Analysis of HLA Profiles in 390 Uveitis Cases: Insights into Clinical Presentations.

Objective: This study aimed to explain the associations between different types of uveitis and human leukocyte antigen (HLA)-B27, HLA-DR4, and HLA-DRw53. Methods: A retrospective analysis of 390 uveitis cases was conducted among inpatients and outpatients diagnosed at Weifang Eye Hospital from 2013 to 2016. All 390 patients underwent HLA-B27 examination, and an additional 40 patients underwent examination for HLA-DR4 and HLA-DRw53. Gender, age, corrected visual acuity (CVA), and recurrence frequency were statistically analyzed based on the onset site and etiology classification. Results: Among the 390 enrolled patients, 206 were male, and 183 were female, with ages ranging from 6 to 87 years (mean: 44.2). The disease onset was classified into anterior uveitis (AU), panuveitis (panU), posterior uveitis (PU), and intermediate uveitis in 180, 112, 88, and 10 cases, respectively. HLA-B27 was positive in 94 cases (53 males and 41 females), yielding a positive rate of 24.1%. In AU patients, 80 (44.4%) tested positive for HLA-B27, while 8 (7.1%) panU patients and 6 PU patients (6.8%) were HLA-B27 positive; none of the intermediate uveitis (IU) patients exhibited HLA-B27 positivity. HLA-B27, HLA-DR4, and HLA-DRw53 examinations were performed on 40 patients with binocular uveitis, resulting in 2 HLA-B27 positive cases, 15 HLA-DR4 positive cases, and 20 HLA-DRw53 positive cases, with positive rates of 5%, 37.5%, and 50%, respectively. Among 25 Vogt Koyanagi-Harada (VKH) cases, 1 tested positive for HLA-B27, 22 were positive for HLA-DR4, and 24 were positive for HLA-DRw53, with positive rates of 4%, 88%, and 96%, respectively. No positive HLA-B27, HLA-DR4, or HLA-DRw53 cases were found among the 10 cases of Behcet's disease (BD). Conclusions: Human leukocyte antigens (HLAs) play a significant role in the mechanism of uveitis. HLA-B27 exhibits high diagnostic value in acute AU, while HLA-DR4 and HLA-DRw53 are crucial for diagnosing binocular uveitis, particularly Vogt Koyanagi-Harada (VKH) syndrome. Further investigation is warranted to explore the relationship between HLA-DR4, HLA-DRw53, and uveitis.

Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes.

Individuals carrying DRB1*0401 who smoke cigarettes are at an increased risk of developing severe seropositive RA. To determine how cigarette smoke (CS) interacts with host genetic factors in the induction of RA-associated autoimmunity, we used transgenic mice carrying the RA-susceptible HLA genes DR4 and DQ8, but lacking all endogenous murine class II molecules. Cigarette smoke exposure augmented peptidylarginine deiminase (PAD) enzyme expression, and enhanced immune responses to citrullinated collagen and vimentin. Here we show for the first time that DQ molecules can present citrullinated peptides much more efficiently than native peptides. Interestingly, CS exposure suppressed collagen-induced arthritis (CIA) in DRB1*0401 mice although innate immune response was enhanced. On the other hand, CS exposure exacerbated CIA in DQ8 mice, which was accompanied by an increased expression of Th17 gene transcripts in lungs. These observations suggest that cigarette smoke promotes antigen-specific autoimmunity that is profoundly influenced by host genetic factors.

Insulin autoimmune syndrome in a health supplement user: the effectiveness of cornstarch therapy for treating hypoglycemia.

A 70-year-old woman with no history of diabetes was admitted to the hospital for the management of hypoglycemia. Her fasting plasma glucose level was 54 mg/dL with an extremely high serum immunoreactive insulin level (1210 µU/mL). She had high titers of anti-insulin antibodies and exhibited the DRB1*0406 genotype for HLA-DR4, leading to a diagnosis of insulin autoimmune syndrome. She had been taking several health preparations for approximately 10 years; however, all were thiol group-free. Due to frequent episodes of nocturnal hypoglycemia, the health preparations were discontinued and the patient was treated with cornstarch. This protocol successfully ameliorated the hypoglycemic episodes and normalized the patient's laboratory and serological test results.

[Studying the dynamics of the levels CD4+CD25+, CD4+ HLA-DR4 + and CD4+CD95+ cells in the semen of men with oligosymptomatic forms of chronic urogenital infection complicated infertility under the influence of fortege].

