SummarySystemic lupus erythematosus is a multisystem autoimmune disease in which the autoantibody response targets a variety of autoantigens of diverse subcellular location. We show here that these autoantigens are clustered in two distinct populations of blebs at the surface of apoptotic cells. The population of smaller blebs contains fragmented endoplasmic reticulum (ER) and ribosomes, as well as the ribonudeoprotein, Ro. The larger blebs (apoptotic bodies) contain nudeosomal DNA, Ro, La, and the small nuclear ribonucleoproteins. These autoantigen dusters have in common their proximity to the ER and nuclear membranes, sites of increased generation of reactive oxygen species in apoptotic cells. Oxidative modification at these sites may be a mechanism that unites this diverse group of molecules together as autoantigens.

We examined the role of circulating autoantibodies in the pathogenesis of pemphigus vulgaris by passively transferring IgG fractions from five patients with pemphigus vulgaris into neonatal Balb/c mice, in doses of 1.5 to 16 mg per gram of body weight per day. Cutaneous blisters and erosions with the histologic, ultrastructural, and immunofluorescence features of pemphigus occurred in 39 to 55 mice given intraperitoneal injections of IgG from patients with pemphigus and in none of 58 control mice given normal human IgG. IgG fractions with high titers of pemphigus antibodies were most effective in inducing disease, and this effect was dose dependent. Titers of circulating IgG in mouse serum closely correlated with the extent of disease induced (P less than 0.002). This study strongly supports the proposed role of pemphigus autoantibodies in the pathogenesis of pemphigus vulgaris in human beings and demonstrates that pemphigus can be passively transferred to laboratory animals.

No abstract

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease that occurs in association with underlying neoplasms. Patients with PNP develop characteristic IgG autoantibodies directed against multiple antigens, most of which have been identified as cytoplasmic proteins of the plakin family (desmoplakin I, II, BPAG1, envoplakin, and periplakin). This study identified cell surface target antigens of PNP. We focused on desmoglein (Dsg) 3 and Dsg1, the autoantigens of pemphigus vulgaris and pemphigus foliaceus. ELISA using baculovirus-expressed recombinant Dsgs (rDsg3, rDsg1) has revealed that 25 out of 25 PNP sera tested were positive against Dsg3 and 16 of 25 were positive against Dsg1. All of 12 PNP sera tested immunoprecipitated Dsg3. Removal of anti-Dsg3 autoantibodies by immunoadsorption was sufficient to eliminate the ability of PNP sera to induce cutaneous blisters in neonatal mice in vivo. Furthermore, anti-Dsg3-specific antibodies that were affinity purified from PNP sera were proven to be pathogenic and caused blisters in neonatal mice. These findings indicate that Dsg3 and Dsg1 are the cell surface target antigens in PNP and that IgG autoantibodies against Dsg3 in PNP sera play a pathogenic role in inducing loss of cell adhesion of keratinocytes and causing blister formation. ( J. Clin. Invest.

SummaryProteolytic cleavage of key substrates appears to be an important biochemical mechanism underlying the apoptotic process, and the centrality ofinterleukin 1 [3-converting enzyme (ICE)-like proteases as mediators of apoptosis has been suggested . The identification of the relevant substrates of the ICE protease family during apoptosis therefore constitutes a major challenge . Using human autoantibodies, we demonstrate here that a subset of autoantigens is specifically cleaved early during apoptosis. One of these cleaved molecules is identified as the catalytic subunit of the DNA-dependent protein kinase . The time courses of all proteolytic cleavages are identical and coincide with the onset of morphologic apoptosis. Furthermore, all cleavages share the same inhibition characteristics, which implicate an ICE-like activity(ies) . We propose that cleavage ofthese autoantigens targets these molecules for an autoimmune response by revealing immunocryptic fragments in a proimmune apoptotic setting . Study of the immunogenicity of these fragments may yield insights into the autoimmune targeting ofmolecules . Moreover, the autoantibodies described will be valuable tools for the elucidation of mechanistically important proteolytic steps along the apoptotic pathway .

No abstract

Patient 2 was a 39-year-old man who received chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone for low-grade B-cell non-Hodgkin's lymphoma in 1993. The lym-The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF PITTSBURGH -MAIN on August 11, 2015. For personal use only. No other uses without permission.

No abstract