Role of Citrullinated Fibrinogen Peptides in the Activation of CD4 T Cells from Patients with Rheumatoid Arthritis

This study was conducted to determine whether CD4 T cell responses to citrullinated fibrinogen occur in patients with rheumatoid arthritis (RA), especially in HLA-DR4-positive subjects. Whole peripheral blood mononuclear cells (PBMCs) of RA patients and control subjects were stimulated with citrullinated fibrinogen peptides, and T-cell production of proliferation and proinflammatory cytokines, such as interferon-gamma(IFN-gamma) and interleukin-17A (IL-17A), were measured. In addition, CD4 T cells from RA patients were stimulated with the citrullinated fibrinogen peptide, Fib-alpha R84Cit, identified as a DRB1*0401-restricted T cell epitope in HLA-DR4 transgenic mice, and the degree of T cell activation was examined similarly. No proliferative responses to the citrullinated fibrinogen peptides were observed in whole PBMCs or CD4 T cells from RA patients. Furthermore, no increased production of IFN-gamma or IL-17A was found in whole PBMCs or CD4 T cells stimulated with the citrullinated fibrinogen peptides, although these cells responded to recall antigen, a mixture of tetanus toxoid, purified protein derivative (PPD) from Mycobacterium tuberculosis, and Candida albicans. The results of this study indicate that anti-citrulline immunity in RA patients may be mediated by fibrinogen because there is no evidence of CD4 T cell-mediated immune responses to citrullinated fibrinogen peptides.

Coexisting ankylosing spondylitis and rheumatoid arthritis: a case report with literature review / 中华医学杂志(英文版)

A 30-year-old female patient with coexisting ankylosing spondylitis and rheumatoid arthritis was diagnosed and treated. The human leukocyte antigen (HLA)-B27 is a predisposing factor of ankylosing spondylitis and HLA-DR4 is a predisposing factor of rheumatoid arthritis. This patient was HLA-B27 and HLA-DR4 positive, and ankylosing spondylitis manifested before rheumatoid arthritis. After disease modifying anti-rheumatic drugs successfully arrested ankylosing spondylitis activity the patient conceived and delivered a healthy baby. One year later, she developed peripheral polyarthritis and was diagnosed with rheumatoid arthritis. We hypothesized that pregnancy may be one of the environmental factors that can activate rheumatoid arthritis, and that disease modifying anti-rheumatic drugs play an important role in keeping the disease under control.

Association of HLA-DR4, PAD4, and STAT4 expression in the peripheral blood with disease activity in patients with rheumatoid arthritis / 南方医科大学学报

<p><b>OBJECTIVE</b>To explore the association of the expressions of human leukocyte antigen (HLA)-DR4, peptidyl arginine deiminase type4(PAD4), and signal transducer and activator of transcription 4 (STAT4) in the peripheral blood with the disease activity in patients with rheumatoid arthritis (RA).</p><p><b>METHODS</b>Twenty-four RA patients in active stage (DAS28 score>or=2.6) and 14 RA patients in remission stage (DAS28 score<2.6) were enrolled in this study, with 12 healthy volunteers as the control. The QuantiGene Plex method was used to measure the expression level of HLA-DR4, PAD4, and STAT4 mRNA, and the relationship between the expressions of these genes and the DAS28 score, levels of anti-cyclic citrullinated peptide antibody (anti-CCP antibody) and rheumatoid factor (RF) was analyzed.</p><p><b>RESULTS</b>The expressions of HLA-DR4, PAD4, and STAT4 were significantly higher in RA patients than in the healthy controls (P<0.05). The level of HLA-DR4 mRNA in the two RA groups showed no significant difference, but was significantly higher than that in the healthy controls. HLA-DR4 expression was not found to correlated to DAS28 score, anti-CCP antibody level or RF in the RA patients. The expressions of PAD4 and STAT4 were significantly different between the two RA groups (P<0.05). In the RA patients, PAD4 mRNA expression was positively correlated to DAS28 and anti-CCP antibody level (P<0.05), and STAT4 expression showed positive correlations to DAS28 and RF levels (P<0.05).</p><p><b>CONCLUSION</b>HLA-DR4, PAD4 and STAT4 are overexpressed in RA patients and may be involved in the pathogenesis of RA. The expressions of PAD4 and STAT4, but not HLA-DR4, are closely related to the disease activity of RA. Detection of peripheral blood PAD4 and STAT4 expressions can be helpful for evaluating the disease activity of RA.</p>

