Association between HLA-A and -B polymorphisms and susceptibility to Henoch-Schönlein purpura in Han and Mongolian children from Inner Mongolia

We examined a possible association between HLA-A and -B polymorphisms and susceptibility to Henoch-Sch?nlein purpura (HSP) in Han and Mongolian children in Inner Mongolia, through a case-control study. Two hundred and sixty-eight unrelated children were enrolled, including 56 Mongolian and 50 Han children with HSP, 66 healthy Mongolian and 96 healthy Han children as a control group. HLA-A and -B alleles were indentified by PCR-sequence-specific oligonucleotide analysis and were further analyzed by PCR-sequencing-based typing (SBT). Frequencies of HLA-A*11, HLA-B*15 in Mongolian patients and HLA-A*26, HLA-B*35, HLA-B*52 in Han patients were higher than those in the corresponding control group (P < 0.05), while frequencies of HLA-B*07 and -B*40 in Mongolian HSP patients were lower than those in the control group (P < 0.05). Further analysis using PCR-SBT showed that all HLA-A*11 were HLA-A*1101, and most HLA-B*15 were HLA-B*1501 in Mongolian HSP patients. All HLA-A*26 were HLA-A*2601 and HLA-B*35 were mostly HLA-B*3503 in Han patients. There were more Han patients with severe manifestations than Mongolian patients (P < 0.05). Frequencies of HLA-A*26, HLA-B*35 and HLA-B*52 in Han patients were higher than in Mongolian patients (P < 0.05). We conclude that HLA-A*11(*1101) and -B*15(*1501) are associated with susceptibility to HSP in Mongolian children and HLA-A*26(*2601), HLA-B*35(*3503) and HLA-B*52 are associated with susceptibility to HSP in Han children. HLA-B*07 and -B*40 may be protective genes in Mongolian children. The different frequencies of HLA-A and -B in Mongolian and Han children may be responsible for the different manifestations in these two ethnic groups.     

小剂量糖皮质激素联合消炎痛治疗亚急性甲状腺炎的临床效果

目的:探讨小剂量糖皮质激素联合消炎痛治疗亚急性甲状腺炎(Subacute thyroiditis,ST)的临床效果及安全性。方法:选取我院内分泌科2012年6月-2014年7月收治的150例亚急性甲状腺炎患者,按照随机平均原则即药物治疗的不同将其分为三组,每组50例,即泼尼松与消炎痛联合治疗(A组)、泼尼松单独治疗(B组)、消炎痛单独治疗(C组),对比并分析三组的治疗效果,包括甲状腺疼痛和肿大平均消失时间,治疗1周的ESR平均水平,治疗4周后的血清TSH、FT3、FT4水平,并通过随访,观察治疗后8周患者不良反应的发生率、复发率。结果:(1)A组患者甲状腺疼痛和甲状腺肿大的消失时间与B组比较无显著差异(P0.05),A、B组均显著短于C组(P0.05)。A组患者治疗后1周、4周的ESR水平与B组对比差异不明显,无统计学意义(P0.05);A、B组患者治疗后1周的ESR水平明显低于C组(P0.05)。A、B组治疗后的血清TSH、FT3、FT4水平改善程度均优于C组,差异有统计学意义(P0.05)。(2)A组、C组的不良反应发生率、复发率均低于B组,差异具有统计学意义(P0.05)。结论:采用小剂量糖皮质激素联合消炎痛治疗亚急性甲状腺炎的临床效果显著,且不良反应和复发情况少。     

Histological, clinical and laboratory findings of acute exacerbation of Hashimoto's thyroiditis--comparison with those of subacute granulomatous thyroiditis

