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Immunochemical characterization of, and isolation of the gene for Borrelia burgdorferi immunodominant kilodalton antigen common to a wide range of bacteria. Each of these lines of evidence has important limitations in establishing a causal role for abnormalities in specific brain regions in producing OCD. The genome of Mobiie.de cruzi contains a constitutively expressed tandemly arranged multicopy gene homologous to a major heat shock protein. In many cases, antibody titers exceeded the levels found in healthy top gun flugzeug. When adoptively transferred, isolated CD8 T-cell clones from mice immunized with mycobacterial hsp60 mediate partial protection against infection with M. Another question, raised specifically by findings of the prospective study described above Grados et al. Uppdrag inom institutionen, fakulteten och universitetet: Sant A, Miller J. Second, anatomical ROIs may not correspond to functionally meaningful units because gross anatomical structures or landmarks do not always reflect anatomical connectivity or cytoarchitecture. Focal striatal abnormalities in a patient with obsessive-compulsive disorder. Down-regulation of Overwatch mai cell receptors sugarhouse online casino nj app 100 besten online casinos T cell as novel mechanism for eisen kießling tolerance induction. The T cell repertoire against self determinants and its involvement in autoimmunity and cancer.

Both pathways of T-cell selection require a high diversity of self peptides present in the thymus 2. Thymic selection deletes the majority of self-reactive T cells.

Poor display or absence of self peptides in the thymus as well as self-reactive T cells with low avidity may result in incomplete negative selection.

Such T cells then leave the thymus and enter the periphery Under normal conditions, potentially self-reactive T cells in the periphery are effectively controlled by different mechanisms leading to peripheral tolerance 76 , , In some models, downregulation of TCR maintains tolerance among peripheral T cells in response to continuous challenge with self antigen 76 , The extent of downregulation, however, depends on the availability of antigen.

Downregulation of both TCR and CD28, a costimulatory molecule involved in T-cell activation, has been shown to initiate a stage of unresponsiveness in T cells that is termed anergy , It is suggested that the inhibitory effects of CTLA-4 on T cells lead to termination of the immune response by curtailing IL-2 production and inducing cell cycle arrest Conversely, interactions between B7 on APC and CD28 on lymphocytes are involved in the reversal of the anergic state , Therefore, the increased expression levels of B7 in the periphery found during microbial infection may play a critical role by supporting the activation of both the T cells controlling infection and the T cells with self-reactive potential.

In recent studies, correlation of hsp and B7 expression has been found on APC from patients with inflammatory disease, suggesting that coexpression of hsp and B7 participates in initiation and maintenance of autoimmune responses in inflammatory diseases The observation that hsp is presented by B7-positive cells indicates that sensitization to hsp may contribute to the loss of immune tolerance and to inflammation in patients with autoimmune disorders.

During infection, potentially self-reactive T cells can be activated by dominant determinants of microbial antigens. Molecular mimicry between self and foreign molecules has been proposed to represent one possibility for activation of such cells in the periphery , Among microbial antigens implicated in autoimmunity induced by molecular mimicry, hsp may play an exclusive role.

Homology between hsp from the pathogen and the host confronts the immune system with the dilemma of distinguishing self from foreign. Poor expression of self-hsp peptides in the thymus could allow T cells specific for self hsp to evade selection.

In the periphery, elevated expression of conserved epitopes from pathogen-derived hsp could break tolerance and activate immune reactions against self-hsp determinants.

During microbial infections, hsp determinants expressed on the cell surface can be recognized by antibodies with specificity for self-hsp epitopes.

The mechanisms involved in translocating hsp to the cell surface are still not fully understood, since hsp are typical cytosolic proteins that lack the specific leader sequences normally required for cell surface expression.

Nevertheless, numerous studies have reported hsp presentation on the cell surface So far, the consequences of hsp expression and recognition by self-reactive antibodies for autoimmunity remain to be elucidated.

Other studies identified cell surface-expressed hsp on nontransformed cells. Surface-expressed hsp60 was identified on macrophages , oligodendrocytes 86 , and endothelial cells 3 , Moreover, hsp70 or hsp90 products were identified on B cells and monocytes Surface-expressed hsp70 may also function as a target structure for natural killer NK cells Although these studies strongly favor cell surface expression of hsp, cross-reactivity of antibodies with other cell surface proteins cannot be excluded.

Therefore, the identity of these proteins awaits precipitation of the surface molecules by monoclonal antibodies followed by amino acid sequencing.

Accordingly, the question remains whether self-hsp expression is associated with autoimmune disease. In a number of autoimmune disorders in human and animal models, hsp expression in affected cells has been observed, supporting the idea that hsp expression contributes to immunopathologic changes.

For example, a significant proportion of patients with systemic lupus erythematosus SLE expressed hsp90 on lymphocytes and monocytes Recently, another hsp member, which is recognized by T cells specific for myelin, was identified in MS 14 , In these studies, increased expression of alpha B-crystallin, a member of the small hsp family, was found in astrocytes and oligodendrocytes in MS lesions.

A beneficial role of hsp60 in inflamed synovium of patients with rheumatoid arthritis RA has been proposed recently. Expression of self hsp60 at sites of autoaggression may actively ameliorate disease by stimulating lymphocytes of the Th2 type There are, therefore, several examples that provide evidence for hsp presentation on the cell surface.

