Function Of HLA Class Research Articles

Fifty years after the discovery of the association of HLA B27 with ankylosing spondylitis

The human lymphocyte antigen B27 (HLA B27) is a member of the HLA class I family of genes in the major histocompatibility complex whose name goes back to its discovery...

302-OR: Hypoimmune Human Primary Pancreatic Islets Survive and Function in Humanized Diabetic Mice

Treatment of type 1 diabetes mellitus (T1DM) via allogeneic donor transplant has limited success due to morbidities from immunosuppression (IS) and a gradual loss of engrafted pancreatic islet function. We set out to engineer human primary pancreatic islets (PI) using our hypoimmune strategy that could engraft and evade host immune detection in the absence of IS. Human cadaveric PIs were engineered to knock-out function of HLA class I and II and overexpress CD47 (HIP PI) . Unedited PIs were cultured identically (Wt PI) as controls. NSG-SGM3 mice were reconstituted with human CD34+ cells and had >45% engraftment of human CD45+ cells. Mice were rendered diabetic (streptozotocin) . A total of 300 HIP PI or Wt PI were transplanted IM. After 6 days, splenocytes and serum were obtained for immune analyses. HIP PI showed no T cell recognition (ELISpot) , no graft-specific antibodies (Abs) , and were protected from NK cell and macrophage killing. Wt PI had a strong adaptive immune response with high ELISpot frequencies and an increase in graft-directed Abs. Serial BLI showed survival of all HIP PI grafts but rapid rejection of Wt PI, confirmed by histopathology at 4 weeks. Glucose levels gradually decreased after HIP PI transplantation and remained stable around 200 mg/dl after 14 days. These data suggest that hypoimmune engineering may generate HIP PI capable of persisting and functioning in diabetic patients without IS. Disclosure X.Hu: None. C.Gattis: None. C.Young: Employee; Sana Biotechnology Inc. A.G.Olroyd: None. E.Y.L.Chu: None. K.White: None. A.Friera: None. S.Schrepfer: Other Relationship; Sana Biotechnology Inc.

Transport of cellular misfolded proteins to the cell surface by HLA-B27 free heavy chain

HLA class I molecules play a central role in the immune system by presenting peptide antigens to cytotoxic T cells. Although most HLA class I molecules are associated with β2-microglobulin, HLA class I heavy chain that is not associated with β2-microglobulin is also expressed on certain cells. We recently found that cellular misfolded proteins are transported to the cell surface by HLA class II molecules via association with their peptide-binding grooves. Furthermore, misfolded self-antigens bound to autoimmune disease-susceptible HLA class II molecules are the targets for autoantibodies produced in certain autoimmune diseases. In the present study, we found that misfolded proteins were also transported to the cell surface by specific HLA class I molecules including HLA-B27, which is strongly associated with ankylosing spondylitis. In addition, the efficiency with which HLA class I molecules encoded by each allele transport misfolded proteins to the cell surface was significantly correlated with HLA class I free heavy chain expression on that surface. Moreover, misfolded proteins were coprecipitated with HLA class I free heavy chain but not with correctly folded HLA class I molecules. These findings reveal a novel function of HLA class I molecules to transport misfolded proteins to the cell surface, which might help us to understand the pathogenesis of HLA class I-associated diseases.