The markers of activating of lymphocytes in sperm of men with the oligosymptomatic forms of chronic urogenital infection depending on fertility. It is set that the increasing of correlation of CD25/CD95 brings to growth of pathological forms of spermatozoa and, consequently, to the decline of impregnating ability of men. Fortege application leads to the normalization of this correlation and a reduction of pathological forms of sperm and thus to the increasing of the fertilizing potential.

Association of HLA-DR1 with the allergic response to the major mugwort pollen allergen: molecular background.

BACKGROUND: Mugwort pollen allergens represent the main cause of pollinosis in late summer. The major allergen, Art v 1, contains only one single immunodominant, solely HLA-DR-restricted T cell epitope (Art v 125-36). The frequency of HLA-DRB1*01 is highly increased in mugwort-allergic individuals and HLA-DR1 serves as restriction element for Art v 125-36. However, Art v 125-36 also binds to HLA-DR4 with high affinity and DR1-restricted Art v 125-36 -specific T cell receptors can be activated by HLA-DR4 molecules. To understand the predominance of HLA-DR1 in mugwort allergy in spite of the degeneracy in HLA/peptide-binding and TCR-recognition, we investigated the molecular background of Art v 125-36 /MHC/TCR interactions in the context of HLA-DR1 compared to -DR4. RESULTS: The majority of Art v 125-36 -specific T cell lines and clones from HLA-DR1 carrying, mugwort pollen-allergic donors reacted to synthetic and naturally processed Art v 1-peptides when presented by HLA-DR1 or HLA-DR4 expressing antigen presenting cells. However, at limiting peptide concentrations DR1 was more effective in T cell stimulation. In addition, the minimal epitope for 50% of Art v 125-36 -specific T cells was shorter for DR1 than for DR4. In vitro binding assays of Art v 125-36 mutant peptides to isolated DR1- and DR4-molecules indicated similar binding capacities and use of the same register. In silico simulation of Art v 125-36 binding to HLA-DR1 and -DR4 suggested similar binding of the central part of the peptide to either molecule, but a higher flexibility of the N- and C-terminal amino acids and detachment at the C-terminus in HLA-DR1. CONCLUSIONS: The predominance of HLA-DR1 in the response to Art v 125-36 may be explained by subtle conformation changes of the peptide bound to DR1 compared to DR4. Computer simulation supported our experimental data by demonstrating differences in peptide mobility within the HLA-DR complex that may influence TCR-binding. We suggest that the minor differences observed in vitro may be more relevant in the microenvironment in vivo, so that only presentation by HLA-DR1, but not -DR4 permits successful T cell activation.

Design of glycopeptides used to investigate class II MHC binding and T-cell responses associated with autoimmune arthritis.

The glycopeptide fragment CII259-273 from type II collagen (CII) binds to the murine A(q) and human DR4 class II Major Histocompatibility Complex (MHC II) proteins, which are associated with development of murine collagen-induced arthritis (CIA) and rheumatoid arthritis (RA), respectively. It has been shown that CII259-273 can be used in therapeutic vaccination of CIA. This glycopeptide also elicits responses from T-cells obtained from RA patients, which indicates that it has an important role in RA as well. We now present a methodology for studies of (glyco)peptide-receptor interactions based on a combination of structure-based virtual screening, ligand-based statistical molecular design and biological evaluations. This methodology included the design of a CII259-273 glycopeptide library in which two anchor positions crucial for binding in pockets of A(q) and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to A(q) and DR4. Glycopeptides that retained high affinities for these MHC II proteins and induced strong responses in panels of T-cell hybridomas were also identified. An analysis of all the responses revealed groups of glycopeptides with different response patterns that are of high interest for vaccination studies in CIA. Moreover, the SAR understanding obtained in this study provides a platform for the design of second-generation glycopeptides with tuned MHC affinities and T-cell responses.

Identification of small-molecule inhibitors against human leukocyte antigen-death receptor 4 (HLA-DR4) through a comprehensive strategy.

