A common epitope on S-antigen (arrestin), a potent autoantigen inducing experimental autoimmune uveoretinitis (EAU), and on human tumor necrosis factor alpha (hTNF alpha) was revealed using two monoclonal antibodies to S-antigen which inhibit EAU induction. The minimal common sequence for monoclonal antibody recognition is GVxLxD in the S-antigen/hTNF alpha amino acid sequences. Peptides containing this sequence motif exhibited monocyte activating capacity similar to the autocrine stimulatory capacity of hTNF alpha itself. In the S-antigen this activity was located from residue 40 to 50, corresponding to the peptide PVDGVVLVDPE (epitope S2). In hTNF alpha, the monocyte activating capacity correlated to residue 31 to 53, corresponding to the peptide RRANALLANGVELRDNQLVVPSE (peptide RRAN). The identified regions define common functional structures in the autoantigen and in the hTNF alpha molecule. The data suggest a regulatory function of this particular structure in TNF alpha expression and in autoimmunity.