This pathway includes smoking and periodontal disease as sources of citrullination of proteins, specific HLA-DRB1 alleles to present citrullinated peptides, and other genetic factors as positive modulators of antibody mediated autoreactivity; epitope spreading together with maturation of the antibody response as steps preceding clinical onset of RA, and the effect of ACPA in stimulating osteoclasts for the RA bone erosions. This evidence concerns the gene HLA-DRB1 and rheumatoid arthritis.