Self epitopes that are surface expressed enhance the opportunity for cells to become targets of self-reactive antibodies with specificity for hsp.

Frequently, hsp surface expression is increased in affected tissue in autoimmune diseases, emphasizing a role of hsp determinants in autoimmune disease.

T cells specific for self-hsp epitopes have been found in both human and animal studies. An important prerequisite for stimulation of hsp-reactive T cells is the presentation of the corresponding peptides by MHC molecules.

Since stressful conditions raise hsp synthesis in cells , , , , , it can be assumed that increased levels of hsp in cells correlates with intensified degradation of these proteins and subsequent generation of hsp peptides in the cytosol.

Under these circumstances, hsp peptides, like other peptides, gain access to the loading compartments of MHC class I molecules.

Among the many natural peptides that have been identified so far, self-hsp peptides were also isolated from MHC molecules , , , Although the cytosolic localization of hsp would suggest MHC class I loading only, self-hsp peptides have also been isolated from MHC class II molecules, which normally present endosomal peptides derived from exogenous proteins.

This emphasizes that the division between loading of MHC class I and class II molecules is not as rigid as was originally assumed.

In several instances, hsp were found to serve as target antigens for T cells in autoimmune processes. In healthy individuals, T cells specific for self hsp that escaped thymic selection are effectively controlled.

Tolerance of T cells to self hsp may be additionally maintained by the permanent encounter of cross-reactive hsp epitopes derived from food and commensal organisms , Induction of tolerance by oral administration of antigens has been demonstrated in other systems In these studies, introduction of self antigens via the gut mucosa effectively suppressed several experimental autoimmune diseases in an antigen-specific fashion.

Comparison of the amino acid sequence of naturally processed self-hsp peptides eluted from MHC molecules with the database of known proteins revealed similarity to antigens from food and microbes Particularly in pathologic situations, e.

If the immune system fails to ignore these cross-reactive regions, a protective immune responses may be converted to a pathological one.

In healthy individuals, there exists a well balanced network of potentially self-reactive antibodies and T cells that have evaded deletion processes.

In this situation, the immune system responds to its own hsp in a manner that could promote the recognition and elimination of aberrant cells.

However, when hsp expression and hsp-specific immune responses are regulated inappropriately, autoimmune reactions may follow.

Tolerance to self antigens in particular may become distorted by the frequent encounter of the immune system with foreign e. In fact, molecular mimicry is widely discussed as one mechanism responsible for the induction of autoimmune disease Immune responses to conserved regions shared by pathogen and self hsp in individuals during active infection were not unexpected.

Hence, in several infectious diseases, increased titers of antibodies reactive for conserved regions of hsp shared by the pathogen and host have been identified.

For example, increased levels of antibodies against self hsp60 have been found in sera of patients with Lyme disease, suggesting an association between self-reactive antibodies and infection with Borrelia burgdorferi Another example of harmful hsp effects is found in chlamydial infections, where hsp frequently represent strong antigens.

Immune responses to chlamydial hsp60 significantly correlate with disease sequelae in humans, and hsp-specific antibodies cause marked inflammatory reactions in animal models of experimental Chlamydia trachomatis infection A direct contribution of antibodies specific for chlamydial hsp60 to disease pathogenesis has been described It is assumed that in chlamydial infection, bacterial hsp60 induces cross-reactive immune responses to self hsp60 and thus is in the focus of immune damage during chronic infection.

Similarly, in sera from patients with malaria, antibodies responding to hsp70 of Plasmodium falciparum and self can be found Moreover, a detrimental role of hsp-specific antibodies was discussed as part of the infection-induced autoimmune response in onchocerciasis Together, these findings suggest that autoantibodies directed against host hsp can be induced by the homologous microbial protein.

For example, in leprosy patients, antibodies directed to the mycobacterial hsp60 cross-react with self hsp60 expressed by sciatic nerves Moreover, T cells specific for self hsp60 have been found in leprosy patients.

Activation of self-hspreactive T cells seems to occur preferentially during inflammatory responses 7. This indicates that some epitopes recognized by patient antibodies or T cells are shared by the mycobacterial hsp60 and that cross-reactivity may contribute to autoimmune processes found in patients with leprosy.

Similarly, cross-reactive CD8 T cells recognizing regions of the mycobacterial hsp70 and the human hsp70 have been identified in patients with tuberculosis In other studies, CD4 T cells that were isolated from leprosy patients and had specificity for mycobacterial hsp70 also recognized epitopes of the human hsp70 cognate Although conclusive evidence is missing, it has been proposed that cross-recognition by hsp-reactive T cells plays a unique role in autoimmune processes in chronic inflammation, such as during leprosy and tuberculosis.

Further support for T-cell cross-recognition of hsp regions shared by the host and pathogen comes from epitope-mapping studies with a T-cell clone derived from mice primed with mycobacterial hsp Interestingly, two cross-reactive peptides of the mycobacterial hsp60 and self hsp60 that have only intermediate homology were identified , This strongly suggests that during mycobacterial infection, an increased expression of such hsp60 epitopes by MHC class I molecules allows the stimulation of CD8 T cells with the aforementioned cross-reactivity.

Because these CD8 T cells also respond to stressed host cells in vitro, these findings provide further support that foreign hsp epitopes with homology to self hsp can trigger autoimmune responses.

