Regulation of Mycobacterial Heat‐Shock Protein‐Reactive T Cells by HLA Class II Molecules: Lessons from Leprosy

Ottenhoff, Tom H. M.; Haanen, John B.A.G.; Geluk, Annemieke; Muns, Tuna; Ab, Birhane Kale; Thole, Jelle; Schooten, W. C. A. Van; Elsen, Peter J. van den; Vries, R. R. P. De

doi:10.1111/j.1600-065x.1991.tb00828.x

Cited by 54 publications

(39 citation statements)

References 58 publications

(27 reference statements)

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“…However, inhibition studies showed in patients with RAS that the HSP 65-stimulated proliferative response is inhibited with MoAb to HLA class II, but not class I, and this is consistent with HLA class II being a restricting molecule for the 65 kD HSP [17]. Proliferative responses to the RASspecific mycobacterial (aa91-105) or the homologous human peptide (aa116-130) were either significantly greater or only found with CD4 + T cells, as compared with CD8 + T cells.…”

Section: Discussionsupporting

confidence: 54%

Defining a T-cell epitope within HSP 65 in recurrent aphthous stomatitis

Hasan¹,

Shinnick

Mizushima

et al. 2002

Clinical and Experimental Immunology

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Recurrent aphthous stomatitis (RAS) is the most common disease of the oral mucosa, affecting at least 10% of the general population [1]. The onset of RAS usually presents during adolescence, and the course of the disease is characterized by recurrences followed by remissions. The disease may persist for many years and varies from minor ulcers, which may cause transient discomfort, to major ulcers which are associated with pain, inability to eat and loss of weight [2].The aetiology of RAS has not been determined, but Streptococcus sanguis or its L-form [3,4] has been implicated, as has autoimmunity to the oral mucosal homogenate [5][6][7]. A common or cross-reactive antigen between streptococci and oral epithelium has been suggested [6][7][8][9] and demonstrated between the streptococcal 60-65 kD heat shock protein (HSP) and oral mucosal tissue [10]. Significant increase in serum antibodies to HSP has been detected in patients with RAS [10].Heat shock proteins (HSP) are a group of highly conserved proteins found in eukaryotic and prokaryotic cells, including Gram-positive and Gram-negative micro-organisms [11,12]. Viruses can enhance the production of host HSP. The high degree of homology between microbial and human HSP 60 [13] has led to the concept that molecular mimicry between the microbial and self HSP may be involved in the pathogenesis of autoimmune diseases [14]. A comprehensive investigation of T-cell epitopes within the 65 kD mycobacterial-and 60 kD human HSP-derived peptides has identified four T-cell epitopes specific for Behcet's disease, in which oral ulceration is the most consistent manifestation [15]. All but one of the four peptides (amino acids 219-233) showed significantly greater stimulation of lymphocytes from patients with Behcet's disease than those from RAS. However, the investigation raised the possibility that another peptide (amino acids 91-105) might specifically stimulate lymphocytes from RAS and not Behcet's disease. Indeed, specific lymphoproliferative responses are stimulated with peptide 91-105 in RAS [16]. A comparative investigation with the homologous human 60 kD HSP peptide 116-130 also revealed significantly greater lymphoproliferative responses in RAS than in controls.The objectives of this investigation in patients with RAS were to define the critical residues within the T-cell epitope 91-105, and to investigate the role of HLA class I and II restriction elements in the lymphoproliferative response. The possibility that g d T cells may be involved was also explored. 318 Defining a T-cell epitope within HSP 65 in recurrent aphthous stomatitis SUMMARYThe 65 kD heat shock protein (HSP) has been implicated in the aetiology of recurrent aphthous stomatitis (RAS). We have previously demonstrated that peptide 91-105 derived from the sequence of mycobacterial 65 kD HSP stimulates specifically lymphocytes from patients with RAS. In this investigation, we show that both CD4 + and CD8 + T cells were significantly stimulated with mycobacterial peptide 91-105. In contrast, the human h...

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Section: Discussionsupporting

confidence: 54%

Defining a T-cell epitope within HSP 65 in recurrent aphthous stomatitis

Hasan¹,

Shinnick

Mizushima

et al. 2002

Clinical and Experimental Immunology

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“…HLA-B51 may thus relate to the severity of the disease. We found that peptide 336-351 exclusively stimulated CD4 þ T cells, and this response was inhibited by anti-HLA-DR and anti-CD4 MoAbs [42,43]. We also found that any HLA-DR haplotypes in BD patients were not associated with T cell proliferative responses in our studies (data not shown).…”

Section: Discussionsupporting

confidence: 53%

Characterization of T cells specific for an epitope of human 60-kD heat shock protein (hsp) in patients with Behçet's disease (BD) in Japan

