Pathophysiological roles of calreticulin in autoimmune disease

Autoantibodies against the endoplasmic reticulum (ER) luminal protein, calreticulin are often present in sera from patients with systemic lupus erythematosus, rheumatic disease and various parasitic diseases including onchocerciasis. New information has revealed that calreticulin is implicated in a number of autoimmune processes, including molecular mimicry, epitope spreading, complement inactivation and stimulation of inflammatory mediators, such as nitric oxide production. Calreticulin also binds to the Ro/SS-A antigen complex, which is composed of at least three immunologically distinct proteins bound to a group of small cytoplasmic RNAs that together form a common target for autoimmune responses. Up-regulation of calreticulin at the protein and RNA levels can be triggered by cell stresses, including heat shock, exposure to heavy metals and perturbation of normal ER function, which may in some cases lead to its secretion from cells. Calreticulin is targeted by autoantibodies following its release into the extracellular environment, possibly as a result of cell death, or its presence at the cell surface in response to insults such as viral infection or ultraviolet irradiation. These findings suggest that calreticulin is not just an autoantigen, but plays an active role in the pathology of various autoimmune disease through determinant spreading.