Abstract 3773: Tapping CD4 T cells for cancer immunotherapy

Abstract T-cell based immunotherapy represents an attractive strategy for the treatment of cancer. Whereas cellular anti-tumor immune responses have typically been attributed to CD8 T cells, CD4 T cells play a critical role in tumor elimination and the priming and maintenance of CD8 T-cell responses. Recent findings have highlighted new opportunities for CD4 T cells in cancer immunotherapy. We have isolated CD4+ T cells reactive against tumor antigens from patients who experienced clinical benefit from treatment with cancer vaccines targeting antigens such as hTERT, survivin and frequent neoantigens such as frameshift mutated TGFβRII. Strong T-cell responses against the vaccine or unrelated cancer antigens suggesting epitope spreading correlated with enhanced survival and tumor regression in late stage cancer patients. These HLA class II restricted T-cell clones recognised target cells loaded with long peptides or protein and for some CD4+ T cell clones we could also show direct tumor recognition. TCRs were expressed in expanded third-party T cells by mRNA electroporation or retroviral transduction and tested for functionality. Both CD8+ and CD4+ T cells expressing the TCRs produced TNF-α, IFN-γ and redirected T cells had the capacity to kill following co-incubation with their targets. Selecting highly functional CD4+ T-cell clones reactive against tumor-associated or -specific antigens from patients with clinical responses after treatment with immunotherapy is a successful method for identifying highly functional HLA class II restricted TCRs for adoptive immunotherapy. These HLA class II-restricted TCRs may be of therapeutic value both in haematopoietic malignancies and in melanoma where tumor cells frequently express HLA class II. Furthermore, combining HLA class I- and class II-restricted TCRs for T-cell redirection may provide a more potent therapeutic effect in adoptive T cell therapy. Citation Format: Sébastien Wälchli, Marit R. Myhre, Nadia Mensali, Anne Fåne, Kari Lislerud, Gunnar Kvalheim, Gustav Gaudernack, Else M. Inderberg. Tapping CD4 T cells for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3773. doi:10.1158/1538-7445.AM2017-3773

Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes.

Aims/hypothesisHuman pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30 years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it.MethodsPancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones. RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays.ResultsHyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels. The expression of β2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated. Both ‘classical’ HLA class I isoforms (i.e. HLA-ABC) as well as a ‘non-classical’ HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets. This hyperexpression did not correlate with detectable upregulation of the transcriptional regulator NLRC5. However, it was strongly associated with increased STAT1 expression in all three cohorts. Islet hyperexpression of HLA class I molecules occurred in the insulin-containing islets of patients with recent-onset type 1 diabetes and was also detectable in many patients with disease duration of up to 11 years, declining thereafter.Conclusions/interpretationIslet cell HLA class I hyperexpression is not an artefact, but is a hallmark in the immunopathogenesis of type 1 diabetes. The response is closely associated with elevated expression of STAT1 and, together, these occur uniquely in patients with type 1 diabetes, thereby contributing to their selective susceptibility to autoimmune-mediated destruction.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4067-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Abstract 2310: With a little help from CD4 T cells in adoptive T-cell transfer

Abstract Adoptive transfer of genetically engineered T cells offers great opportunities in cancer immunotherapy, however until recently, HLA-Class II-restricted TCRs have been largely ignored. We have identified and cloned HLA class II-restricted CD4+ T cells isolated from patients vaccinated with long peptides derived from antigens such as hTERT, survivin and frameshift mutated TGFβRII. Several of these cancer patients demonstrated outstanding clinical responses to peptide- or dendritic cell based cancer vaccines with >10-year survival. In these patients strong T-cell responses against peptides other than those used for vaccination were detected, suggesting epitope spreading. Responses against certain peptides associated with clinical benefit were identified and CD4+ T-cell clones recognizing such peptides were isolated. In depth studies of their specificities lead to the selection of HLA-DR and -DQ restricted T-cells having high functional avidity for the HLA-peptide complexes. We studied tumor cell and/or protein recognition and found one telomerase-specific CD4+ T-cell clone recognizing a melanoma cell line with the corresponding HLA allele. The TCR sequences of the interesting clones were identified. The ribosome skipping 2A sequence technique was used to express these TCRs in an mRNA expression vector or retrovirus. When expanded T cells were electroporated with these TCRs, both redirected CD8+ and CD4+ T cells produced TNF-α, IFN-γ and the degranulation marker (CD107a) following co-incubation with specific peptide-loaded targets. We have demonstrated that choosing highly functional CD4+ T-cell clones specific for tumor-associated or -specific antigens from patients with clinical responses after immunotherapy treatment is a successful method for identifying highly functional HLA class II restricted TCRs for adoptive T-cell transfer. The use of HLA class II-restricted TCRs may be of therapeutic value both in haematopoietic malignancies and in melanoma where tumor cells often express HLA class II. In addition, combining the redirection of T cells with both HLA class I- and class II-restricted TCRs may provide a more powerful therapeutic effect in adoptive T cell therapy. Citation Format: Else M. Inderberg, Sébastien Wälchli, Marit R. Myhre, Kari Lislerud, Gunnar Kvalheim, Gustav Gaudernack. With a little help from CD4 T cells in adoptive T-cell transfer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2310.