As reported previously, acute exacerbation of Hashimoto's thyroiditis shows quite unique histological findings, namely localized edematous inflammation. Similar histological characteristics and clinical manifestations were observed in 7 of 492 patients with Hashimoto's thyroiditis (A group). Their clinical and laboratory findings were compared with those of 15 cases with subacute granulomatous thyroiditis (S group). Age and sex distribution and goiters in A group were 39 +/- 21 years old (mean +/- s.d.), 7/0 (F/M), and 6/1 (diffuse/nodular), respectively. These were somewhat different from those of S group (45 +/- 9, 12/3, and 3/12, respectively). Thyroid functions in A group showed wide variation: 3 cases were euthyroid, 2 were mildly hypothyroid, and one was mildly thyrotoxic and one borderline thyrotoxic, and all of the S group patients were thyrotoxic. Their thyroid radiopertechnetate uptake, scintigraphy, duration from the onset till the first visit, and ESR and CRP values were also different from those of S group. Clinical courses and outcomes of A group were generally favorable, but one of them finally underwent a total thyroidectomy. Per os and intrathyroidal administrations of steroid were effective, but there was observed a recurrence of symptoms in 3 cases. Finally, all 6 cases were left with diffuse goiters, 4 of them remaining euthyroid, and 2 falling into hypothyroidism. The acute exacerbation of Hashimoto's thyroiditis is a rare complication, which is found to be different from subacute thyroiditis on histological, clinical and laboratory findings and is generally subtle. Steroid medication is considered to be the therapeutic choice but careful observation is necessary to avoid a recurrence.     

Histocompatibility lymphocytic antigen (HLA) typing in patients with acute exacerbation of Hashimoto's thyroiditis

Histocompatibility lymphocytic antigen (HLA) typing was performed in 6 patients with acute exacerbation of Hashimoto's thyroiditis whose diagnoses were established on the basis of typical histological findings, and was compared with those of 12 with subacute thyroiditis, 33 with general Hashimoto's thyroiditis and also with a control group. There was a high incidence of BW35 in patients with subacute thyroiditis, although it was only seen in 1 of 6 patients with acute exacerbation. The difference was statistically significant (p less than 0.01). Four of 6 patients with acute exacerbation had DR2 and none of them had DR4, which was the reverse of the findings for Hashimoto's thyroiditis patients in general, and the difference in the incidence of DR2 was significant (p less than 0.001). None of the HLA types in patients with acute exacerbation was significantly different from those of the control group. In conclusion, HLA typing in patients with acute exacerbation was different from those of subacute thyroiditis and general Hashimoto's thyroiditis. Acute exacerbation was considered to involve quite a limited and rather unique population among patients with Hashimoto's thyroiditis.     

Serum free thyroxine and thyroxine-binding globulin concentrations in early phase of subacute thyroiditis

Serum total thyroxine (T4), total triiodothyronine (T3), T4-binding globulin (TBG), free T4(FT4) and free T3(FT3) concentrations and the T3-uptake(T3-U) value were estimated in 11 patients with subacute thyroiditis, and compared with the same parameters in 11 patients with Graves' disease, whose serum T4 concentrations were similar to the former group. Seven patients with subacute thyroiditis, who were treated with dicrofenac sodium alone, were investigated as to the sequential changes in serum parameters during their clinical courses. The mean serum T3-U value and FT4, T3 and FT3 concentrations in patients with subacute thyroiditis were increased, but all were significantly lower than those in patients with Graves' disease (p less than 0.01, p less than 0.001, p less than 0.001 and p less than 0.001, respectively). Three patients with subacute thyroiditis, who showed shorter duration of symptoms than 10 days, had serum TBG excess. Thus the mean (+/- SD) serum TBG concentration (26.5 +/- 8.4 micrograms/ml) was significantly higher than that (18.3 +/- 2.9 micrograms/ml) in patients with Graves' disease (p less than 0.02). The ratios of serum T3 to T4 and FT3 to FT4 in patients with subacute thyroiditis were also significantly lower than those in patients with Graves' disease (p less than 0.001 and p less than 0.001, respectively). The serum FT4 in 7 patients treated with dicrofenac sodium alone decreased to the normal range after 3 to 8 weeks from the onset of the illness. In 3 patients with TBG excess and one patient (TBG; 29.0 micrograms/ml), serum TBG declined in consequence of the serum FT4 normalization.(ABSTRACT TRUNCATED AT 250 WORDS)     

Partial C4 deficiency in subacute sclerosing panencephalitis

In an immunogenetic study, 23 subacute sclerosing panencephalitis (SSPE) patients and their families were studied for the HLA region markers HLA-A, B, C, DR, BF, C2, C4A, C4B, GLO I, and PGM3. In addition, C3, C4, and factor B serum levels were determined. A highly significant association of C4A^*QO with SSPE was found. Furthermore, two rare haplotypes, C4A*QOB*9QO, two C4ACh+ allotypes, and four Ch partial inhibitors were detected, which possibly impair the function of the C4 molecules. HLA-DR5 was increased. In addition, a number of rare HLA-A, C, B, DR haplotypes were observed. It is postulated that rare C4 molecular deficiency might be a predisposing factor in the pathogenesis of SSPE.     