Kaneko

Suzuki

Yamashita

et al. 1997

Clinical and Experimental Immunology

119

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SUMMARYBD is prevalent in the area of the Silk Route. It has been shown that hsp are involved in the T cell activation in patients with BD in the UK, where this disease has developed sporadically. We have thus examined whether the T cell response to the hsp-derived peptides may be induced in patients with BD in Japan, an east pole of the Silk Route. As with patients in the UK, the human 60-kD hsp peptide 336-351 also yielded vigorous proliferation of T cells in Japanese patients with BD, but neither in normal subjects nor in patients with rheumatoid arthritis (RA); there was significant association between proliferation by this peptide and the presence of ocular lesion, but not any other symptoms of BD. To clarify whether the peptide stimulates T cells as a polyclonal activator, a specific antigen or a superantigen-like substance, we analysed T cell receptor (TCR) usage of responding T cells by means of MoAbs specific for TCR Vb subfamily and polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP)-based technique. We found that T cells with certain TCR Vb subfamilies (including Vb5.2-3, 8, 13.6, 18, 21.3) were increased in circulation and responded to the hsp peptide in an antigen-specific fashion. In addition, TCR Vb gene-amplified products of freshly isolated T cells of patients with BD formed several bands in the PCR-SSCP analysis; some of them became prominent after stimulation with the peptide. This suggests that T cells in patients with this disease have already been expanded oligoclonally in vivo, which may be a result of stimulation by triggering antigens, including the hsp peptide. In addition, hsp peptide stimulation induced proinflammatory cytokine mRNA expression in peripheral blood mononuclear cells, including IL-8, tumour necrosis factor-alpha (TNF-a) and TNF-b in eight out of eight patients studied. Taken together, the results suggest that hsp antigen may play a role in the pathogenesis of BD, not only in the area of the Silk Route, but also outside the Silk Route area.

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“…HLA-DRB polymorphism plays an important regulatory role in controlling human T-cell reactivity against mycobacteria (20,21). Previously, we demonstrated that the 15-mer Rv1733c p63-77 epitope was immunogenic in vivo either alone or as part of an HLA-DR3-restricted multistage polyepitope.…”

Section: Identification Of M Tuberculosis Antigens That Induce Dendrmentioning

confidence: 98%

“…In this respect, HLA-DR3, a major class II allele that is present in 20% of the human population, is associated with strong T-cell activity to mycobacterial Ags, in vitro and in vivo, and with high-responder (tuberculoid) leprosy (21). Since HLA transgenic (tg) mice are efficient models to study HLA-restricted T-cell responses to mycobacteria in vivo (22)(23)(24), SLP vaccine efficacy was tested in vivo in the context of HLA-DR3.…”

mentioning

confidence: 99%

Synthetic Long Peptide Derived from Mycobacterium tuberculosis Latency Antigen Rv1733c Protects against Tuberculosis

Coppola

Eeden

Wilson

et al. 2015

Clin Vaccine Immunol

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Despite the availability of a vaccine and chemotherapeutic agents, tuberculosis (TB) remains the second leading cause of death from an infectious disease worldwide, annually causing around 9 million new cases and almost 2 million deaths (1). The highest burdens are found in low-income regions: Africa harbors about 25% of the world's TB cases and more than half have been counted in Asia (1). Furthermore, surveys with tuberculin skin tests (TST) suggest that one-third of the world's population is latently infected with Mycobacterium tuberculosis, which constitutes a huge reservoir with a 3 to 10% lifetime risk of developing TB (1, 2).It has long been recognized that the efficacy of vaccination with Mycobacterium bovis BCG, still the only registered TB vaccine, can be enhanced by a booster or replacement vaccine protecting against reactivating TB from latency (3). M. tuberculosis latency antigens (Ags), encoded by the DosR regulon, are upregulated in vitro under conditions that tubercle bacilli are thought to encounter in vivo during persistence in immunocompetent hosts (4) and in mouse models for latent M. tuberculosis infection (LTBI) (5). This discovery caused a change in focus in the search for a novel antigen(s) able to enhance long-term vaccine efficacy. Various human cohort studies showed preferential recognition of DosRencoded proteins, in particular Rv1733c, Rv2029c, Rv2627c, and Rv2628, by T cells from individuals with LTBI and to a lesser extent by TB patients (6-9). Also, latency antigens can induce CD4 ϩ and CD8 ϩ T cells in TST-converted individuals who were infected with M. tuberculosis decades ago in the preantibiotic era and yet never developed TB (10, 11).In mouse models using chronic, low-dose M. tuberculosis infection mimicking human LTBI, the preferential recognition of the DosR regulon in latent infection was further established (5) and provided evidence that BCG fails to induce a significant response to latency antigens despite their presence in the BCG genome. Also, a triple fusion protein, designated H56, including the latency/starvation antigen Rv2660 coupled to the early-stage proteins Ag85B and ESAT-6, provided protection by both pre-and postinfection vaccination in nonhuman primates (12,13). A similar improvement in long-term protection against M. tuberculosis was observed in mice after intradermal inoculation of recombinant BCG expressing the latency-associated antigens Rv2659c, Rv3407, and Rv1733c (14).Synthetic long peptides (SLPs), administered with adjuvants, are proven efficient vaccines for tumor therapy (15)(16)(17)(18)(19). Despite the success of this vaccine strategy, SLPs have not yet been applied to design new TB vaccines. Recognition of cognate antigen presented by either T cells or B cells will lead to an abortive proliferative response and death of the responding T cells.The immunogenicity of Rv1733c, which was the most commonly recognized latency antigen in M. tuberculosis-exposed household contacts from South Africa, Gambia, and Uganda (9), as well as the improved long...

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Regulation of Mycobacterial Heat‐Shock Protein‐Reactive T Cells by HLA Class II Molecules: Lessons from Leprosy

Cited by 54 publications

References 58 publications

Defining a T-cell epitope within HSP 65 in recurrent aphthous stomatitis

Defining a T-cell epitope within HSP 65 in recurrent aphthous stomatitis

Characterization of T cells specific for an epitope of human 60-kD heat shock protein (hsp) in patients with Behçet's disease (BD) in Japan

Synthetic Long Peptide Derived from Mycobacterium tuberculosis Latency Antigen Rv1733c Protects against Tuberculosis

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