In this study, the immune microenvironment of periodontitis was found to be characterized by increased infiltration of immunocytes, higher activities of immune-related pathways, and upregulated HLA expression, among which, activated B cells, BCR signaling pathway, and HLA-DOB were ones of those showing the most significant difference from periodontally healthy samples, as well as being significantly upregulated in the subtype of periodontitis with more intense immune reactions. This evidence concerns the gene HLA-DOB and periodontitis.