Anti-CCP antibodies predict progression of palindromic rheumatism to rheumatoid arthritis / 대한내과학회지

BACKGROUND/AIMS: Palindromic rheumatism (PR) is an episodic arthropathy that may precede typical rheumatoid arthritis (RA). The objective of this study was to determine whether anti-cyclic citrullinated peptide (anti-CCP) antibodies in patients with PR contribute to the progression to RA. METHODS: The study group included 115 patients who were initially diagnosed with PR. Baseline serum samples were stored and analyzed for the presence of anti-CCP antibodies, APF, and RF or for anti-CCP antibodies and HLA-DR4. A multiple logistic regression analysis was used to identify predictive factors for progression to RA. RESULTS: The anti-CCP antibodies APF and RF were found in 33.3%, 28.9%, and 35.7% of the 115 patients with PR, and 36 (31.3%) of these patients eventually progressed to RA. Comparing the risk factors for patients who progressed to RA (31.3%) and those who did not (68.7%), only the presence of anti-CCP antibodies was found to affect progression to RA (95% CI for OR, 0.0001-0.114; p<0.001). HLA-DR4-positivity was noted in 40% of the patients with PR, although it did not affect progression to RA and was not significantly associated with the presence of anti-CCP antibodies. CONCLUSIONS: Anti-CCP antibodies are found more frequently in patients with PR who eventually progress to RA. Therefore, anti-CCP antibody testing of patients with PR may facilitate prediction of progression to RA.

Possible Role of lnterleukin-6 in Rheumatoid Arthritis

Rheumatoid Arthritis [RA] is an autoimniune disease. Many etiological agents are proposed to play a role in its pathogenecisy. One of these factors is cytokines such as Interleukin6. ELISA method has been used for IL-6 estimation in 75 RA patients in comparison with 67 SLE as patient controls and 39 apparently healthy controls. This study showed that there was an elevation of IL -6 in the sera of RA patients with high significant differences between RA patients and controls [P < 0.001]. Moreover a good correlation between IL-6 level and RE titer were observed However, for most patients with high IL-6 were shown to be HLA-DR4. Interleukin-6 play a crucial role in the disease which may be participate in the severity of RA and subsequently its treatment

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>

Is There Any Relationship Between Human Leucocyte Antigen Class II and Chronic Urticaria? (Chronic Urticaria and HLA Class II)

Human Leukocyte Antigen (HLA) typing of large groups of patients with various autoimmune diseases has demonstrated that some HLA alleles occur at higher frequencies in specific diseases than in the general population. Chronic urticaria has been shown to have an autoimmune basis by a previous study which found an association between chronic urticaria and specific HLA groups. We investigated the HLA subtypes of Turkish chronic urticaria patients. For this purpose 42 Turkish patients with chronic urticaria and 115 healthy controls were typed for HLA-DR and DQ by PCR-SSP (Polymerase Chain Reaction Sequence Specific Primers) low resolution DNA technique. We found an increased frequency of DR4 (42.9%, p=0.01) in chronic urticaria patients in comparison with that in healthy controls. This study supports the hypothesis that HLA alleles may be involved in the pathogenesis of chronic urticaria and that they appear to be directly involved in the initiation of the immune response.

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.

DRB1*04 subtype in Thai patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) in a Thai population is significantly associated with HLA-DR4. The frequency of DR4 was 43 per cent in RA patients and 20 per cent in the healthy controls (p = 0.00008, OR = 3.06, 95% CI = 1.71, 5.52). To analyze which DR4 alleles were associated with the disease, the authors subtyped 52 DR4-positive RA patients compared to 28 DR4-positive healthy controls by amplification with DR4-specific primers followed by direct sequencing. Six DR4 alleles (DRB1*0401, *0403, *0404, *0405, *0406, and *0410) were found in the RA patient group while 5 alleles (DRB1*0401, *0403, *0405, *0406, and *0407) were found in the control group. Both groups were predominated by DRB11*0405, but there was a significant increase in the frequency of DRB1*0405 in DR4+ RA patients compared to DR4+ healthy controls (84.6% vs 46.4%, p = 0.0008, OR = 6.35, 95% CI = 1.96, 21.08). DR4 which shared epitope alleles (DRB1*0401, *0404, *0405) were observed in 47 (90.3%) DR4+ patients and 15 (53.5%) DR4+ controls (p = 0.0005, OR = 8.15, 95% CI = 2.29, 33.2). In addition, the authors found that DRB1*0403 was significantly decreased in DR4+ RA patients compared to controls (p = 0.0065, OR = 0.07, 95% CI = 0, 0.67).