Especially in chronic inflammatory diseases, structural homology between microbial hsp and self hsp was originally postulated to provide a basis for autoimmunity , Indeed, immune responses to conserved regions shared by self hsp and microbial hsp are found frequently in chronic inflammatory diseases.

This cross-reactivity prompted the idea that at least in some autoimmune disorders, the trigger for autoaggression may lie in a microbial infection which activated immunity against self hsp.

Increased antibody reactivities to hsp60 have been detected in the sera of patients with inflammatory bowel diseases, e.

Similarly, the humoral response against hsp60 and hsp70 of M. In patients with recurrent oral ulcers, cross-reactive lymphocytes which respond to a shared epitope of the mycobacterial hsp60 and human hsp60 have been isolated It has been proposed that the high load of microorganisms that colonize the oral mucosa, combined with the molecular mimicry between microbial and human hsp epitopes, elicits autoimmune responses in the oral mucosa.

While these studies favor a role for microbial hsp in inducing cross-reactive hsp responses in chronic inflammatory diseases, the role of autoimmune antibodies or T cells in disease pathogenesis still remains to be elucidated.

The fact that antibodies as well as T cells cross-reactive for epitopes shared between pathogen hsp and mammalian hsp have been identified in healthy individuals , , probably because of the abundant presence of commensal organisms, argues against a disease-provoking role for hsp antibodies in autoimmune disease.

Cross-reactive T-cell responses against hsp from the microbe and host have been found in a number of studies 7 , , , However, most of these studies were based on the use of synthetic peptides and hence fail to directly demonstrate natural processing of cross-reactive determinants.

Experiments have been performed to evaluate whether physiologic processing generates self-epitopes presented by host cells to cross-reactive T cells specific for microbial hsp.

Since cells augment hsp synthesis under stressful conditions, these results favored cross-recognition of mycobacterial hsp60 peptides and peptides derived from self hsp These cells recognized host cells previously exposed to stress-inducing agents, thus demonstrating cross-reactivity with naturally processed determinants.

Experiments in which target cell lysis by CD8 T cells was inhibited by treatment of stressed target cells with hspspecific antisense oligonucleotides further emphasize that autoimmune lysis by hspreactive CD8 T cells is based on recognition of self-hsp peptides In these studies, although recognition by T cells was restricted exclusively to peptide presentation by the murine MHC class I molecule H-2D b , the mycobacterial hsp60 peptide did not fully correspond to the characteristic motif of naturally eluted H-2D b peptides.

The CD8 T cells failed to respond to a peptide from a conserved region of the mammalian hsp60 representing highest homology in the self-hsp60 sequence.

Rather, T cells responded to a self-hsp60 peptide with intermediate homology but encompassing the characteristic anchor residue essential for binding to H-2D b.

Apparently, the lack of reaction with the homologous peptide from the mammalian hsp60 was caused by the lack of a single residue required for anchoring the peptide in the H-2D b groove.

In sum, these findings suggest that T-cell cross-reactivity is influenced primarily by two features. First, the requirements for binding of peptides to the MHC molecule have to be fulfilled; and second, homology of the MHC-bound peptide to a stimulatory peptide decides whether cross-reactive T cells are activated.

Significant homology between regions shared by host hsp and microbial hsp therefore does not necessarily imply cross-reactivity.

Additionally, different origins of both proteins—exogenous or endogenous—may result in distinct MHC-processing pathways.

Further, it has been shown that flanking sequences of epitopes in proteins strongly influence the enzymatic cleavage site, leading to different epitopes 33 , In conclusion, cross-reactive determinants of microbial hsp can prime self-hsp-reactive T cells.

However, cross-reactivity between hsp peptides is more complex and influenced not only by highest homology but also by other factors.

For a better understanding of the mechanisms underlying human autoimmune diseases, several experimental models have been exploited.

Data from several arthritis models such as adjuvant arthritis AA , pristane-induced arthritis, streptococcal cell wall-induced arthritis, and collagen type II-induced arthritis favor a role for hsp60 autoimmune T cells in disease 22 , , , Perhaps the most striking evidence for the role of hsp60 as a critical autoantigen in the development of autoimmune disease has been obtained in two animal models, AA in rats and insulin-dependent diabetes mellitus IDDM in NOD mice.

Certain rat strains immunized with heat-killed M. T cells are critical, since this disease can be adoptively transferred to naive recipients by CD4 T cells from arthritic rats.

Epitope analysis of an arthritogenic T-cell clone revealed specificity for a nonconserved mycobacterial hsp60 peptide aa to , with only 3 of 9 residues identical to those of the mammalian hsp60 Paradoxically, the same antigen specificity was described for CD4 T cells which conferred protection against this disease Attempts to induce AA by immunization with mycobacterial hsp60 alone failed; instead, immunization with mycobacterial hsp60 induced a state of resistance to AA 22 , Moreover, complete protection from AA was induced by treatment with the immunodominant peptide aa to of the mycobacterial hsp60, and adoptive transfer of T cells from immunized donors to naive recipients conferred protection Similarly, a therapeutic effect against AA was achieved by administering a recombinant vaccinia virus expressing the hsp60 Further, suppression of AA was induced by oral administration of mycobacterial hsp60 or nasal tolerization with the hsp60 peptide aa to In other studies, immunization with a mycobacterial hsp60 peptide, which primes for cross-reactive T-cell responses to the corresponding region of the self hsp60, protected against AA 8.

