In silico Analysis of the Binding Affinities of Antigenic Epitopes of Vaccines Administered to Gulf War Veterans to Specific HLA Class II Alleles Protective for Gulf War Illness

Abstract

Gulf War Illness (GWI) is a chronic, multi-symptom disorder of unknown etiology affecting veterans of the 1990-91 Gulf War. We identified previously¹ a set of 6 Human Leukocyte Antigen (HLA) class II alleles that are protective for GWI, namely DPB1*01:01, DPB1*06:01, DQB1*02:02, DRB1*01:01, DRB1*08:11, and DRB1*13:02. Since the function of HLA class II molecules is to connect with matching extracellular antigens of various pathogens (mostly viruses), as an initial step in the sequence of events leading to the development of antibodies against the matched antigen and its subsequent elimination, we hypothesized that GWI may be due, in part, to the persistence of offending antigens which could not be eliminated^2,3. We further hypothesized^4,5 that such antigens were contained in the 16 vaccines administered to GW veterans against adenovirus, anthrax, botulinum, cholera, diphtheria, hepatitis B, influenza A, Japanese encephalitis, measles, meningococcus, poliomyelitis, rabies, smallpox, tetanus, typhoid, yellow fever.⁶ This hypothesis predicts that antigens present in those vaccines should have a high affinity for matching with the 6 HLA class II protective alleles above. Here we tested this prediction by using the Immune Epitope DataBase (IEDB⁷) to determine the ranked affinity of each one of the 6 GWI protective alleles to the 10 most frequently assayed epitopes of each pathogen for which a vaccine was administered. We found that our 6 GWI protective alleles above collectively covered all vaccine antigens except for rubella for which all alleles above showed low binding affinity. Affinity strength varied among antigen-allele pairs, with DRB1*01:01 and DRB1*13:02 showing overall higher affinities. These two alleles also had the highest binding affinities for the anthrax antigen contained in the anthrax vaccine administered to GW veterans. These findings document a good match between the 6 GWI HLA protective alleles above and the antigens contained in the GW vaccines, and support the fundamental assumption that the HLA protection for GWI is mediated through the successful elimination of potentially harmful persistent antigens contained in those vaccines.

Keywords: Gulf War Illness (GWI); HLA epitope affinity; Human Leukocyte Antigen (HLA); immunity; persistent antigens; vaccines.

Figure 1:

Bars are minimum percentile ranks (best binding affinity) for HLA allele DPB1*01:01 and epitopes of 20 pathogens. Bars in red below the red horizontal line drawn at the 10^th percentile indicate good binders. See text for details.

Figure 2:

Bars are minimum percentile ranks (best binding affinity) for HLA allele DPB1*06:01 and epitopes of 20 pathogens. Bars in red below the red horizontal line drawn at the 10^th percentile indicate good binders. See text for details.

Figure 3:

Bars are minimum percentile ranks (best binding affinity) for HLA allele DQB1*02:02 and epitopes of 20 pathogens. Bars in red below the red horizontal line drawn at the 10^th percentile indicate good binders. See text for details.

Figure 4:

Bars are minimum percentile ranks (best binding affinity) for HLA allele DRB1*01:01 and epitopes of 20 pathogens. Bars in red below the red horizontal line drawn at the 10^th percentile indicate good binders. See text for details.

Figure 5:

Bars are minimum percentile ranks (best binding affinity) for HLA allele DRB1*08:11 and epitopes of 20 pathogens. Bars in red below the red horizontal line drawn at the 10^th percentile indicate good binders. See text for details.

Figure 6:

Bars are minimum percentile ranks (best binding affinity) for HLA allele DRB1*13:02 and epitopes of 20 pathogens. Bars in red below the red horizontal line drawn at the 10^th percentile indicate good binders. See text for details.

Figure 7:

Dendrogram derived from the minimum percentile ranks (Table 1) shows the grouping of the 6 HLA alleles tested to the 3 HLA class II genes to which the 6 alleles belong. See text for details.

Figure 8:

A, position and color coding scheme of the 6 alleles in a radial plot. B, radial plots of allele affinity for each pathogen listed. The radius of the circle is the 10^th percentile and the length of the arm is 10 - minmum rank. See text for details.