The relationship between tumor necrosis factor A-308 gene polymorphism and susceptibility of severe periodontitis in adults / 中华口腔医学杂志

<p><b>OBJECTIVE</b>To investigate the relationship between tumor necrosis factor A-308 gene polymorphism and susceptibility of severe periodontitis in adults.</p><p><b>METHODS</b>Buccal swabs from 65 adult patients with severe periodontitis and 96 periodontal healthy adult controls were obtained. DNA was extracted from each sample using Chelex-100 method, then PCR-RFLP was performed to determine the TNFA-308 genotype. Data were analyzed by statistics software.</p><p><b>RESULTS</b>A significant difference of genotype distribution was found between the patients and controls. The percentage of 1/1 type of the patients was much higher (P < 0.001). Risk Analysis showed odds ratio for allele 1 was 4.64.</p><p><b>CONCLUSION</b>This study suggested that TNFA-308 allele 1 maybe a marker of susceptibility to severe periodontitis.</p>

Relationship between type I autoimmune hepatitis and alleles of HLA-DRB1 in Chinese patients of Shanghai area / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To analyze the association between alleles of HLA-DRB1 and type I autoimmune hepatitis (AIH) in patients from Shanghai, China.</p><p><b>METHODS</b>In 32 Chinese patients with type I AIH and 48 healthy controls in Shanghai area, polymerase chain reaction amplification with sequence-specific primers (PCR-SSP) was performed to examine the association of the alleles of HLA-DRB1 and its subtypes with type I AIH.</p><p><b>RESULTS</b>HLA-DRB1 typing by PCR-SSP showed that DR4 had a significantly increased frequency among patients with AIH versus healthy control (46.9% versus 20.8%; relative risk=3.35, chi(2)=5.99, P=0.014). No other alleles differed significantly between the two groups. In subtypes of DRB1*04, there was a trend for an increase in gene frequency of DRB1*0405 increased in patients with type I AIH versus healthy controls (21.9% vs 6.3%, chi(2)=4.23, P=0.04, but Pc=0.08). The frequency of arginine at position HLA-DR beta 71 of third hypervariable region significantly increased among patients with AIH versus healthy control (46.9% versus 18.8%, chi(2)=7.14, P=0.008).</p><p><b>CONCLUSIONS</b>Type I AIH in Chinese patients of Shanghai area is associated with HLA-DR4 and arginine at position DR beta 71 of third hypervariable region</p>

Association between Korean Schizophrenics and HLA-DRB1 Alleles / 신경정신의학

OBJECTIVE: A genetic predisposition is widely accepted in schizophrenia. This study was intended to find any association of HLA-DRB1 alleles with Korean schizophrenics and thereby compare the results of other ethnic groups. METHODS: The subjects were 70 unrelated Korean patients. Low and high resolution typing of HLA-DRB1 alleles were performed. The comparison groups were 2,000 unrelated healthy Koreans for low resolution HLA-DR and 229 unrelated healthy Koreans for HLA-DRB1 alleles. RESULTS: Gene frequencies of HLA-DR11(patients 9.0%, healthy control 3.8%, p=0.005) and HLA-DRB1*1101(patients 9.0%, healthy control 1.8%, p< .001) were significantly higher in Korean schizophrenics. CONCLUSIONS: The frequency of HLA-DR11 (HLA-DRB1*1101) is significantly higher in Korean schizophrenics than in healthy Koreans. HLA-DR4 and HLA-DR1, which were known to be associated with Caucasian and Japanese schizophrenics, respectively, did not show statistical association with Korean schizophrenics. This association need to be reassured through further studies with families or association study with larger numbers of subjects.

The Clinical and Immunogenetic Characteristics of Adult - Onset Insulin - Dependent Diabetes Mellitus in Korea / 대한내과학회지