This runs counter to the accepted theory that cross-reactive T-cell responses are responsible for autoimmunity. It has been suggested that in AA, cross-reactivity between bacterial hsp60 and self hsp60 maintains a regulatory protective T-cell population which becomes fully activated by immunization with the cross-reactive mycobacterial hsp60 epitope.

These data provide evidence that recognition of self-hsp60 can have beneficial effects in arthritis and may offer new strategies for improved control measures in inflammatory processes by administration of peptides cross-reactive to self determinants.

Other studies extended these findings by showing that the development of diabetes in such mice is prevented by infection with M.

Here, mycobacteria, and probably their hsp60, may be responsible for modulating the immune response in NOD mice and preventing diabetes.

Although circulating antibodies to the self-hsp60 are increased in NOD mice, the T-cell response is mainly in charge of the onset of diabetes.

Interestingly, this peptide differs only by 1 aa from mouse hsp After adoptive transfer, T-cell clones produced profound insulitis in mice. Similarly, immunization of NOD mice with the hsp60 peptide p conferred significant protection 65 , 68 whereas immunization of standard strains of mice induced diabetes Recent data suggest that p treatment of NOD mice induces a Th2 cytokine burst which downregulates the Th1-mediated autoimmune response to hsp60 Although these results provide strong evidence that one of the antigens in diabetes is related to hsp60, recent observations favor a kDa protein, glutamic acid decarboxylase GAD , as a major self-antigen of IDDM in both NOD mice and humans The fact that hsp60, like other stress proteins, is expressed in every cell raises the question of how T-cell immunity to hsp60 causes organ-specific diseases such as AA or IDDM.

It can be assumed that hsp, together with other organ-specific self antigens, serve as targets for the autoimmune response. Several studies do point to a role of hsp in human autoimmune diseases.

Involvement of hsp in autoimmune responses depends on two criteria: Humoral immune responses to hsp have been found in a number of human autoimmune diseases However, because titers against hsp varied from patient to patient and because hsp-specific antibodies were occasionally found in healthy individuals, the role of these proteins in autoimmune diseases is incompletely understood.

Despite these inconsistencies, a correlation between anti-hsp antibodies and the severity of disease holds true for certain autoimmune or chronic inflammatory diseases.

In many cases, antibody titers exceeded the levels found in healthy individuals. Other studies have provided direct evidence that antibodies against hsp specifically bind to target tissues of the autoaggressive response.

Thus, hspspecific antibodies show reactivity for synovial tissue in AA in rats and in patients with RA Similarly, in juvenile chronic arthritis, such hsp antibodies react with synovial membranes and expression of self-hsp60 in inflamed synovium is raised significantly Antibodies to hsp60 have also been detected in patients with cystic fibrosis, SLE, or juvenile chronic arthritis, who apparently have significantly elevated titers compared to healthy individuals It has been claimed that antibodies to the mycobacterial hsp60 play a role in ankylosing spondylitis and RA, and cross-reactivity to self-hsp may play a role in these diseases to some extent Antibodies against human hsp60 cross-reacting with E.

Anti-self-hsp60 antibodies could be induced by commensal organisms such as E. Similarly, elevated levels of hspreactive antibodies have been detected in some autoimmune diseases, implying that these antibodies participate in autoimmune processes.

Consequently, increased antibody levels to hsp90 have been described for a group of SLE patients High titers of antibodies against hsp70 were identified in serum and cerebrospinal fluid of these patients Despite these reports of autoantibodies to hsp in human autoimmune diseases, the general significance of the humoral anti-hsp response with respect to pathogenesis remains to be determined.

The low prevalence of hsp in patients indicates that expression of hsp and formation of antibodies plays a pathogenic role in a subset of patients only.

As with autoantibodies against hsp, hsp-reactive T cells seem to be less prominent in human autoimmune diseases than in experimental models.

The concept of overexpression of self hsp either on the cell surface proper or as peptides presented by MHC products has been central to the hypothesis that hsp-specific antibodies and T cells play a role in the pathogenesis of human autoimmune diseases.

Many events, such as bacterial or viral infections or ischemic processes which cause inflammation, may trigger the expression of self hsp.

In fact, evidence for increased hsp expression has been presented for various inflammatory diseases in humans In atherosclerosis, the intensity of hsp60 expression correlates with recruitment of hsp-specific T cells Whenever hsp overexpression includes conserved hsp determinants, activation of cross-reactive T cells may occur.

Interestingly, children with juvenile RA showed T-cell responses to hsp60 and to aa to of mycobacterial hsp60, which also serves as a dominant antigen in AA in rats Epitope mapping revealed that the response of hspspecific T cells is directed to conserved epitopes This notion is supported by the isolation from synovial fluid of Y.

These cells also react with heat-stressed APC and with mononuclear cells from the synovial fluid of inflamed joints These findings provide further support for induction of hsp-directed autoimmune T-cell responses by natural infection.

Obviously, the relative importance of T-cell responses to hsp60 in reactive arthritis needs to be further evaluated. At present, it appears likely that T cells specific for conserved regions of hsp60 in reactive arthritis play a role in the maintenance of disease rather than causing pathogenesis.