Urinary N-acetyl-beta-D-glucosaminidase (NAG) activity in patients with Graves' disease, subacute thyroiditis, and silent thyroiditis: a longitudinal study.

Urinary N-acetyl-beta-D-glucosaminidase (NAG) activity was measured longitudinally in 12 patients with Graves' disease, 5 patients with subacute thyroiditis, and 1 patient with silent thyroiditis, and compared with that of 36 normal controls. The patients with Graves' disease and subacute thyroiditis were treated with anti-thyroid drug (methimazole or propylthiouracil) and prednisolone, respectively. On the other hand, no treatment was given to the patient with silent thyroiditis. Since two patients with Graves' disease clearly showed transient deterioration of the thyroid function during the treatment period, data from these two patients were separately investigated. Urinary levels of NAG in the remaining ten patients with Graves' disease before, 1, 3, 6 and 12 months after the treatment were 15.59 +/- 7.93 (SD), 8.96 +/- 6.82, 4.39 +/- 2.33, 3.46 +/- 2.24, and 3.63 +/- 2.38 U/g.creatinine (g.Cr.), respectively. Those obtained before, 1 and 3 months after the treatment were significantly higher than those of the controls (2.85 +/- 1.12 U/g.Cr.). Free thyroid hormone levels became normal or low 3 months after the treatment. The two Graves' patients mentioned above showed a transient increase in urinary NAG with concomitant changes in free thyroid hormone levels. Urinary NAG levels in the patients with subacute thyroiditis before, 2, 4, and 6 weeks after the treatment were 16.56 +/- 10.97, 6.76 +/- 2.79, 3.14 +/- 0.48 and 3.70 +/- 1.44 U/g.Cr., respectively. Those obtained before and 2 weeks after the treatment were significantly higher than those of the controls. Free thyroid hormones were normal 2 weeks after therapy. Urinary NAG in the patient with silent thyroiditis was 9.60 U/g.Cr. on the first visit and gradually decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Three-dimensional cytomorphology in fine needle aspiration biopsy of subacute thyroiditis

OBJECTIVE: To elucidate 3-dimensional (3-D) cytomorphology in fine needle aspiration biopsy (FNAB) of subacute thyroiditis. STUDY DESIGN: Ultrasound-guided FNAB was performed on the inflamed area of the thyroid from 4 patients with subacute thyroiditis. The aspirates were stained and observed under a light microscope (LM). The aspirates were also fixed, dehydrated, critical point dried, spattered with gold ions and observed with a scanning electron microscope (SEM). For transmission electron microscopy (TEM), the specimen was fixed, dehydrated, embedded in an Epon mixture, cut with an ultramicrotome, mounted on copper grids, electron doubly stained with uranium acetate and lead citrate, and observed with TEM. Findings with SEM were correlated with those with LM and TEM. RESULTS: Under SEM, 3-D cytomorphology of subacute thyroiditis displayed loss of a uniform, honeycomb cellular arrangement; variation in size; and decrease or shortening of microvilli in follicular cells, which corresponded to varying degrees of cellular degeneration under TEM. Giant cells that were round or ovoid were also noted with SEM. CONCLUSION: Loss of a uniform, honeycomb cellular arrangement; variation in size and decrease or shortening of microvilli in follicular cells; and appearance of round or ovoid giant cells were characteristic 3-D cytomorphology findings in FNAB of subacute thyroiditis.     

Riedel's thyroiditis in a patient with multiple sclerosis

Our patient developed Riedel's thyroiditis soon after having an exacerbation of multiple sclerosis (MS). MS has been associated with other autoimmune diseases, including thyroiditis, and both Hashimoto's thyroiditis and subacute thyroiditis have been described in connection with MS. Yet, we are not aware of any other patient reported to have concomitant MS and Riedel's thyroiditis. The association between MS and Riedel's thyroiditis remains obscure but may reflect an autoimmune disorder common to both diseases.     

