The patients included in the present study had frequent asthmatic attacks, with signs of wheezing and higher levels of IgE and IL4 and low levels of FEV1 %Pre that are characteristics of asthma. We found that these asthma patients also had a significantly higher incidence of autoantibodies against combined Hsp60 and Hsp70 than the matched non-asthmatic controls and that, in particular, the presence of anti-Hsp70 was associated with asthma. Furthermore, there was a significant positive correlation between anti-Hsp60 and anti-Hsp70 and symptom severity of asthma. Thus among asthma patients, those who had positive anti-Hsp60 and anti-Hsp70 were more likely to report a family history of asthma and had higher levels of IgE and IL-4 than those without such antibodies. These findings provide evidence to support the hypothesis that the presence of anti-Hsp60 and especially anti-Hsp70 in asthma patients is strongly associated with asthma and the presence of these antibodies may predict symptom severity of asthma and provide new strategies for diagnosis and perhaps treatment of this disease.
Asthma is an immune and inflammatory disease, arising from complex interactions among genetic and environmental factors including bacterial or viral infection [14
]. The production of autoantibodies against Hsps may result from genetic factors, infection, denaturation and release of Hsps as a result of cell damage, and the presence of antigen-specific lymphocytes [22
Hsps are often the target of humoral and T cell-mediated immune responses to infection and may provide a link between the immune response to infection and autoimmunity caused by T lymphocyte cross-reactivity among Hsps of different origins [8
]. It remains to be determined whether there is a relationship between the induction of Hsp70 and production of plasma autoantibodies against this Hsp and whether there is a cross-response of induced Hsps and autoantibodies against Hsps before and during the development of asthma. However, there are several lines of evidence that support an association between anti-Hsp60 and anti-Hsp70 and symptom severity in asthma patients. Firstly, as molecular chaperones, Hsps facilitate the synthesis, folding, assembly and intracellular trafficking of many functional proteins [3
] and protect cells and organs against different types of damages [30
] as observed in transient protection from ischemic injury in whole organs such as heart, brain and kidney [31
]. Hsp70 has also been suggested to play an autoprotective role in asthma and lung injury [35
]. Secondly, autoantibodies against Hsps may have significant roles in the pathogenesis and prognosis of diseases. For example, Shinghai et al reported the presence of antibodies against Hsps in patients with autoimmune liver diseases and suggested that the presence of anti-Hsp70 was an indicator for the disease activity of primary biliary cirrhosis [8
]. Earlier results from our lab also suggested that the presence of such antibodies might help assess if workers are experiencing abnormal stress within their living and working environment [21
]. Xu et al and Schett et al have shown that mycobacterial Hsp65 may serve as an antigen to instigate chronic immune responses characteristic of human atherosclerosis. These antibodies were sustained among patients with the most severe degree of underlying atherosclerosis and were demonstrated to predict 5-year mortality [11
]. Thirdly, enhanced expression of Hsp70 has been detected in bronchi and alveolar macrophages of patients with asthma and correlated with intrapulmonary eosinophilia, airway inflammation, hyperresponsiveness of bronchi [38
], and severity of the disease [14
]. A cross-response of induced plasma and cellular Hsps and autoantibodies against Hsps in human, has been suggested to play a role in the development and prognosis of atherosclerosis [40
]. However, it is still unknown whether there is a cross-response between the induction of Hsps in bronchi of patients with asthma and the presence of anti-Hsps and its biological effects.
The development of most immune diseases depends on the cytokines interleukin-2 and interferon-γ produced by type 1 helper T cells (Th1), whereas the development of allergic diseases requires IL-4 and IL-5, both of which are produced by type 2 helper T cells (Th2). The reciprocal down-regulation of Th1 cells by Th2 cytokines raises the possibility that these cytokines are involved in allergy or immunity [42
]. IL-4 is one of the first signals for a switch to the synthesis of IgE and IL-4 binds to receptors on B cells to induce and amplify the synthesis of IgE [43
]. There is a cross-linking of IgE with allergens to activate a series of response seen in asthma [44
]. Epidemiological and clinical observations have linked IgE antibodies to the severity of asthma and the initial and sustained responses of the airways to allergens [45
]. At this time, the molecular events that link antibody to Hsp70 to the production of IL-4 and IgE and the interaction among these factors in patients with asthma remain to be investigated.