Rheumatoid arthritis (RA) is an autoimmune disease mediated by T-lymphocytes and associated with the human leukocyte antigen-death receptor 4 (HLA-DR4). The HLA-DR4 protein selectively interacts with the antigenic peptides on the cell surface and presents them to the T cell receptor (TCR) on CD4+ T cells. The HLA-DR4-antigen-TCR complex initiates the autoimmune response and eventually causes the chronic inflammation within patients bodies. To inhibit HLA-DR4-restricted T cell activation, an ideal approach is to discover non-T cell stimulating substrates that specifically bind to HLA-DR4. In this paper, a comprehensive structure-based design strategy involved de novo design approach, pharmacophore search, and dock method was presented and applied to "simplify" the known binding peptide ligand of HLA-DR4 and identified specific small-molecule inhibitors for HLA-DR4. The designed three-step strategy successfully identified five nonpeptide ligands with novel scaffolds from a chemical library containing 4 × 10(6) commercially available compounds within a tolerable computing time. The identified five chemicals, BAS-0219606, T0506-2494, 6436645, 3S-71981, and KM 11073, are all non-T cell stimulators and are able to significantly inhibit HLA-DR4-restricted T cell activation induced by type II collagen (CII) 263-272 peptide. IC(50) for the best two potentials, BAS-0219606 and T0506-2494, was 31 and 17 µM, respectively, which is equivalent or better than the known peptide ligands. It is hopeful that they can be used as effective therapeutic means for further treatment of RA patients. In addition, the comprehensive strategy presented in this paper exhibited itself to be an effective flow line from peptide ligands to small-molecule inhibitors and will have applications to other targets.

Effect of Yangqixue Qufengshi Recipe on rheumatoid arthritis model mice under different genetic backgrounds.

OBJECTIVE: To study the effect of Yangqixue Qufengshi Recipe (YQXQFS) on rheumatoid arthritis (RA) model mice under different genetic backgrounds. METHODS: Collagen Induced Arthritis (CIA) were established on HLA-DR4 transgenic (TG) mice and non-transgenic (NTG) mice, which partly were raised with YQXQFS, and the onset day of CIA, the level of type II collagen (CII)-reactive antibodies and the pathological scores of CIA were assessed. RESULTS: Under HLA-DR4 TG background (compared with NTG mice), the earlier onset day of CIA (11.22 +/- 3.35 days vs 16.56 +/- 4.75 days, P < 0.05) and higher level of CII-reactive antibodies (0.2274 +/- 0.1390 microg/ml vs 0.1101 +/- 0.0560 microg/ml, P < 0.05) were observed, but the pathological scores of CIA remained unchanged. YQXQFS could not influence the onset day of CIA and the level of CII-reactive antibodies, but had a certain effect on the total pathological scores (6.56 +/- 3.43 scores vs 11.11 +/- 5.64 scores) and bone erosion (0.22 +/- 0.44 scores vs 1.67 +/- 1.50 scores) of CIA on NTG mice (P < 0.05), NTG YQXQFS group compared with NTG experimental group. CONCLUSION: YQXQFS had a certain effect on RA model, but had no significant effect on HLA-DR4 related CIA.

Effect of Yangqixue Qufengshi Recipe on rheumatoid arthritis model mice under different genetic backgrounds / 中国结合医学杂志

<p><b>OBJECTIVE</b>To study the effect of Yangqixue Qufengshi Recipe (YQXQFS) on rheumatoid arthritis (RA) model mice under different genetic backgrounds.</p><p><b>METHODS</b>Collagen Induced Arthritis (CIA) were established on HLA-DR4 transgenic (TG) mice and non-transgenic (NTG) mice, which partly were raised with YQXQFS, and the onset day of CIA, the level of type II collagen (CII)-reactive antibodies and the pathological scores of CIA were assessed.</p><p><b>RESULTS</b>Under HLA-DR4 TG background (compared with NTG mice), the earlier onset day of CIA (11.22 +/- 3.35 days vs 16.56 +/- 4.75 days, P < 0.05) and higher level of CII-reactive antibodies (0.2274 +/- 0.1390 microg/ml vs 0.1101 +/- 0.0560 microg/ml, P < 0.05) were observed, but the pathological scores of CIA remained unchanged. YQXQFS could not influence the onset day of CIA and the level of CII-reactive antibodies, but had a certain effect on the total pathological scores (6.56 +/- 3.43 scores vs 11.11 +/- 5.64 scores) and bone erosion (0.22 +/- 0.44 scores vs 1.67 +/- 1.50 scores) of CIA on NTG mice (P < 0.05), NTG YQXQFS group compared with NTG experimental group.</p><p><b>CONCLUSION</b>YQXQFS had a certain effect on RA model, but had no significant effect on HLA-DR4 related CIA.</p>

Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule.