HLA-Universal Platelet Transfusions Prevent Platelet Refractoriness in a Mouse Model

Refractoriness to platelet (PLT) transfusion caused by alloimmunization against HLA class I antigens constitutes a significant clinical problem. Thus, it would be desirable to have PLT units lacking HLA antigens on the cell surface. Previously, we showed that the generation of functional HLA class I-silenced (HLA-universal) PLTs from CD34(+) cells, using a short hairpin RNA (shRNA) to target β2-microglobulin (β2m) transcripts, is feasible. Here, we assessed the capacity of HLA-silenced PLTs to escape HLA antibody-mediated cytotoxicity in vitro and in vivo. Generation of megakaryocytes (MKs) and PLTs was performed by thrombopoietin-mediated differentiation of HLA-silenced CD34(+) cells within 10 days. Lymphocytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) reporter assays using anti-HLA antibodies and a mouse model for PLT refractoriness were used to assess the immune-evasion capability of HLA-universal MKs and PLTs. To mimic PLT refractoriness in vivo, NOD/SCID/IL-2Rγc(-/-) mice were injected with specific anti-HLA antibodies followed by the infusion of 1 × 10(6) HLA-universal MKs. In vivo PLT generation was evaluated by flow cytometry using anti-CD42a and CD61 antibodies. Cells expressing a nonspecific shRNA were used as control. Lymphocytotoxicity and ADCC reporter assays showed that HLA silencing protects MKs against HLA antibody-mediated complement-dependent and cell-mediated cytotoxicity. In lymphocytotoxicity assays, 80-90% of HLA-expressing MKs but only 3% of HLA-silenced MKs were lysed. In the circulation of mice, HLA-expressing and HLA-silenced MKs showed PLT production in the absence of anti-HLA antibodies, with human PLT frequencies of up to 0.5% within the PLT population. However, in presence of anti-HLA antibodies HLA-expressing MKs were rapidly cleared from the circulation of mice, whereas HLA-silenced MKs escaped HLA antibody-mediated cytotoxicity and produced PLTs that were detectable up to 11 days. Our data show that HLA-silenced PLTs are efficiently protected against HLA antibody-mediated cytotoxicity and prevent PLT refractoriness in vivo. Provision of HLA-silenced PLTs may become an important component in the management of patients refractory to PLT transfusion.

Genome-wide differential genetic profiling characterizes colorectal cancers with genetic instability and specific routes to HLA class I loss and immune escape

We compared the expression of genes related to inflammatory and cytotoxic functions between MSI and MSS (HLA-class I-negative and HLA-class I-positive) colorectal cancers (CRCs), seeking evidence of differences in inflammatory mediators and cytotoxic T-cell responses. Twenty-two CRCs were divided into three study groups as a function of HLA class I expression and MSI phenotype: 8 MSI tumours, 6 MSS/HLA- tumours and 6 MSS/HLA+ tumours (controls). A first comparison between eight MSI and six MSS/HLA-positive (control) cancers, based on microarray analysis on an Affymetrix(®) HG-U133-Plus-PM plate, identified 1974 differentially expressed genes (P<0.05). We grouped genes in Gene Ontology functional categories: apoptotic programme (72 genes, P=5.5·10(-3)), leucocyte activation (43 genes, P=1.8·10(-5)), T-cell activation (24 genes, P=6.3·10(-4)), inflammatory response (40 genes, 2.3·10(-2)) and cytokine production (10 genes, P=1.9·10(-2)). Real-time PCR and immunohistochemical evaluation were used to validate the data, finding that increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators were associated with greater infiltration by CD8+T lymphocytes in the MSI group (P<0.001). Finally, HLA-class I-negative tumours were not grouped together but rather in accordance with features of the gene expression profile of MSI or MSS tumours. As expected, genes associated with antigen processing machinery and MHC class I molecules (TAP2, B2m) were downregulated in MSS/HLA-class I-negative CRCs (n=6) in comparison to controls. In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour-host interactions and differentiate MSI from MSS cancers. The two types of tumour, MSI/HLA-class I-negative and MSS/HLA-class I-negative, showed marked differences in the composition and intensity of infiltrating leucocytes, suggesting that their immune escape strategies involve distinct pathways.