It appears most likely that tissue destruction in autoimmune disease is initiated primarily by T cells specific for organ-specific antigens.

Because these conditions promote the expression of self hsp, T cells specific for hsp may arise in a second wave and then may be attracted to sites of inflammation, where they contribute to autoaggression.

The possibility also exists that tissue-specific antigens have sequence similarity between hsp and consequently allow the activation of hsp-reactive T cells.

In fact, homology of hsp to a major autoantigen has been shown in IDDM While the original proposal that hsp60 serves as an important target of the immune response in IDDM has not been confirmed, sequence similarities between hsp60 and GAD in IDDM may reflect a common relation between hsp and other autoantigens in a number of autoimmune disorders.

This difference may play a role in the autoaggression found in RA. This review has attempted to summarize evidence for a functional role of hsp in antigen processing and recognition.

It has also summarized data which corroborate the role of hsp as an antigen in infection and autoimmune disease, a role which is probably related to the high sequence homology of hsp cognates in different species.

It was this homology which, more than a decade ago, led to the notion that hsp could be more important than other antigens in host defense and autoaggression.

Since then, a vast number of data supporting this notion have accumulated. Indeed, it is safe to state that in certain infections and autoimmune diseases, hsp play a role in protection and pathogenesis, respectively.

However, the evidence to support generalization of this conclusion is far from convincing, since after a wave of corroborative findings, data in support of the contrary viewpoint emerged.

Thus, in several infections and especially autoimmune diseases, the implications of immune responses against hsp are still not fully understood.

It is therefore important to collect more data emphasizing unique situations and to refrain from overgeneralization. For these reasons, this review has focused on assembling the available data, has tried to present the pros and cons for the role of hsp in immunity to infections and autoimmune diseases, and has abstained from far-fetched conclusions.

However, an equal overinterpretation would be to negate any role of hsp in infection and autoimmune disease. As is often the case, the truth is midway between the extremes, with major deflections to either side in different situations.

If there is any general conclusion to be drawn today, it is that hsp, rather than initiating anti-infectious or autoaggressive immune responses, chaperone the immune response induced by other antigens and thus both influence its strength and sustain it.

We thank our colleagues U. Thanks also to R. McCoull for secretarial help and to U. Steinhoff for critically reading the manuscript. National Center for Biotechnology Information , U.

Journal List Clin Microbiol Rev v. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC.

Abstract Increased synthesis of heat shock proteins hsp occurs in prokaryotic and eukaryotic cells when they are exposed to stress.

How Heat Shock Proteins Function as Chaperones Proper folding and assembly of polypeptides depends on a set of conserved proteins known as molecular chaperones.

Open in a separate window. Role of Heat Shock Proteins in Antigen Processing and Presentation Formation of stable MHC complexes capable of presenting antigenic peptides to T cells depends on their proper folding and assembly in the ER, as well as on the availability of peptide ligands.

Control of Infection Both host cells and microbes are confronted with dramatic alterations in their living conditions during infection.

Heat Shock Proteins Promote Antigen Delivery into the Major Histocompatibility Complex Class I Presentation Pathway In an attempt to elicit optimal peptide-specific immune responses in vivo, various proteins such as ovalbumin, bovine serum albumin, and tetanus toxoid have been used in animal models as carriers for peptides in immunization protocols.

Vaccination with Pathogen Heat Shock Proteins Because hsp represent dominant antigens in numerous microbial infections, a potential use of pathogen-derived hsp for vaccination has been suggested.

Cell Surface Expression of Self Heat Shock Proteins During microbial infections, hsp determinants expressed on the cell surface can be recognized by antibodies with specificity for self-hsp epitopes.

Role of Sequence Homology for Cross-Reactivity of T-Cell Epitopes Cross-reactive T-cell responses against hsp from the microbe and host have been found in a number of studies 7 , , , Anti-Heat Shock Protein Responses in Animal Models of Autoimmune Disease For a better understanding of the mechanisms underlying human autoimmune diseases, several experimental models have been exploited.

Disease Finding Reference s IDDM in NOD mice GAD is the major disease-inducing antigen , Levels of anti-self-hsp60 antibodies do not exceed levels in control mice Reactive arthritis The frequency of hspreactive T cells is low in patients with reactive arthritis In inflammatory synovitis, no response to self-hsp60 of synovial fluid cells is observed RA Synovial-fluid-derived T cells do not respond to hsp60 in adults with chronic RA 56 Inconsistent levels of self-hsp-reactive antibodies are found in patients with RA Similar T-cell responses of synovial fluid and peripheral samples from patients and normal individuals are found with respect to hsp60 reactivity 81 SLE No evidence is found for increased anti-self-hsp antibody levels An inconsistent pattern of elevated IgM antibody levels to hsp60 is found in SLE patients MS hsp60 expression is absent in MS lesions Antibodies to Heat Shock Proteins Humoral immune responses to hsp have been found in a number of human autoimmune diseases Human T-cell clones to the kilodalton heat shock protein of Mycobacterium leprae define mycobacterium-specific epitopes rather than shared epitopes.

Peptide in positive and negative selection: Identification of the C-terminal region of 70 kDa heat shock protein from Leishmania Viannia braziliensis as a target for the humoral immune response.

