Antibodies to heat-shock protein 27 are associated with improved survival in patients with breast cancer.

The overexpression of the heat-shock proteins hsp90, hsp70 and hsp27 in human mammary carcinomas has previously been shown to correlate with reduced overall survival. Moreover, antibodies to hsp90 were detectable in the serum of a large proportion of breast cancer patients but they were not found in normal controls. High antibody levels also correlated with reduced survival. Here, we show that antibodies to hsp27 were also detectable in the sera from breast cancer patients but not from normal controls, whereas antibodies to hsp70 were detectable in approximately one-third of both groups. The presence of antibodies to hsp27 was correlated with an improved rather than a reduced survival, particularly beyond the first 5 years. Hence, the overexpression of hsps in breast cancer cells does not provoke a generalized immune response to all the hsps. Moreover, the presence of antibodies to different hsps has distinct associations with survival. These effects are discussed in terms of the mechanisms that provoke an immune response to the hsps and the protective/non-protective effects of such a response.

Do heat shock proteins have a role in breast cancer?

It is clear therefore that hsps are overexpressed in patients with malignant tumours compared with healthy controls and this overexpression does show some correlation with disease features. Furthermore, expression of hsps has been reported on the cell surface of tumour cell lines. This could be associated with the immune response which has been reported with hsp90 and which also correlates with some disease features. It now appears that hsps may be involved in the presentation of tumour antigens leading to the possibility of hsps being used as a means of therapy. Hsp65 expression has not been investigated in patients with breast cancer. However, transfection of bacterial hsp65 into a tumour cell line resulted in the hsp65-expressing tumour cells losing their tumorigenicity in mice (Lukacs et al., 1993). Thus, hsps and the immune response to them are of interest as diagnostic and prognostic tools as well as a novel form of immunotherapy.

Prolactin levels and antinuclear antibody profiles in women tested for connective tissue disease.

Hyperprolactinemia has been reported in some patients with active systemic lupus erythematosus (SLE). To determine if there was an association between selected autoantibodies and hyperprolactinemia, we assayed prolactin concentrations in sera from women submitted to a reference antinuclear antibody laboratory. Autoantibody-positive samples were separated into groups that contained antibodies to double-stranded DNA (anti-DNA), antibodies to SSA/Ro (anti-SSA/Ro), or antibodies to both SSA/Ro and SSB/La (anti-SSA/Ro-SSB/La). Results were compared with autoantibody-negative sera from age-matched women, submitted to the same laboratory. We also compared the study groups with a separate cohort of 84 healthy women who were not referred for autoantibody testing. Elevated prolactin levels were clustered in 20% of sera from anti-DNA-positive women < or = 50 years of age. Twenty-one percent of anti-SSA/Ro-SSB/La-positive women < 50 years of age were hyperprolactinemic. Four of the 15 hyperprolactinemic women identified in this survey had no known cause of elevated prolactin. In the other 11 individuals secondary causes such as hypothyroidism, pregnancy, chronic renal failure, and medications may have accounted for high serum prolactin values. We also examined sera by Western blot, to determine if immunoblot patterns were associated with elevated serum prolactin concentrations. The hyperprolactinemic sera yielded novel bands migrating at 70 kd, 32 kd, and 16.5 kd. This study confirmed the reported associations of hyperprolactinemia with SLE and Sjögren's syndrome. Multiple factors appeared to contribute to elevated serum prolactin levels in women with connective tissue diseases, and the presence of hyperprolactinemia was related to unique findings on immunoblot analysis.

Incidence of anti Hsp 90 and 70 antibodies in children with SLE, juvenile dermatomyositis and juvenile chronic arthritis.

OBJECTIVE: To determine the incidence of anti-hsp90 and 70 antibodies in children with SLE, juvenile dermatomyositis and juvenile chronic arthritis. METHODS: We utilized a previously described ELISA to detect the presence of antibodies to mammalian hsp90 and 70 in 33 children with SLE, 55 with juvenile chronic arthritis (JCA) and 11 with dermatomyositis. Sera from 19 children with non-autoimmune conditions served as controls. RESULTS: Antibodies reactive with hsp90 and/or 70 were detected in 35% of the children with SLE, and the numbers of children with SLE who have raised IgG anti-hsp90 antibodies (24%) is very similar to our adult onset cases, although the prevalence of IgM antibodies is much smaller. However, serum antibodies to hsp70 were as infrequent in children with SLE or JCA as in adults with SLE or RA, although IgG antibodies to hsp70 were detected in 50% of the synovial fluid of JCA patients. CONCLUSION: The incidence of antibodies to hsp90 in childhood-onset SLE resembles that described in adult onset disease suggesting that, despite clinical differences between the two, a subset of each may share a similar pathological mechanism of disease.

The occurrence, nature and distribution of flares in a cohort of patients with systemic lupus erythematosus: a rheumatological view.

This study examines the occurrence, nature and distribution of disease flares in systemic lupus erythematosus (SLE) according to organ involvement. One-hundred-and-fourteen patients were seen in the Lupus Clinic of the Bloomsbury Rheumatology Unit over a 3-yr period. At each visit a data sheet was completed to assess their disease activity in eight separate organs/systems according to the British Isles Lupus Assessment Group (BILAG) activity index. This information was entered into a computer and a score for each organ system was obtained. The record of each individual patient was examined to identify flares in the individual organs; 458 flares occurred in 107 patients. The majority of patients (69%) experienced more than one flare during the study period. Fifty-four per cent of patients had flares in more than one system simultaneously, but the majority (70%) of flares involved only one system. The most severe organ involvement (A score) was most commonly observed in the musculoskeletal system, whereas severe renal disease occurred only three times. These results indicate that although SLE is a multisystem disease, the flares that occur tend to be confined to one system at a time. Further, these results demonstrate that in our rheumatology practice the most common 'A' flare observed was severe polyarthritis (A score in musculoskeletal).

Detection of autoantibodies to the 90 kDa heat shock protein in systemic lupus erythematosus and other autoimmune diseases.

Expression of the highly conserved 90 kDa heat shock protein (Hsp90) is elevated in the peripheral blood mononuclear cells of approximately 25% of patients with SLE. Conflicting data have been published about the frequency of antibodies to Hsp90 with the previous methodology using a complex Western blot system. We now describe an ELISA to measure autoantibodies to Hsp90 and Hsp70 in SLE patients, healthy controls and patients with a variety of autoimmune rheumatic diseases. IgG and IgM antibodies were elevated in 26 and 35% of SLE patients, respectively. These results show autoantibodies to Hsp90 (but not Hsp70) are elevated in a significant proportion of patients with SLE (P < 0.025) compared to healthy controls; and that those with raised antibody levels were more likely to have renal disease and a low C3 level (P < 0.02).