A haplotype of the HLA-DRA gene promoter region was associated with susceptibility to gastric cancer in a Korean population (88.1)

Abstract Gastric cancer, the second leading cause of mortality by cancer in the world, shows particularly high incidence and mortality in Korea. To screen the causative genes or loci that control the transition from gastritis to gastric cancer, whole genome approach was applied using Illumina's 510S SNP chip technology. One of the interesting associated genes, HLA-DRA1 was investigated. HLA-DRA gene is very limited in polymorphism compared to the highly polymorphic HLA-DRB1, 3, 4, and 5 loci. HLA-DR alpha protein has roles as a non-polymorphic partner for HLA DR-beta for transport and surface expression as a functional HLA-class II protein. The expression level of the HLA-DR alpha/beta on the cell surface may be controlled by the transcriptional level of the HLA-DR alpha. To test this hypothesis, we tested susceptibility to gastric cancer compared to gastritis in terms of SNPs, haplotypes, and diplotypes covering the HLA-DRA promoter region. To find causative SNP(s), the whole linkage disequilibrium (LD) region of the significant haplotype using more than 20 Koreans were sequenced. We found that a diplotype composed of significantly associated SNPs and a haplotype was associated with susceptibility to gastric cancer significantly. These data suggested that the expression level of HLA-DRA might control the HLA-DR protein levels on the cell surface.

HLA Class II Protein Expression in Prostate Cancer Cells (48.22)

Abstract Prostate cancer is the second most commonly diagnosed cancer in men. Presently, there is no effective treatment for patients who develop recurrence, or for those who have metastatic disease at the time of diagnosis. Recent evidence suggests that reduced expressions of target protein antigens as well as HLA molecules are the predominant immune escape mechanisms of malignant prostate tumors. The purpose of this study was to investigate the prospect of antigen specific immunotherapy against prostate cancer via the HLA class II pathway of immune recognition. Here, we show for the first time that prostate cancer cells express functional HLA class II proteins that are recognized by T cells. We also show that prostate cancer cells can be induced with IFN-γ to express high levels of class II proteins as well as an enzyme, lysosomal thiol reductase (GILT), that may facilitate enhanced class II antigen presentation and CD4+ T cell recognition. Select prostate tumors can be transduced with HLA class II molecules resulting in efficiently presented antigenic peptides that also stimulate CD4+ T cells. These data suggest that prostate cancer cells can be targeted via the HLA class II pathway, and that genetically manipulated prostate tumor cells can be employed for direct antigen presentation, and CD4+ T cell mediated tumor therapy.

Immune Escape Associated with Functional Defects in Antigen-Processing Machinery in Head and Neck Cancer

Recent revival of interest in the role of immune surveillance in the pathogenesis and control of malignant diseases has focused attention on escape mechanisms used by tumor cells to evade immune recognition. Defects in the host's tumor antigen-specific immune responses and abnormalities in tumor cell expression of HLA class I molecules and tumor antigen are known to contribute to tumor progression. However, the mechanism(s) responsible for the lack of tumor cell recognition by functional HLA class I antigen-restricted, tumor antigen-specific CTLs despite expression of the restricting HLA class I allele and targeted tumor antigen by tumor cells remain(s) unexplained. In squamous cell carcinomas of the head and neck (SCCHN), this type of tumor escape is a rule rather than the exception. Here, we discuss evidence pointing to functional defects in the antigen-processing machinery as one mechanism underlying resistance of SCCHN cells to recognition and lysis by HLA class I antigen-restricted, tumor antigen-specific CTL. In addition, based on the restoration by IFN-gamma of SCCHN cell sensitivity to recognition by these CTL, we suggest strategies that may improve the clinical course of the disease by enhancing susceptibility of malignant cells to immune recognition.