Rheumatoid arthritis (RA) is genetically associated with MHC class II molecules that contain the shared epitope. These MHC molecules may participate in disease pathogenesis by selectively binding arthritogenic peptides for presentation to autoreactive CD4(+) T cells. The nature of the arthritogenic Ag is not known, but recent work has identified posttranslationally modified proteins containing citrulline (deiminated arginine) as specific targets of the IgG Ab response in RA patients. To understand how citrulline might evoke an autoimmune reaction, we have studied T cell responses to citrulline-containing peptides in HLA-DRB1*0401 transgenic (DR4-IE tg) mice. In this study, we demonstrate that the conversion of arginine to citrulline at the peptide side-chain position interacting with the shared epitope significantly increases peptide-MHC affinity and leads to the activation CD4(+) T cells in DR4-IE tg mice. These results reveal how DRB1 alleles with the shared epitope could initiate an autoimmune response to citrullinated self-Ags in RA patients.

Atypical Vogt-Koyanagi-Harada Syndrome in a 7-Year-Old Boy

PURPOSE: Vogt-Koyanagi-Harada syndrome is more common in adults than in children. We report a atypical case of Vogt-Koyanagi-Harada syndrome like white dot syndromes in a 7-year-old child. METHODS: A 7-year-old child visited with complaints of decreased binocular visual acuity. Under ophthalmologic examination, anterior uveitis and optic neuropathy were found. But there was no other retinal lesion. After high-dose intravenous corticosteroids pulse therapy, yellow pigment lesions like white dot syndromes developed in peripheral retina and enlarged without serous retinal detachment. RESULTS: In 5 months after high-dose intravenous corticosteroids pulse therapy, anterior inflammation was decreased and visual acuity was 0.8 in both eyes. But depigmented retinal lesions were increased and sunset glow occurred. Alopecia and poliosis of hair were found. Human leukocyte antigen typings revealed HLA-DR4 antigen.

Genotipagem na artrite reumatóide, Alelos HLA-Classe II: HLA-DRB1 *0102 associados á sucetibilidade e HLA-DRB1 *0401 e 0404 associados á agressividade / Genotyping in the rheumatoid arthritis, Alelos HLA-class II: HLA-DRB1 *0102 associated to the susceptibility and HLA-DRB1 *0401 and 0404 associated to aggressiveness

A associação de antígenos de histocompatibilidade com artrite reumatóide (AR) vem sendo demonstrada em inúmeros estudos. A principal associação em população caucasóide é como HLA-DR4, contudo, também vem sendo observada com HLA-DR4 está mais associado com a gravidade do que com suscetibilidade. Com a introdução das técnicas de biologia molecular foi possível determinar que, os substipos do HLA-DR4, relacionados com AR, são os alelos HLA-DRB1 *0401, 0404 e 0405, que estão mais associados á gravidade da doença do que com a suscetibilidade. Em alguns estudos verificou-se, também os subtipos do HLA-DR1 associados com a doença são os alelos HLA-DRB1 *0101 e *0102. Os propósitos deste estudo foram analisar a frequência dos antígenos HLA-DR, identificar os alelos específicos do HLA-DRB1, determinar sua frequência, correlacionar estes alelos com as manifestações clínicas e laboratoriais e caracterizar aqueles que podem predizer o padrão evolutivo da AR em pacientes causasóides.(AU)

Frequencies of HLA-A24 and HLA-DR4-DQ8 are increased and that of HLA-B blank is decreased in chronic toxic oil syndrome.

The cause of toxic oil syndrome (TOS) has not yet been definitively determined, but some genetic susceptibility factors (certain HLA antigens and female sex) have been identified in 236 patients. Similarities with genetic factors for scleroderma and hydralazine-induced lupus (i.e. in TOS female sex and HLA-A24, Pcorrected = 0.00001 and DR4, Pcorrected = 0.04, respectively) may provide a clue to the responsible xenobiotic and its pathogenesis, and may also help in understanding the basis of the related eosinophilia-myalgia syndrome associated with tryptophan ingestion. In this paper it is also established that a human class I antigen (HLA-A24) and, independently, an HLA class II haplotype (DR4-DQ8, Pcorrected = 0.04) and arginine 52 in the alpha-DQ chains (Pcorrected = 0.03) are associated with TOS susceptibility, similarly to insulin-dependent diabetes. This further supports the classification of TOS as an autoimmune disease. Also, the increased frequency of a particular set of low-frequency HLA class I antigens in chronic TOS patients (i.e. B27, B37, B38 and B49) and the probable decrease in the frequency of HLA-B homozygotes in surviving patients (Pcorrected = 0.008) may provide an objective model to explain the maintenance of the HLA polymorphism: less frequent HLA alleles may be more advantageous in the event of unexpected human contact with unusual xenobiotics (not only microbes); however, other mechanisms working together to preserve and generate HLA polymorphism may coexist.