Anderson K S, Cresswell P. Anderton S M, van Eden W. T-lymphocyte recognition of hsp60 in experimental arthritis.

Stress proteins in medicine. Inflammation activates self hspspecific T cells. Activation of T cells recognizing self kD heat shock protein can protect against experimental arthritis.

Borrelia burgdorferi HSP70 homolog. Characterization of an immunoreactive stress protein. Influences of transporter associates with antigen processing TAP on the repertoire of peptides associated with the endoplasmic reticulum-resident stress protein gp Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp Evidence for a differential avidity model of T cell selection in the thymus.

Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Expression of alpha B-crystallin in glia cells during lesional development in multiple sclerosis.

Expression of mammalian kD heat shock protein in the joints of mice with pristane-induced arthritis. B- and T-cell autoantigens in pristane-induced arthritis.

Mycobacterial heat-shock proteins as carrier molecules. The use of the kDa mycobacterial heat-shock protein as carrier for conjugated vaccines can circumvent the need for adjuvants and bacillus Calmette Guerin priming.

Heat shock proteins as carrier molecules: Specificity of antibodies induced after immunization of mice with the mycobacterial heat shock protein of 65 kD.

The Mycobacterium tuberculosis kDa heat-shock protein induces proliferation and cytokine secretion by murine gut intraepithelial lymphocytes.

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A role of Hsp60 in autoimmune diabetes. Analysis in a transgenic model. Birnbaum G, Kotilinek L. Antibodies to kD heat shock protein are present in CSF and sera from patients with multiple sclerosis.

Spinal fluid lymphocytes from a subgroup of multiple sclerosis patients respond to mycobacterial antigens. Heat shock proteins and experimental autoimmune encephalomyelitis EAE: Affinity panning of a library of peptides displayed on bacteriophages reveals the binding specificity of BiP.

Identification and characterization of protective T cells in hsp65 DNA-vaccinated and Mycobacterium tuberculosis -infected mice. Two monoclonal antibodies generated against human hsp60 show reactivity with synovial membranes of patients with juvenile chronic arthritis.

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Evidence for MHC-specific hindering structure on the products of processing. Class II-restricted presentation of an endogenously derived immunodominant T-cell determinant of hen egg lysozyme.

Secretory granule autoantigen in insulin-dependent diabetes mellitus is related to the 62 kDa heat-shock protein hsp60 J Autoimmun.

Immunocytochemical localization of heat-shock protein related protein in beta-cell secretory granules and its altered distribution in non-obese diabetic mice.

Buchmeier N A, Heffron F. Induction of Salmonella stress proteins upon infection of macrophages. Clonal expansion of mycobacterial heat-shock protein-reactive T lymphocytes in the synovial fluid and blood of rheumatoid arthritis patients.

Immunization with a lymphocytic choriomenigitis virus peptide mixed with heat shock protein 70 results in protective antiviral immunity and specific cytotoxic T lymphocytes.

Autoimmunity to chaperones in the pathogenesis of arthritis and diabetes. Autoimmunity, microbial immunity and the immunological homunculus.

Detection of autoantibodies to the 90 kD heat shock protein in SLE and other autoimmune diseases. Incidence of anti Hsp90 and 70 antibodies in children with SLE, juvenile dermatomyositis and juvenile chronic arthritis.

Molecular chaperones of protein biogenesis. Heat shock proteins and molecular chaperones: Heat shock enhances antigen processing and accelerates the formation of compact class II alpha beta dimers.

Antibodies to mycobacterial 65 kDa heat shock protein in systemic sclerosis scleroderma J Autoimmun. The kilodalton protein of Chlamydia trachomatis: Identification and characterization of a DR4-restricted T cell epitope within chlamydia heat shock protein A protective domain of heat-shock protein 60 from Histoplasma capsulatum.

Antibodies to the mycobacterial kd heat-shock protein are reactive with synovial tissue of adjuvant arthritic rats and patients with rheumatoid arthritis and osteoarthritis.

Recognition of human 60 kD heat shock protein by mononuclear cells from patients with juvenile chronic arthritis.

Heat shock proteins and juvenile chronic arthritis. In vivo carrier effect of heat shock proteins in conjugated vaccine constructs.

Priming to heat shock proteins in infants vaccinated against pertussis. A case of chaperones in antigen processing.

Surface expressed heat-shock proteins by stressed or human immunodeficiency virus HIV -infected lymphoid cells represent the target for antibody-dependent cellular cytotoxicity.

The genome of Trypanosoma cruzi contains a constitutively expressed tandemly arranged multicopy gene homologous to a major heat shock protein.

Hsp60 peptides therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various beta-cell antigens.

Elias D, Cohen I R. Peptide therapy for diabetes in NOD mice. Induction of diabetes in standard mice by injection with the p peptide of a kDa heat shock protein.

Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human kDa heat shock protein. Disease association of antibodies to human and mycobacterial hsp70 and hsp60 stress proteins.

Molecular cloning of mtp70, a mitochondrial member of the hsp70 family. Surface expression of heat shock protein 90 by blood mononuclear cells from patients with systemic lupus erythematosus.

Identification of naturally processed viral nonapeptides allows their quantification in infected cells and suggests on allele-specific T cell epitope forecast.

