Autoimmune diseases are, as the name implies, pro-inflammatory, translating in a high degree of immune cell infiltration, including many cell types which express GzmB, such as cytotoxic lymphocytes (CTLs), mast cells, macrophages, natural killer (NK) cells and others. These cells induce targeted cell death in resident tissue cells, a process known as apoptosis. Infiltrating immune cells can also release GzmB extracellularly, in both a targeted or non-specific manner, resulting in high extracellular GzmB levels in tissues and bodily fluids such as plasma, synovial fluid and cerebral spinal fluid. As GzmB is elevated in the plasma of patients with autoimmune conditions but present at low levels in healthy individuals, it is a potential biomarker for autoimmune disease diagnosis.
There are several mechanisms by which elevated levels of intracellular and extracellular GzmB contribute to the pathogenesis of autoimmune disease.
1 GzmB can induce the death of resident tissue cell types, compromising the functionality of the tissue.
2 Extracellular GzmB induces tissue destruction through the cleavage of ECM components,
compromising tissue structure and function.
3 GzmB can process several pro-inflammatory cytokines involved in autoimmune disease such as
IL-1α. The protease also increases the availability of the growth factor TGF-β, which plays a key
role in tissue pathogenesis through its influence on cellular processes and ECM production.
4 GzmB has been shown to cleave specific proteins resulting in autoantigen production. These protein
fragments are recognized as foreign by the immune system and results in the production of
auto-antibodies and induction of an immune response again a host’s own tissue.
Although GzmB is expressed at high levels in autoimmunity and contributes to autoimmune conditions through a wide array of mechanisms, the therapeutic potential of targeting GzmB has never been pursued.
Autoimmune Bullous Disorders