HLA class I defects in malignant lesions: what have we learned?

Depending on the tumor types, HLA class I antigen downregulation or loss has been found in 16% to 50% of malignant lesions in many malignancies with a clinical association with histopathological markers of poor prognosis of the disease and with reduced free interval and survival. These findings may reflect the escape of tumor cells with HLA class I abnormalities from recognition and destruction by HLA class I-restricted, tumor-associated antigen-specific cytotoxic T lymphocytes. This possibility has stimulated investigations on the mechanisms underlying HLA class I antigen abnormalities in malignant cells. Distinct molecular defects underlying an abnormal HLA class I phenotype have been identified and characterized. These defects range from structural alterations of the genes which encode HLA class I antigen subunits to deregulation of antigen processing machinery components responsible for a functional HLA class I antigen expression. These findings, in conjunction with those of clinical recurrence of lesions with HLA class I antigen loss following T cell-based immunotherapy in patients, suggests that immunoselection may play a role in the generation of malignant lesions with HLA class I antigen abnormalities. This possibility has stressed the need to effectively monitor functional HLA class I antigen expression in malignant lesions in the application of T cell-based immunotherapy as well as to develop strategies to circumvent the negative impact of immunoselection.

Induction of MAGE-3 expression in lung and esophageal cancer cells

Background. Although MAGE-3 has been detected in approximately 40% of lung and esophageal cancers, expression of this cancer testis antigen appears to be below the threshold for immune recognition in patients with these malignancies. The aim of this study was to determine if the demethylating agent, 5-Aza-2′-deoxycytidine (DAC) and if the histone deacetylase inhibitor Depsipeptide FR901228 (DP) could enhance MAGE-3 expression in lung and esophageal cancer cells. Methods. Eleven lung and esophageal cancer lines and cultured normal human bronchial epithelial (NHBE) cells were exposed to normal media (NM), DAC, DP, or combination DAC/DP at varying concentrations and exposure durations. MAGE-3 expression was evaluated by quantitative RT-PCR (TaqMan) and immunohistochemistry techniques. Trypan blue exclusion techniques were used to examine the proliferation of cancer cells after drug exposure. Results. Relative to untreated controls, MAGE-3 expression was enhanced 32-fold (range 3.9 to 110) by DAC alone (0.1 μmol/L × 72 h), 2.1-fold (0.4 to 4.2) by DP alone (25 ng/mL × 6h), and 57-fold (4.6 to 209) by sequential DAC/DP exposure. Increased MAGE-3 mRNA copy numbers coincided with enhanced protein levels in these cells. MAGE-3 expression persisted after drug exposure. Flow cytometry confirmed the presence of functional HLA class I expression in these cells. Sequential DAC/DP treatment mediated pronounced growth inhibition in cancer cells but not NHBE. Conclusions. Sequential DAC/DP treatment may be a novel strategy to simultaneously augment MAGE-3 expression and induce growth arrest in thoracic malignancies.

