Heat shock proteins have been shown to be among the dominant antigens recognized by both the regulatory (helper T lymphocytes) and effector (B lymphocytes and cytotoxic T cells (CTLs)) arms of the adaptive immune system for a variety of pathogenic infections and experimentally induced immune reactions.
B cell responses In mice, immunization with a mycobacterial lysate elicits antibody responses to only a limited number of Mycobacterium tubercu losis or M. leprae antigens, including hsp70, hsp60, hspl8 and hspl2. In a World Health Organization sponsored workshop, a collection of 24 murine monoclonal antibodies raised against M. leprae were found to recognize six proteins, of which three were stress proteins. Seven of these antibodies identified six different epitopes of hsp60. Similar results were obtained with monoclonal antibodies raised against M. tuberculosis. Mycobacterial stress proteins are also recognized by the sera of patients suffering from tuberculosis (and tuberculoid leprosy). hsp60 is the dominant target antigen of serum antibodies in a wide variety of other bacterial infections including those due to Coxiella, Legionella, Treponema and Borrelia. In fact, an immunodominant antigen long known to be shared by most bacterial species called 'common antigen' turns out to be hsp60. Antibodies to hsp70 have been found in the sera of patients with diverse parasitic infections, for example malaria, trypanosomiasis, leishmaniasis and schistosomiasis. In addition, hsp90 is a target for antibodies in malaria and trypanosomiasis and a member of the small hsp family is recognized by sera from some patients with schistosomiasis.
T cell responses Twenty per cent of the CD41 T cells cloned from the draining lymph nodes of mice immunized with M. tuberculosis recognize hsp60. Some of these have been shown to secrete interleukin 2 (IL-2). hsp60 is also a major target antigen in mycobacteria-infected humans. Typically 25-30% of the mycobacteria-reactive CD4+ T cell clones isolated from infected individuals react against M. leprae hsp60. Around 12 separate epitopes have been mapped in the hsp60 protein of mycobacteria which are recognized by MHC class II restricted CD4" T cells. CD4+ T cells recognizing hsp60 have also been isolated from individuals immunized with heat-killed M. tuberculosis. Mice immunized with a cryptic digest of M. tuberculosis have been shown to yield CD8* CTLs specific for epitopes on hsp70. In addition, CD8+ CTLs recognizing M tuberculosis hsp70 have been isolated from the pleural effusion of patients with tuberculosis. Human 78 receptor-bearing T cells which recognize hsp60 have been isolated from the peripheral blood of individuals immunized with BCG.
Because hsps are ubiquitous and highly conserved, and have been shown to be dominant antigens in a range of infections (see above), they have been proposed to provide a link between anti-infectious and autoimmune responses. Thus, antibodies and T cells elicited to hsps encoded by a pathogen might cross-
react with self-hsps. Indeed, peptides derived from endogenous (self) hsps have been isolated from the binding grooves of both MHC class I and class II molecules. Anti stress protein reactive T cells have been implicated in two experimentally induced animal models of autoimmune disease and also in rheumatoid arthritis.
Adjuvant arthritis Intradermal injection of heat-killed M. tuberculosis in rats induces a disease simi lar in many respects to rheumatoid arthritis. An autoimmune process involving T lymphocytes is responsible for the generation of the disease, and transfer of T cells from arthritic rats to irradiated recipients can cause a transient form of the disease in the latter. One arthritogenic T cell clone was shown to recognize a mycobacterial hsp60 epitope. Also, immunization of mice with mycobacterial hsp60 in immunostimulating complexes (ISCOMS) will induce CD8+ a|3 CTLs which cross-react with murine hsp60 and are therefore autoreactive.
Streptococcal cell wall induced arthritis (SCIA) Similar results have been obtained for a second poly-arthritic disease in rats, SCIA, which can be induced by intraperitoneal injection of Streptococcus pyrogenes cell walls. Streptococcal cell wall preparations contain an antigen recognized by antimycobacterial hsp60 antibodies and T cells. Again, the disease condition can be transferred with purified T cells.
Rheumatoid arthritis Results with adjuvant arthritis prompted investigators to ask whether T cells from rheumatoid arthritis patients can also recognize mycobacterial hsps. In some studies, mycobacterial hsp60 and hsp70 have been shown to be among the antigens recognized by polyclonal synovial T cells, and there is evidence that these can cross-react with human hsp70. yS T cells have also been cloned from rheumatoid synovia which respond to mycobacterial hsps. Moreover, elevated levels of IgG and IgA antibodies that bind mycobacterial hsp60 and hsp70 have been detected in some patients with rheumatoid arthritis. However, any role for mycobacteria '.or indeed any other infectious agent) in the development of rheumatoid arthritis in humans remains highly speculative.
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