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease occurring among genetically susceptible individuals. Although the HLA class II genes and immunological abnormalities are clearly associated with IDDM in all racial groups, there are considerable variations in associated genotypes and prevalence of autoantibodies. Especially, it seems that adult-onset IDDM is somewhat different from childhood-onset IDDM in clinical and immunogenetic aspect. In order to determine the characteristics of the immunogenetic patterns and to use these results as an early diagnostic tool and a guideline of the therapeutic plan in Korean adult- onset IDDM, we investigated the clinical and immunogenetic characteristics in adult-onset IDDM patients. METHODS: We investigated the clinical and biochemical characteristics, and measured anti-GAD antibody by immunoradiometric assay or immunoprecipitation after in vitro translation of human GAD cDNA and IA-2 antibody by immunoprecipitaion after in vitro translation of human IA-2cDNA. The distribution of HLA-DR serotypes by lymphocyte microcytotoxicity method, HLA-DQA1 genotypes by restriction fragment length polymorphism and HLA-DQB1 genotypes by dot-blotting analysis using sequence specific oligonucleotide probe were analysed in 233 IDDM patients and controls. RESULTS: 1) Adult-onset patients had more preserved beta cell functions and slowly evolving form of clinical pattern rather than childhood-onset cases. 2) Each prevalences of anti-GAD and IA-2 antibody were 64% and 14.4% in adult-onset patients. Among them, the group with DR9-DQ9 had higher prevalence of antiGAD antibody rather than DR4-DQ4 group. 3) There were increased frequencies of HLA-DR4 and -DR9 in adult-onset patients. Considering the frequency of HLA-DQA1 and -DQB1 and the distribution of DQ heterodimers, they had no significantly increased genotypes or haplotypes. But childhood-onset cases had high frequencies in HLA DR3, -DR4, -DR9 serotypes and DQA1*0301, DQA1*0501, DQB1*0201 genotypes. CONCLUSION: Korean adult-onset IDDM patients have relatively higher prevalence of anti-GAD antibody implicating autoimmune pathogenesis. HLA genetic markers in adult-onset IDDM were somewhat different from those in childhood-onset cases. This pathogenetic heterogenesity according to age of onset may be due to the influences of other genetic markers and environmental factors involved in the etiology of Korean IDDM.

Analysis of Typing in Patients with Uveitis in Korean Population

In order to evaluate association of particular HLA typing with certain uveitis in Korean population, HLA antigens were analyzed in 114 uneitis patients(acute anterior uveitis: 32 cases, Behcet`s disease: 25 cases, intermediate uveitis: 19 cases, Vogt-Koyanagi-Harada (V-K-H) syndrome: 10 cases, retinal vasculitis: 12 cases, Eale`s disease: 3 cases, posterior uveitis: 9 cases, pan.uveitis: 4 cases). The stronger association between acute anterior uveitis and HLA-B27 was statistically significant, and this result was similar to reports in other ethnic groups. Also, the association between V-K-H syndrome and HLA-DR4 showed same results. But the high frequency of HLA-DR7 in the patients with V-K-H syndrome was unque in patients of Korean popjlation and statistically significant. The association between HLA-A2 and posterior uveitis was high in patients of Korean population and statistically significant. Behcet`s disease was stronger association with HLA-B51 but not statistically significant and much weaker association than reports in Japanese group. Although many similarities of associations between particular uveitis and HLA typing were detected as compared with other ethnic groups, distinctive HLA associations were demonstrated in Korean population. Additional cases and long-term follow-up are required to confirm the association with HLA typing and the relationship with prognosis including clinical and laboratory variabilities.

Rheumatoid Arthritis and HLA Class II Genotypes in Korean / 대한정형외과연구학회지

To determine which HLA antigens are associated with rheumatoid arthritis in Korean, we studied the HLA class II genotypes in 40 patients with rheumatoid arthritis and 35 normal healthy persons by the two step polymerase chain reaction. At first we designed 20 pairs of group specific primers followed by the alleles which have the same nucleotide sequences in the exon 2 region. We performed amplification reaction with these 20 pairs of primers for 32 cycles. Reaction products were electrophoresed and only specifically amplified products were reamplified for 15 cycles with total 76 pairs of allele specific primers. We typed the HLA class II genotypes with specific band patterns of each allele. The genotypes in patients were compared with those of normals. HLA-DR4 gave the highest relative risk for rheumatoid arthritis (RR=4), which was statistically significant (P0.05). Among HLA-DR4 subtypes, the frequency of Dwl4(0404) in patient group was relatively higher (19.2%) than that in normal control group(7.7%). The relative risk was high (2.85), although it was not statistically significant (P>0.05). From this study, HLA-DR4 was found to be highly associated while DRI was not associated with rheumatoid arthritis patients in Koreans.