Thrombocyte HLA molecules retain nonrenewable endogenous peptides of megakaryocyte lineage and do not stimulate direct allocytotoxicity in vitro

AbstractThe origin and the function of HLA class I molecules present on the surface of human platelets are still unclear. In particular, it is controversial which fraction of these class I molecules represents integral membrane components derived from the megakaryocyte-platelet lineage versus soluble plasma HLA molecules acquired by adsorption. Results of the present study show that HLA-A2 ligands isolated from platelets possess the same peptide motif as described for HLA-A2-associated peptides obtained from nucleated cells. Sequencing of these platelet-derived peptides reveals that they originate mainly from ubiquitously expressed proteins also present in the megakaryocyte-platelet lineage. Moreover, one of these peptides derives from the GPIX protein, which is specifically expressed by platelets and their precursors. Platelet HLA molecules are unstable in vitro at 37°C, but can be partially stabilized by addition of exogenous β2-microglobulin and HLA class I binding peptide, suggesting that platelets cannot load HLA molecules with endogenous peptides. In in vitro experiments platelets were used to stimulate peripheral blood mononuclear cells. No allospecific cytotoxicity was observed after primary stimulation, or secondary restimulation, with allogenic resting or activated platelets, even in the presence of additional third-party helper activity. These data indicate that HLA class I molecules from platelets cannot directly induce allogenic CD8+ cytotoxic T-cell response in vitro.

Thrombocyte HLA molecules retain nonrenewable endogenous peptides of megakaryocyte lineage and do not stimulate direct allocytotoxicity in vitro

The origin and the function of HLA class I molecules present on the surface of human platelets are still unclear. In particular, it is controversial which fraction of these class I molecules represents integral membrane components derived from the megakaryocyte-platelet lineage versus soluble plasma HLA molecules acquired by adsorption. Results of the present study show that HLA-A2 ligands isolated from platelets possess the same peptide motif as described for HLA-A2-associated peptides obtained from nucleated cells. Sequencing of these platelet-derived peptides reveals that they originate mainly from ubiquitously expressed proteins also present in the megakaryocyte-platelet lineage. Moreover, one of these peptides derives from the GPIX protein, which is specifically expressed by platelets and their precursors. Platelet HLA molecules are unstable in vitro at 37°C, but can be partially stabilized by addition of exogenous β2-microglobulin and HLA class I binding peptide, suggesting that platelets cannot load HLA molecules with endogenous peptides. In in vitro experiments platelets were used to stimulate peripheral blood mononuclear cells. No allospecific cytotoxicity was observed after primary stimulation, or secondary restimulation, with allogenic resting or activated platelets, even in the presence of additional third-party helper activity. These data indicate that HLA class I molecules from platelets cannot directly induce allogenic CD8+ cytotoxic T-cell response in vitro.

HLA restriction patterns of gliadin- and astrovirus-specific CD4+ T cells isolated in parallel from the small intestine of celiac disease patients.

Celiac disease is a common HLA-DQ2-associated enteropathy caused by an abnormal T-cell-mediated immune response to ingested wheat gliadin proteins. We have previously isolated in situ activated mucosal T cells from celiac disease patients and demonstrated that these T cells were gliadin specific and predominantly DQ2 restricted. In contrast to this, gliadin-specific T cells isolated from peripheral blood display a variable HLA restriction pattern, thereby indicating that the skewed DQ restriction of T cells resident in the celiac lesions could be dictated by a preference for DQ-mediated antigen presentation in the mucosa of CD patients. To address this, we analyzed the HLA restriction of T cells recognizing astrovirus, a common gastroentetitis virus, isolated from intestinal mucosa of six celiac disease patients. As an internal control, gliadin-specific T cells were isolated and analyzed in parallel. The gliadin-specific mucosal T cells were marked in their DQ2 restriction, whereas the parallel astrovirus-specific T cells were predominantly restricted by DR molecules. Our data indicate that the repertoire of T cells present in celiac lesions is determined by the priming antigen(s) and not by a skewing in the expression of functional HLA class II isotypes in the disease affected small intestinal mucosa.