Residues in chaperon in GroEL required for polypeptide binding and release. Levels of peripheral T cell tolerance induced by different doses of tolerogen.

Unusual expression and localization of heat-shock proteins in human tumor cells. The GroES homolog of Helicobacter pylori confers protective immunity against mucosal infection in mice.

Mutants of Salmonella typhimurium that cannot survive within the macrophage are avirulent. Limiting dilution analysis of proliferative T cell responses to mycobacterial kD heat-shock protein fails to show significant frequency differences between synovial fluid and peripheral blood of patients with rheumatoid arthritis.

Peptide binding and release by proteins implicated as catalysts of protein assembly. Peptide-binding specificity of the molecular chaperone BiP.

Schwann cells are able to present exogenous mycobacterial hsp70 to antigen-specific T lymphocytes. Differential expression of heat shock proteins by human glial cells.

Gamma delta T-cell-human glial cell interactions. Relationship between heat shock protein expression and susceptibility to cytolysis.

Folding of nascent polypeptide chains in a high molecular mass assembly with molecular chaperones. Gammon G, Sercarz E. How some T cells escape tolerance induction.

Qualitative and semiqualitative differences in heat shock protein 60 expression in the central nervous system.

Homology of the kilodalton antigens from Mycobacterium leprae and Mycobacterium tuberculosis kilodalton antigen and with the conserved heat shock protein 70 of eucaryotes.

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The role of the T cell costimulator B in autoimmunity and the induction and maintenance of tolerance to peripheral antigen.

Listeria monocytogenes can grow in macrophages without the aid of proteins induced by environmental stresses. Immunochemical characterization of, and isolation of the gene for Borrelia burgdorferi immunodominant kilodalton antigen common to a wide range of bacteria.

Suppression of adjuvant arthritis in rats by induction of oral tolerance to mycobacterial kDa heat shock protein. Antigen expressed by Salmonella typhimurium is processed for class I major histocompatibility complex presentation by macrophages but not infected epithelial cells.

Harding C V, Song R. Phagocytic processing of exogenous particular antigens by macrophages for presentation by MHC class I molecules.

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Schistosome heat-shock proteins are immunologically distinct host-like antigens. Purification and properties of GroE, a host protein involved in bacteriophage assembly.

Synovial fluid-derived Yersinia-reactive T cells responding to human kDa heat-shock protein and heat-stressed antigen-presenting cells.

Immunohistochemical detection and localization of a kilodalton heat shock protein in autoimmune thyroid disease.

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Cloning and temperature-dependent expression in Escherichia coli of a Legionella pneumophila gene coding for a genus-common kilodalton antigen.

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A kD heat shock protein hsp from Mycobacterium tuberculosis has modulatory effects on experimental rat arthritis. Whether abnormalities in the development of the ACC may lead to deficits in the self-regulation of intrusive thoughts, images, or feelings, or to the well-documented deficits in inhibitory control in OCD Chamberlain et al.

Some evidence suggests that such decreases may be most pronounced between 4 and 12 years of age Giedd, Snell et al.

These age ranges are consistent with the ages during which childhood-onset OCD typically begins, raising the possibility that abnormal development of the caudate could cause childhood-onset OCD.

Volumes of the lenticular nuclei Giedd et al. In addition, white matter tracts within the basal ganglia and between the basal ganglia and thalamus also develop during childhood and adolescence Barnea-Goraly et al.

Together with the findings of maturation of frontal cortex during childhood and adolescence Barnea-Goraly et al. OCD may conceivably be caused by abnormalities in the development of one or more of the key structures or white matter tracts in these loops.

Many studies have reported sexual dimorphisms in the human brain Gilmore et al. These tend to occur in regions that have high concentrations of sex steroid receptors during brain development Goldstein et al.

Sex differences in brain structure and development during childhood and adolescence may provide an explanation for the significantly higher prevalence of childhood-onset OCD in boys than in girls.

Comparisons of volumes of brain structures between males and females are therefore usually performed after adjusting for overall brain volume.

When this is done, girls have greater caudate volumes than boys Caviness et al. In addition, the decline in volumes of the caudate and lenticular nuclei during childhood and adolescence may be restricted to boys Giedd et al.

Potential sexual dimorphisms in the human OFC during childhood or adolescence remain to be studied. In adulthood, women have larger OFC volumes than men Goldstein et al.

These anatomical differences have functional implications, as males perform better on average than females on tasks that rely on OFC function Overman, Such performance differences seem to apply across most age groups, and have been found even in children younger than 3 years of age Overman, In short, the structure, function, and development of the OFC seem to differ between males and females.

The contribution of these differences to the differing susceptibilities of boys and girls to OCD remains, however, to be elucidated. Several lines of evidence suggest that these differences in OFC structure, function, and development in males and females are caused by the effects of gonadal hormones on the OFC during development.

The finding of more extensive dendritic fields in the OFC of female rats may also help to explain the findings of larger volume Goldstein et al.

These findings do not, however, per se license any conclusions regarding a causal role for those abnormalities in OCD.

Studies of OCD as a consequence of brain injury suggest that lesions in key components of these loops may also cause OCD; however, much of this evidence is based on case reports.

Whole-brain approaches such as VBM have also found gray matter abnormalities in all of these areas. First, the etiology of OCD may involve some mechanism that causes widespread abnormalities in all of these structures.

