Early recovery from cow's milk allergy is associated with decreasing IgE and increasing IgG4 binding to cow's milk epitopes.
BACKGROUND
The dynamics and balance of allergen-specific IgE, IgG4, and IgA binding might contribute to the development of tolerance in patients with cow's milk allergy (CMA). Profiling of antibody binding to cow's milk (CM) protein epitopes might help in predicting the natural history of allergy.


OBJECTIVE
We sought to investigate differences in IgE, IgG4, and IgA binding to CM epitopes over time between patients with early recovery or with persisting CMA.


METHODS
We studied serum samples at the time of diagnosis (mean age, 7 months), 1 year later, and at follow-up (mean age, 8.6 years) from 11 patients with persisting IgE-mediated CMA at age 8 to 9 years and 12 patients who recovered by age 3 years. We measured the binding of IgE, IgG4, and IgA antibodies to sequential epitopes derived from 5 major CM proteins with a peptide microarray-based immunoassay. We analyzed the data with a novel image-processing method together with machine learning prediction.


RESULTS
IgE epitope-binding patterns were stable over time in patients with persisting CMA, whereas binding decreased in patients who recovered early. Binding patterns of IgE and IgG4 overlapped. Among patients who recovered early, the signal of IgG4 binding increased and that of IgE decreased over time. IgE and IgG4 binding to a panel of alpha(s1)-, alpha(s2)-, beta-, and kappa-casein regions predicted outcome with significant accuracy.


CONCLUSIONS
Attaining tolerance to CM is associated with decreased epitope binding by IgE and a concurrent increase in corresponding epitope binding by IgG4.
Savilahti
Emma M
EM
Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
Rantanen
Ville
V
Lin
Jing S
JS
Karinen
Sirkku
S
Saarinen
Kristiina M
KM
Goldis
Marina
M
Mäkelä
Mika J
MJ
Hautaniemi
Sampsa
S
Savilahti
Erkki
E
Sampson
Hugh A
HA
D000818:Animals; D002364:Caseins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D002417:Cattle; D002648:Child; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism*; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism*; D007223:Infant; D007231:Infant, Newborn; D016269:Milk Hypersensitivity / Q000097:blood / Q000175:diagnosis* / Q000276:immunology; D011379:Prognosis; D011485:Protein Binding
D002364:Caseins; D018985:Epitopes, B-Lymphocyte; D007074:Immunoglobulin G; D007073:Immunoglobulin E
J Allergy Clin Immunol. 2008 Nov;122(5):977-983.e1
18851876
J Allergy Clin Immunol. 2005 Oct;116(4):893-9
16210066
J Allergy Clin Immunol. 2008 Dec;122(6):1154-60
18951617
J Allergy Clin Immunol. 2005 Oct;116(4):869-75
16210063
J Allergy Clin Immunol. 2007 Nov;120(5):1172-7
17935766
Ann Allergy Asthma Immunol. 2004 Nov;93(5 Suppl 3):S2-11
15562868
Clin Exp Allergy. 2001 Oct;31(10):1599-606
11678861
Clin Exp Allergy. 2007 Jun;37(6):831-8
17517096
Clin Exp Allergy. 2000 Mar;30(3):400-6
10691899
J Allergy Clin Immunol. 2009 Aug;124(2):292-300, 300.e1-97
19577283
J Immunol. 2004 Mar 1;172(5):3252-9
14978133
Clin Exp Allergy. 2010 Feb;40(2):251-6
19958365
J Allergy Clin Immunol. 2002 Aug;110(2):293-7
12170271
J Allergy Clin Immunol. 2008 May;121(5):1120-1125.e2
18374405
Clin Exp Allergy. 2007 Sep;37(9):1277-85
17845407
J Allergy Clin Immunol. 1999 Aug;104(2 Pt 1):457-61
10452771
Clin Exp Allergy. 2007 Jul;37(7):1103-10
17581206
J Allergy Clin Immunol. 2009 Aug;124(2):315-22, 322.e1-3
19577281
J Allergy Clin Immunol. 2008 Sep;122(3):589-94
18774394
J Immunol. 2007 Apr 1;178(7):4658-66
17372025
Biotechnol Adv. 2005 Sep;23(6):423-9
15978770
Genes Immun. 2009 Mar;10(2):112-9
18923431
Clin Exp Allergy. 2002 Sep;32(9):1293-8
12220466
J Immunol. 1999 Sep 1;163(5):2944-52
10453043
J Pediatr. 2004 Feb;144(2):218-22
14760265
Nat Biotechnol. 2008 Sep;26(9):1011-3
18779814
Allergy. 1990 Nov;45(8):587-96
2288394
J Allergy Clin Immunol. 2008 Aug;122(2):342-7, 347.e1-2
18620743
J Allergy Clin Immunol. 2003 Nov;112(5):915-22
14610480