Cell Surface Expression of Stress Proteins

Although primarily intracellular, certain data suggest that stress proteins, or close homologues thereof, may be expressed on plasma membranes of lymphocytes and other cells. For example, a hsp 70-related peptide-binding protein that appears to act in antigen presentation (11,12) has been detected on the surface of mouse B cells. Similarly, our laboratory has described a GroEL-related ~77-kDa protein on the surface membrane of yS cells, which is not present on T cells with ap receptors (13). In an extension of this latter finding, we used monospecific antibodies as probes to define the surface localization of several large stress proteins (hsp 60, hsp 70, hsp 90, and hsp 110), or cross-reactive molecules thereof, on various types of resting, heat-shocked, or activated lymphocytes and phagocytic cells from normal peripheral blood or other non-SLE

sources (W.N.J., et al., unpublished observations). B-cell lines, T cells with y8 receptors, and mitogen-activated peripheral T cells were shown to react with anti-hsp 60 in indirect immunofluorescence and complement-dependent micro-cytotoxicity assays. Mitogen-activated T cells, but not resting T cells or other cell types, also reacted with anti-hsp 90. Surface expression of proteins related to hsp 110 or members of the hsp 70 family of stress proteins on T cells, B cells, and several monomyelocytic cell lines was not observed. In contrast to our preliminary data suggesting that the monomyelocytic line HL60 expressed hsp 90 after heat shock or stimulation with phorbol esters (14), positive anti-hsp 90 staining of this cell line and several other phagocytic cell lines was not demonstrable when cell death was limited to 5% or less.

The issue of cell surface expression of hsp 90 on PBMCs from patients with SLE or other autoimmune diseases has been approached by Erkeller-Yuksel and colleagues (15). Using AC88, an IgGl monoclonal antibody raised against hsp 90 isolated from Achyla ambisexualis that recognizes human hsp 90, and flow cytometry, ~2% of PBMCs from 62 patients with SLE exhibited immunofluo-rescent staining, a significantly higher value than the 0.4% staining seen with PBMCs from 42 control subjects. Anti-hsp 90 surface staining was particularly prominent in patients with active SLE, but it was not linked to expression of lymphocyte activation markers. Disease control patients with Sjogren's syndrome, systemic sclerosis, rheumatoid arthritis, and polymyositis/dermato-myositis were only occasionally positive in this investigation.

Excluding molecules with structural characteristics of integral membrane proteins (16,17), stress proteins (or peptides thereof) could be expressed on the cell surface by three mechanisms: (1) presentation of stress protein peptides by MHC class I, class II, class lb molecules; (2) translocation of stress proteins to the cell surface as they chaperon nascent integral membrane proteins or damaged intracellular proteins to the plasma membrane; and (3) secondary binding of released or secreted extracellular stress proteins to surface membrane proteins. Regardless of the mechanism(s) by which stress proteins (or their epitopes) get to the cell surface, the fact that they do broadens their potential significance vis-a-vis repertoire selection, cellular activation, immune surveillance, regulation of lymphocyte growth and differentiation, autoimmunity, and perhaps autoimmune disease (18).

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