Peanut-allergic subjects and their peanut-tolerant siblings have large differences in peanut-specific IgG that are independent of HLA class II.

Hypersensitivity to foods is now recognized as a world-wide problem in the industrialized world and it’s prevalence may be increasing [1, 2]. Reactions to foods are thought to be the most common cause of anaphylaxis when it occurs outside of the hospital [3]. Elevated allergen-specific IgE is the hallmark of allergic sensitization. The fine specificity of IgE binding is important as IgE from those peanut-allergic patients with the most severe clinical reactions recognizes a more diverse array of linear peptides within the family of peanut proteins [4]. Over the last 3 decades there have been multiple reports that allergen-specific IgG (and, when measured, IgG1 and IgG4) tends to be higher in atopic individuals than in non-atopics [5]. This has been reported for grass (Rye 1) [6], ragweed (AgE) [7], birch (Bet v 1) [8], and peanut (crude peanut extract (CPE)) [9, 10]. Lesser differences were reported for cat (Fel d 1) although the allergic subjects again had higher levels [11] and no differences were reported with IgG to ovalbumin [10]. Jones et al. have demonstrated increasing peanut-specific IgG in patients undergoing oral desensitization but did not compare these findings with subjects who are naturally tolerant to peanuts [12]. HLA (human leukocyte antigen) proteins were originally discovered due to their importance in rejection of transplants and eventually understood as the major histocompatiblilty complex (MHC) for their importance in presenting antigen to T cells [13]. Presentation of exogenous antigens to CD4+ T cells occurs via MHC class II on the surface of antigen-presenting cells (APCs) [13, 14]. Peanut proteins are clearly exogenous antigens and are presumably presented via MHC class II [14]. MHC class II molecules have four distinct pockets that serve to anchor peptides and interact with T cell receptors [15, 16]. Shared epitopes (small groups of amino acids having similar surface properties) within these pockets may lead to shared recognition of important peptides by otherwise disparate alleles [15, 17-21]. Two previous studies have examined the possible relationship between HLA class II alleles in peanut-allergic individuals compared with peanut tolerant siblings using low-resolution HLA typing [22, 23]. Howell et al. studied 50 subjects with peanut allergy, 34 non-peanut allergic siblings, and 77 non-peanut allergic parents and compared their findings with those from 293 unrelated controls [22]. After Bonferroni corrections, there were no significant differences between the peanut allergic patients and their non-peanut allergic siblings at any allele. However, they found significant differences between the peanut-allergic subjects and the unrelated controls for the presence of DRB1*08 [22]. Shreffler et al. performed a similar study, enrolling 73 peanut-allergic subjects and 75 peanut-tolerant siblings and found no significant differences between the peanut-allergic and peanut-tolerant siblings [23]. They did not compare their subjects to unrelated controls. These two studies were limited because analyses were performed at a serologic level and this can miss the important details within the peptide-binding groove. Given reports that peanut-specific IgG is higher in allergic than in non-allergic subjects we reasoned that differences in peanut-specific IgG production between peanut-allergic subjects and those who are tolerant to peanuts may be related to differences in the ability to present allergens via HLA class II. To test this hypothesis, we determined anti-peanut IgG, peanut-specific IgE, and HLA-Class II expression at high resolution in a population of well-characterized peanut-allergic subjects and their peanut-tolerant siblings including 14 sibling pairs who are identical at HLA-Class II. We compared the HLA findings to those from a large public database [24]. Our primary finding is that differences in anti-peanut IgG and IgE are unequivocally independent of HLA class II. A secondary finding is that HLA DRB1*08 appears to be increased in the peanut allergic subjects and this may be driven by an increased frequency of HLA DRB1*0803.