CD28 and rheumatoid arthritis: On the other hand, in certain disease processes such as chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis, they have been reported to express increased levels of cytotoxic mediators, perforin and granzyme B, and pro-inflammatory cytokines, IFN-γ and TNFα, where CD8+CD28− T cells can cause significant damages to normal surrounding tissue in an antigen-nonspecific manner [121].