Second, the etiology of OCD may involve some mechanism that causes an abnormality in just one or a small number of these structures, with the abnormalities in the remaining structures being a consequence of dynamic changes prompted by that primary etiologic abnormality.

Thus, abnormalities in one or a few structures in these loops could translate into structural abnormalities in all of the structures within the loops and related structures elsewhere.

Third, the etiology of OCD may, as in the second hypothesis, consist of an initial abnormality in just one or a few structures, with the abnormalities in the remaining structures following from that, but with different cases of OCD possibly arising from initial abnormalities in different structures.

Fourth, the widespread abnormalities may actually be an artifact of averaging across subjects, with individual subjects having more localized abnormalities that vary across subjects.

One way of trying to disentangle these possibilities would be to conduct longitudinal anatomical imaging studies that followed patients with OCD over extended period of time, starting as close to their diagnosis as possible.

Such studies could determine whether the abnormalities start in only one or a few structures with the initial site of the abnormality possibly varying by case and then spread to other structures.

A cruder and less conclusive alternative is to compare the findings from anatomical imaging studies across children and adults with OCD to determine whether the findings in children suggest abnormalities in a smaller subset of regions than do the findings in adults.

If so, this could indicate that abnormalities in OCD start in a specific subset of the regions that have been found abnormal in adults with OCD.

Differences between findings in children and adults OCD could, however, be due to multiple factors, including a comparison across childhood- and adult-onset subtypes, differing types and rates of comorbidity, differing ascertainment biases, and differing durations of illness.

Unfortunately, the extant literature does not allow us to conclude with any certainty which areas are and are not affected in children with OCD.

Existing studies clearly point to anatomical abnormalities in the ACC and metabolite abnormalities in the thalamus. No anatomical abnormalities have yet been reported in the other structures that are affected in adults with OCD, including the OFC and caudate, but that may be attributable either in whole or in part to the fact that those structures have not yet been properly studied in children with OCD.

A large-scale longitudinal study that followed children or adults with high familial risk for OCD from before their diagnosis through several years later would clearly provide a much richer and more dynamic view of the unfolding of pathology in the brain affected by OCD.

Such a study should ideally be multi-modal, including not only anatomical MRI, fMRI, and 1 H-MRS, but also, for example, investigation of white matter fiber tracts using diffusion tensor imaging and investigation of neurotransmitter and receptor levels using PET.

The results of such a study could then inform a more detailed search for the ultimate cause or causes of OCD: National Center for Biotechnology Information , U.

Author manuscript; available in PMC Apr Maia , Rebecca E. Cooney , and Bradley S. Author information Copyright and License information Disclaimer.

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Searching for the Pathogenesis of OCD As noted above, the findings that in patients with OCD the OFC, ACC, and caudate nucleus are hyperactive at rest, become more active under symptom provocation, and show less activity following treatment, have generally been interpreted as evidence that hyperactivity in these areas generates the symptoms of OCD e.

Striatum Studies comparing caudate volumes in adults with OCD and healthy controls have yielded highly variable findings. Summary Volumetric studies in adults with OCD provide convincing evidence for reduced OFC volumes, suggestive evidence for increased thalamic and normal ACC volumes, and inconsistent evidence for caudate or striatum volumes.

Surface Analysis Only two studies, both by the same group and in adults, have used surface analysis to analyze subcortical structures in OCD.

Striatum Two studies detected no significant differences in caudate volumes between children with OCD and matched controls Rosenberg et al.

Voxel-Based Morphometry No cortical thickness or surface analysis studies of children with OCD have been reported in the literature.

Neurosurgical Lesions Neurosurgical lesions are sometimes made to attenuate symptoms in extremely severe cases of OCD that do not respond to psychotherapy and medication.

Footnotes 1 A more recent study using the same paradigm confirmed abnormal recruitment of the hippocampus in patients with OCD, even though it failed to detect differences in activation of the striatum between patients with OCD and healthy controls Rauch et al.

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The fifth generation of progress. American College of Neuropsychopharmacology; Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen labeled carbon dioxide and positron emission tomography.

Volume reduction in the caudate nucleus following stereotactic placement of lesions in the anterior cingulate cortex in humans: A morphometric magnetic resonance imaging study.

Probing striatal function in obsessive-compulsive disorder: A PET study of implicit sequence learning. Neuroimaging studies of amygdala function in anxiety disorders.

Functional magnetic resonance imaging study of regional brain activation during implicit sequence learning in obsessive-compulsive disorder.

Probing striato-thalamic function in obsessive-compulsive disorder and Tourette syndrome using neuroimaging methods. Brain development, gender and IQ in children.

A volumetric imaging study. Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder. A manual and automated MRI study of anterior cingulate and orbito-frontal cortices, and caudate nucleus in obsessive-compulsive disorder: Comparison with healthy controls and patients with schizophrenia.

Increased antistreptococcal antibody titers and anti-basal ganglia antibodies in patients with Tourette syndrome: Lifetime prevalence of specific psychiatric disorders in three sites.

Reduced caudate nucleus volume in obsessive-compulsive disorder. A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder.

Obsessive-compulsive disorder following bilateral globus pallidus infarction. The brain and emotion. Oxford University Press; The functions of the orbitofrontal cortex.

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