Immungenetische Grundlagen der seronegativen Spondarthritiden - Modelle zur pathogenetischen Rolle des HLA-B27-Moleküls

The association of the seronegative spondylarthropathies, notably ankylosing spondylitis and Reiter's syndrome, was first described 20 years ago. However, in spite of an enormous increase in our understanding of the structure and function of HLA class I molecules in the intervening years, the mechanisms whereby the HLA-B27 gene confers disease susceptibility has remained unknown. It has been postulated that there may be a degree of amino acid homologies between the HLA-B27 antigen and antigenic epitopes of "arthritogenic" bacteria which would then be recognized by cross-reactive antibodies (the so-called molecular mimicry theory). A variation of the crossreactivity hypothesis proposes that Klebsiella pneumoniae secrete a "modifying factor" that binds to HLA-B27 and can be recognized as a target for an anti-self response (the hypothesis of HLA-B27 modifying factors). The third possibility is that B27 acts in a non-immunological fashion by favouring the invasiveness of pathogens at mucosal surfaces and thus increasing the dissemination of bacterial antigens. Finally, seronegative spondylarthropathies are thought to be mediated by cytotoxic T lymphocytes (CTL) that recognize a bacterial or self peptide presented by HLA-B27 (the so-called arthritogenic peptide hypothesis). The latter hypothesis has recently been supported by the detection of HLA-B27-restricted synovial CTL with specificity for bacterial antigens or self antigens.

Immunogenetics of the spondyloarthropathies.

In this review, recent data relevant to better understanding of the immunogenetics of the spondyloarthropathies are discussed or, in a somewhat broader sense, the HLA-B27 disease associations. Although in 1993 much more is known about the B27 molecule than was known in 1992, its contribution to the pathogenesis of disease is unclear. Peptide presentation to the T-cell receptor is still the basic, if not the only, function of HLA class I molecules. Nothing special was found for the B27 gene, molecule assembly, protein sequence, and crystal and peptide-binding motif, nor for the function dependent on these physical properties. Nevertheless, the theory regarding an "arthritogenic peptide" seemed to promise an explanation. However, this theory is rather an assembly of older views modified by the new data and is missing any detail or perspective that would answer the specific question: why B27 and not other HLA molecule(s)? If the solution is simple, and B27 is qualified to bind certain (bacterial) peptides that are not bound by any other class I molecule, or the unique complex, B27 + x, has special properties resulting in a "dysfunction," there is still no answer to the question: which peptide and why does its binding with B27 result in disease?

HLA and uveitis

The association between HLA-A29 and birdshot chorioretinopathy is the strongest of all associations between HLA and disease. Determination of HLA-A29 is even of diagnostic significance. The association between HLA-B27 and acute anterior uveitis (AAU) is much weaker, but B27 positive AAU may be considered as a distinct clinical entity. B27 positive patients with AAU should be referred to a rheumatologist, because half of these patients have ankylosing spondylitis or Reiter's syndrome. The determination of HLA-Bw51 is of limited but significant diagnostic value for the diagnosis of Behcet's disease. The present article shows how HLA determinations can serve as diagnostic tests. It is explained how the sensitivity and specificity of such tests can be used to calculate the influence of positive or negative results on the probability of the diagnosis. The structure and function of HLA class I molecules is now known to a great extent. This may lead to a better understanding of the pathogenic role of HLA-A29, HLA-B27, HLA-Bw51 and other HLA molecules which are associated with uveitis.

Ophthalmological significance of HLA associated uveitis

The association between HLA-A29 and birdshot chorioretinopathy is the strongest association between HLA and disease ever described. The determination of HLA-A29 is therefore of diagnostic significance. The association between HLA-B27 and acute anterior uveitis (AAU) is much weaker. However, it is evident that B27+ AAU is clinically different from B27-AAU. Half of the B27+AAU patients have or will have ankylosing spondylitis or Reiter's syndrome. The determination of HLA-B27 is therefore of clinical significance and should be determined in each case of AAU. The B27+ patients should be referred to a rheumatologist. The determination of HLA-Bw51 is of limited but significant diagnostic value for the diagnosis of Behçet's disease in countries around the Mediterranean Sea or Japan. In Northern Europe HLA-Bw51 determination will not give much practical information. The structure and function of HLA class I molecules is now known. It is probable that HLA-A29 and HLA-B27 molecules are directly involved in the pathogenesis of respectively birdshot chorioretinopathy and AAU.