Antigenic distribution of HLA - DRB1 locus in citrus red mite ( Panonychus citri ) - sensitive asthma / 천식및알레르기

BACKGROUND: Specific IgE responses to allergens provide useful models for evaluating the genetic factors that control human immune responses. HLA class II gene products are involved in the antigen presentation of exogenous antigens. OBJECTIVE: The aim of this study was to evaluate whether susceptibility or resistance to asthma induced by the citrus red mite (Panonychus citri, CRM) was associated with HLA class II gene-encoded antigens. METHODS: Peripheral venous blood samples were collected from two groups of unrelated Korean adults. Ninety-one patients with citrus red mite-induced asthma and 98 exposed, healthy control subjects. The second exon of the HLA-DRB1 genes was selectively amplified by the polymerase chain reaction method. HLA typing was carried out using PCR-sequence specific oligonucleotide probes(PCR-SSOP). RESULTS: The frequency of HLA-DR7 was significantly higher among the CRM-sensitive asthmatics than among the controls (17.6% vs 4.1%, RR=3.92, p=0.01). Conversely, the frequency of HLA-DR4 was significantly lower among the CRM-sensitive asthmatics than among the controls(19.8% vs 40.8%, RR=0.36, p=0.01). No significant difference was found in the distributions of the other HLA-DRB1 gene-encoded antigens between the two groups. CONCLUSION: HLA-DRB1 genes may be involved in the development of citrus red mite-induced asthma. In addition, HLA-DR7 may increase, and DR4 decrease, the risk of developing asthma in exposed individuals.

Kleine-Levin Syndrome: Two Cases

Kleine-Levin syndrome (KLS) is characterized by recurring episodes of hypersomnia, megaphagia, and abnormal behavior. We report two cases of KLS. Two boys, aged 18 (case 1) and 17 (case 2), had recurrent episodes of hyper-somnolence with compulsive eating or drinking and hypersexuality for several years. HLA-DR typing was HLA-DR3 and 13 in case 1 and HLA-DR4 and 10 in case 2. Case 1 showed hypersomnia with early onset of REM sleep on MSLT and frequent frontal intermittent rhythmic delta activity on EEG. Both cases showed no abnormalities on brain MRI. HLA-DR typing facilitates differentiation between KLS and narcolepsy by the absence of HLA-DR2.

Idiopathic focal segmental glomerulosclerosis and HLA antigens

The objective of the present study was to investigate a possible association between HLA class II antigens and idiopathic focal segmental glomerulosclerosis (FSGS), HLA-A, -B, -DR and -DQ antigens were determined in 19 Brazilian patients (16 white subjects and three subjects of Japanese origin) with biopsy-proven FSGS. Comparison of the HLA antigen frequencies between white patients and white local controls showed a significant increase in HLA-DR4 frequency among FSGS patients (37.7 vs 17.2 percent, P<0.05). In addition, the three patients of Japanase extraction, not included in the statistical analysis, also presented HLA-DR4. In conclusion, our data confirm the association of FSGS with HLA-DR4 previously reported by others, thus providing further evidence for a role of genes of the HLA complex in the susceptibility to this disease.

Association between hepatitis B virus infection and HLA-DR type in Korean / 대한내과학회지

OBJECTIVES: The course after hepatitis B virus infection appears not to be related to variations in virulence of the HBV itself and may be influenced by the host immune response, which in turn may be regulated by the major histocompatibility complex. The purpose of this study was to determine whether the clearance of HBV was related to a particular HLA allele in Korean. METHODS: We studied total 1372 Korean persons who had visited Yonsei University Medical Center for renal transplantation from January in 1990 to August in 1997. Hepatitis B-viral markers and HLA-DR types were examined by retrospective study. RESULTS: 1) Among 1372 subjects, 924 were male and 448 were female(Mean age, M:37.4yrs, F:38.3yrs). Healthy donors in total subjects were 424. 2) Commonly, HLA-DR4 was most frequent among the total subjects, also in the group of Non-Exposure, Chronic Carrier, Clearance, and Antibody. 3) HLA-DR6 was significantly frequent in the group of Clearance and Antibody compared with the group of Chronic Carrier(p<0.001, RR=3.72 and p<0.001, RR=3.58, respectively). HLA-DR9 was significantly frequent in the group of Chronic Carrier compared with the group of Clearance and Antibody(p<0.001, RR=3.33 and p<0.001, RR=3.32). Results in healthy donors were same as above. 4) HLA-DR13 was significant between the HLA-DR6 subgroups(DR13, DR14) which may influence the clearance of HBV. CONCLUSION: HLA-DR6(esp, HLA-DR13) may be associated with elimination of HBV as one of the host factors influencing the immune response to HBV and HLA-DR9 with persistent HBV infection.