Three dimensional structure directs T-cell epitope dominance associated with allergy

Abstract

Background: CD4+ T-cell epitope immunodominance is not adequately explained by peptide selectivity in class II major histocompatibility proteins, but it has been correlated with adjacent segments of conformational flexibility in several antigens.

Understanding the focused CD4 T cell response to antigen and pathogenic organisms

“…First, the finding that DM-negative APC are active at presentation of the cryptic peptides shows that the cryptic epitopes are neither overproteolyzed nor inadequately released during endosomal processing. This finding argued against differential proteolysis of cryptic vs. immunodominant peptides-one of the common explanations for crypticity in immune responses [2,21,22,[44][45][46][47]. Secondly, all immunodominant peptides behaved similarly, and were enhanced by DM while the cryptic epitopes behaved similarly and were antagonized by DM.…”

“…For example, studies with model protein antigens show that treatment of APC with inhibitors of endosomal proteolysis could either enhance or inhibit antigen presentation, depending on the epitope [19], and that mutation of a peptide flanking sequence by introduction of a protease recognition sequence can enhance epitope display [20]. Similarly, recent studies have reported that immunodominant epitopes cluster in limited regions of protein antigens, often within solvent-exposed regions or at sites that are adjacent to protease-sensitive flexible loops [21][22][23][24][25]. These data, which are largely correlative in nature, suggest that antigens that have a high degree of tertiary structure may be poorly immunogenic, and peptides buried within protease-resistant regions of proteins may sequester them from proteolytic release and subsequent association with class II molecules.…”

“…Test peptides inserted within the MalE protein also contained several flanking amino acid residues from the native sequence on their amino-and carboxy-terminus, in order to preserve potential TcR contact residues [52,53]. An independent set of peptides with previously characterized immunodominance hierarchies were compared in these experiments, including the immunodominant peptides MYO [102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118] [54,55], LACK [156-173] [56,57], OVA [273-288], the subdominant/cryptic peptide HEL [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], and the cryptic peptides HEL [20][21][22][23][24][25][26][27][28]…”

“…Figure 1 shows the comparison of CD4 T cell responses to several heterologous peptides contained in their native protein context (left panel) or inserted within MalE at amino acid 133 (right panel). The data for each peptide are presented as the percent of cytokine spots elicited by peptide relative to the total number of spots that were elicited in [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], HEL [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], and a cryptic variant of the LACK [156-173] peptide consistently displayed an inability to prime CD4 T cell responses, independently of the protein in which they are contained. Also of note is that the same localization in MalE, at amino acid 133, permits immunodominance or crypticity, depending on the primary sequence of the antigenic peptide that is inserted.…”

New concept in allergy: Non-allergic rats becomes allergic after induced by Porphyromonas gingivalis lipopolysaccharide

“…Nevertheless, even without previous OVA-induced allergic sensitization, antigen-antibody reaction also happened, this mechanism is termed as cross reactivity. 22 According to Melton and Landry, 23 cross reactivity may happens if a protein which actually has a 3D shape, in this case the Ovalbumin inhalation in our study, could attach to the non-specific IgEs even not perfect match as "lock and key". (Figure 3), in our study non-OVA spesific IgE recognized OVA as its ligand and activate mast cells.…”