Issue Date FY: 2022 ( Subtotal = $986,177 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	38	8/5/2022	NON-COMPETING CONTINUATION	$363,375
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	38	6/1/2022	NON-COMPETING CONTINUATION	$622,802
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	002	38	9/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $986,177

Issue Date FY: 2021 ( Subtotal = $622,802 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	37	6/9/2021	NON-COMPETING CONTINUATION	$622,802
														Subtotal = $622,802

Issue Date FY: 2020 ( Subtotal = $752,002 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	35	3/9/2020	SUPPLEMENT FOR EXPANSION	$129,200
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	36	6/12/2020	NON-COMPETING CONTINUATION	$622,802
														Subtotal = $752,002

Issue Date FY: 2019 ( Subtotal = $459,892 )
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	35	6/13/2019	NON-COMPETING CONTINUATION	$445,840
2019	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	34	2/11/2019	COMPETING CONTINUATION	$14,052
														Subtotal = $459,892

Issue Date FY: 2018 ( Subtotal = $588,085 )
2018	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	001	34	7/25/2018	COMPETING CONTINUATION	$129,200
2018	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	34	6/15/2018	COMPETING CONTINUATION	$458,885
														Subtotal = $588,085

Issue Date FY: 2001 ( Subtotal = $403,972 )
2001	2001	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	18	6/7/2001	NON-COMPETING CONTINUATION	$403,972
														Subtotal = $403,972

Issue Date FY: 2000 ( Subtotal = $394,371 )
2000	2000	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	17	4/27/2000	NON-COMPETING CONTINUATION	$394,371
														Subtotal = $394,371

Issue Date FY: 1999 ( Subtotal = $385,053 )
1999	1999	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	16	5/6/1999	NON-COMPETING CONTINUATION	$385,053
														Subtotal = $385,053

Issue Date FY: 1998 ( Subtotal = $501,004 )
1998	1998	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	15	5/26/1998	NON-COMPETING CONTINUATION	$501,004
														Subtotal = $501,004

Grand Total All Awards = $6,961,763

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IgE antibodies to the mammalian oligosaccharide galactose-alpha-1, 3-galactose (alpha-gal): immunology, epidemiology and relevance to allergic and inflammatory disease

Award Number: R37AI020565

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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