Pathophysiological Roles of Calreticulin in Autoimmune Disease

Abstract

Eggleton P, Llewellyn DH. Pathophysiological Roles of Calreticulin in Autoimmune Disease. Scand J Immunol 1999;49:466-473 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.

The Rheumatoid Arthritis Shared Epitope Triggers Innate Immune Signaling via Cell Surface Calreticulin

“…Of these, two are of special interest: CRT and HSP60, as both of them are found on the cell surface (13,14) and have been previously implicated in the pathogenesis of RA (15,16). The identities of these two bands as CRT and HSP60 were confirmed by immunoblotting (Fig.…”

Calreticulin requires an ancillary adjuvant for the induction of efficient cytotoxic T cell responses

“…A broad array of molecular chaperones, including calreticulin, have been reported to elicit host immune responses that result in tumor rejection or, in some cases, autoimmunity (Berwin and Nicchitta, 2001;Eggleton and Llewellyn, 1999). Current dogma invokes the ability of chaperones to traffic associated peptides into APCs and concomitantly to induce the maturation of DCs, thereby propagating peptide-specific immune responses that result in the generation of anti-tumor CTL response.…”

“…Chaperones were originally identified as immunogens in a screen for tumor-rejection antigens. Subsequent studies have led to proposals that they may also endogenously function as 'danger signals' when released from dying cells and may exacerbate autoimmune diseases (Eggleton and Llewellyn, 1999;Routsias and Tzioufas, 2006;Srivastava, 2002). A variety of chaperones, including calreticulin (CRT), gp96, hsp70 and hsp60, elicit prophylactic and therapeutic anti-tumor responses (Basu and Srivastava, 1999;Sato et al, 2001;Tamura et al, 1997;Yedavelli et al, 1999) which has resulted in ongoing clinical trials for their evaluation as autologous cancer therapies (Belli et al, 2002;Misra et al, 2006).…”

“…Interestingly, both gp96 and hsp60 have LPS binding activity which augments the activity of LPS to stimulate DCs (Osterloh et al, 2007;Warger et al, 2006); relevant to our present studies, CRT harbors no endogenous LPS binding activity (Reed et al, 2003). DC activation and maturation is invoked as an underlying basis for the CRT contribution to autoimmune disorders (Eggleton and Llewellyn, 1999), to the use of CRT as an adjuvant to elicit peptide-specific responses (Nair et al, 1999), and to its tumor-rejection activity (Basu and Srivastava, 1999;Cheng et al, 2005;Hsieh et al, 2004). However, the ability of purified CRT to activate and mature DCs has not been directly tested.…”

A combination of DNA vaccines targeting human papillomavirus type 16 E6 and E7 generates potent antitumor effects

“…We observed that the presence of the E7 49-57 aa sequence within the E7 gene of the CRT/E7 DNA vaccine suppresses the efficient activation of HLA-A2 restricted E7 (aa [11][12][13][14][15][16][17][18][19][20] peptide-specific CD8 + T cell-mediated immune responses 13 in HLA-A2 transgenic mice. In order to avoid this situation and accurately characterize the HLA-A2-restricted E7-specific CD8 + T-cell immune response in HLA-A2 transgenic mice, we generated pcDNA3-CRT/ mtE7(del aa49-57), a DNA vaccine that deletes aa49-57 from the E7 gene.…”