Indiana University-Purdue University Indianapolis (IUPUI) / Background: Bacterial adherence to the acquired dental pellicle, important in caries, is mediated by receptor-adhesin interactions such as Streptococcus mutans antigen I/II (I/II). Ten I/II epitopes from the A, V, P and C regions were chosen to determine their reactivity in human saliva. Underlying the body’s ability to immunologically respond to bacteria that lead to caries are the human leukocyte antigen (HLA) genes, specifically HLA class II (HLA-II) genes that control antigen presentation. Previous studies suggested that a specific HLA biomarker group (HLA-DRB1*04) may have differential control of immune responses to I/II. However, it was not known whether secretory IgA (SIgA) responses to the selected epitopes from HLA-DRB1*04 positive subjects were different compared to their non-biomarker counterparts (negative), or across other caries factors, since no study to date had thus assessed these questions. Methods: Per IRB approval, the study population was divided into age, sex and race matched DRB1*04 positive (n=16) and negative groups (n=16). SIgA-epitope (and whole cell) reactivity was determined using ELISA. Other caries factors were measured. Subjects received a clinical exam by a trained examiner. ix Differences between DRB1*04 positive and negative groups were examined using a two-sided, two-sample t-test. Results: DRB1*04 positive subjects had numerically, but not statistically, higher reactivity to 9 out of 10 epitopes, the exception being residues 834-853 from the V and P regions of I/II across multiple measures. Though statistically insignificant, DRB1*04 positive subjects also exhibited 25-30 μg mL-1 less total IgA (TIgA) than negative counterparts. All clinical caries data proved inconclusive when comparing groups, likely due to exogenous factors and sample size. Conclusion: DRB1*04 positive subjects showed a trend toward lower TIgA. Moreover, they also showed a lower SIgA response across multiple measures to 834-853, the I/II V and P region epitope. This region forms a sort of functional epicenter involved in collaboration between domains along the entire I/II antigen, and governs the region involved in initial attachment to the acquired dental pellicle. This region may be involved in an in vivo discontinuous conformationally specific immunogenic epitope that serves as an HLA-II binding motif which remains elusive.