Pemphigus and dietary factors. In vitro acantholysis by allyl compounds of the genus Allium.

BACKGROUND: Today it is generally accepted that every drug that possesses an active thiol group in its molecule is capable of inducing pemphigus in vivo and provoking acantholysis in vitro. We therefore suggested that plants, in particular those belonging to the Allium group, that contain several active compounds with stable disulfide and thiol groups in their molecule may cause the same. OBJECTIVE: To verify this hypothesis by investigating the in vitro acantholytic effect of three compounds of garlic. METHODS: Skin samples from donors were cultured in the presence of three compounds of garlic (i.e. allylmercaptan, allylmethylsulfide and allylsulfide) for 3 days. The skin samples were then processed for microscopic control for acantholysis. RESULTS: Results indicate that, indeed, the three garlic compounds tested are capable of inducing acantholysis in vitro. Focal and diffuse acantholysis was observed in the specimens from 4 out of 7 donors cultured in the presence of 6 and 9 mM of each of the allyl compounds for 3 days. Interestingly, tissues from a DR4+ donor proved to be more acantholysis prone than others, showing large blistering due to diffuse acantholysis, thus indicating that individual susceptibility plays a crucial role also in vitro. CONCLUSION: Garlic compounds with stable disulfide and thiol groups in their molecule are capable of inducing acantholysis in vitro. These findings lend further support to the theory that 'harmless' nutritional factors are capable of inducing acantholysis in vitro and possibly also in vivo. In view of these findings, it is suggested that nutritional factors should be added to the ever-growing list of exogenous factors capable of inducing pemphigus.

HLA-DR4-associated nonresponsiveness to mountain-cedar allergen.

We did human lymphocyte antigen (HLA)-DR and DQ typing on 37 subjects with mountain-cedar (MC) pollinosis as defined by history and a positive skin test. Of these 37 subjects, 31 were subdivided into 18 subjects with a single positive skin test (SPST) and 13 subjects with multiple positive skin tests (MPSTs). We also typed 51 subjects without MC sensitivity or atopy as defined by history and negative skin tests to a battery of aeroallergens. We also typed 116 subjects in whom MC sensitivity had not been determined. Total IgE, Mc-specific immunoglobulin E (sIgE), and MC-sIgE binding bands by immunoblot were also determined on the subjects with SPSTs and MPSTs. No significant differences were found between the subjects with SPSTs and MPSTs for HLA type, total IgE, MC sIgE, or bands bound by MC sIgE by immunoblot. There was a strong negative relationship between HLA-DR4 and subjects with MC pollinosis; chi-square, 14.857; p = 0.0096; and odds ratio, 0.139. These findings suggest that there is no difference in genetic immunoregulation between subjects with SPSTs and MPSTs but that the presence of the DR4 gene product is associated with a decreased risk of an IgE response to MC and protection from MC pollenosis.

Superoxide dismutase isoenzymes, glutathione peroxidase and selenium in blood from HLA-B27-positive and -negative subjects.

We studied the activity of superoxide dismutase (SOD) isoenzymes (CuZnSOD, cyanide-resistant MnSOD and extracellular SOD), the concentration of plasma selenium (P-Se), and the activities of CuZnSOD and glutathione peroxidase (GSHPx) in erythrocytes of 10 HLA-B27-positive and 10 HLA-B27-negative subjects whose sera had shown high and low chemokinetic activity, respectively, on migration of polymorphonuclear leukocytes (PMN) in vitro. No significant difference was found between the groups, suggesting that the enhanced chemokinetic activity of HLA-B27-positive sera does not derive from an aberration in serum anti-oxidant potentials. The results were also analysed on the basis of HLA-DR specificities; HLA-DR4-positive plasma samples had significantly lower levels of Se than HLA-DR4-negative ones. We therefore carried out a second series of experiments with sera of 37 subjects; the levels of P-Se in HLA-DR4-positive and -negative groups were much the same, as were the activities of GSHPx. The data suggest that there is no gross aberration in P-Se concentration in HLA-DR4-positive subjects.