Short-Term Versus 6-Week Prednisone In The Treatment Of Subacute Thyroiditis: A Randomized Controlled Trial

Objective: Moderate-to-severe subacute thyroiditis is clinically managed with 6 to 8 weeks of glucocorticoid therapy. However, no studies have evaluated short-term prednisone treatment for subacute thyroiditis.Methods: This 24-week, prospective, single-blind, randomized controlled study enrolled patients (aged 18 to 70 years) with subacute thyroiditis who were hospitalized between August, 2013, and December, 2014. Patients with moderate-to-severe symptoms were randomly assigned to receive either 30 mg/day prednisone for 1 week, followed by 1 week of nonsteroidal anti-inflammatory drugs, or the conventional 6-week prednisone therapy. The primary endpoint was intergroup differences in treatment efficacy at the end of the treatment course. Secondary endpoints included between-group differences in post-withdrawal adverse effect parameters and thyroid function at weeks 6, 12, and 24.Results: We screened 96 patients, randomized 52 participants, and 50 participants completed the study. Efficacy and recurrence rates were not significantly different at withdrawal in both groups (P = .65). At treatment discontinuation, parathyroid hormone (28.8 versus 38.9 pg/mL; P = .011) and systolic blood pressure (113.9 versus 122.4 mm Hg; P = .023) were significantly lower in the experimental group than in the control group. There were no significant intergroup differences in other secondary endpoints at withdrawal and in thyroid function at weeks 6, 12, and 24.Conclusion: Fewer side effects of glucocorticoids and similar efficacy and recurrence rates were observed with short-term prednisone compared with the 6-week treatment for subacute thyroiditis. Short-term prednisone, with a better safety profile, may be an alternative strategy for ameliorating moderate-to-severe symptoms of subacute thyroiditis.Abbreviations: BPPG = breakfast postprandial plasma glucose; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; FPG = fasting plasma glucose; FT3 = free triiodothyronine; FT4 = free thyroxine; GA = glycated albumin; NSAIDs = nonsteroidal anti-inflammatory drugs; OC = osteocalcin; PINP = type I procollagen amino-terminal peptide; PTH = parathyroid hormone; RCT = randomized controlled trial; SAT = subacute thyroiditis; SBP = systolic blood pressure; TC = total cholesterol; TSH = thyroid-stimulating hormone; TBG = thyroid-binding globulin; TG = triglyceride; TGAb = antithyroglobulin antibody; TPOAb = antithyroid peroxidase antibody; TRAb = antithyroid-stimulating hormone receptor antibody     

Painful subacute thyroiditis in Hawaii.

Between 1960 and 1982 we prospectively studied 269 patients with painful subacute thyroiditis to determine the demographic characteristics, seasonality, and natural course of the disease. The mean age for all patients was 37.1 years. The female:male ratio was 6.7:1. At the first visit, disease was bilateral in 69%. No epidemic or seasonal pattern was identified. The mean duration of thyroid tenderness was 2.2 months and that of palpable thyroid lumps was 2.8 months. This time difference, sometimes lasting many months, left a painfree "window" during which the palpable hard residual mass of subacute thyroiditis may be confused with other thyroid problems, especially cancer.     

Seasonal recurrence of transient hypothyroidism in a patient with autoimmune thyroiditis

Two postpartum and 7 spontaneous episodes of transient hypothyroidism developed during 5 years of observation in a florist with autoimmune thyroiditis and seasonal allergic rhinitis. The spontaneous episodes recurred twice a year regularly in spring and in autumn, the seasons of her allergic rhinitis. In most of these episodes as well as in the postpartum ones, hypothyroidism was preceded by transient thyrotoxicosis. In addition to the similarity in the clinical course, the changes in antimicrosomal antibody titers in pregnancy-unrelated episodes were almost identical to those in postpartum episodes. Throughout the observation periods, she had supranormal serum total immunoglobulin (Ig) E concentrations and high antigen-specific Ig E levels for various pollen extracts such as cedar and ragweed. However, we failed to demonstrate a correlation between thyroid function and total or any antigen-specific Ig E level. The present findings suggest that the pregnancy-unrelated thyroid dysfunction in our patient developed as a result of silent thyroiditis and through similar immunological mechanisms to those in postpartum thyroiditis. And it is suspected, though unproved, that the seasonal recurrence of pregnancy-unrelated thyroiditis has some causal relation to her allergic disease.     

Cytomorphologic aspects of thyroiditis. A study of 51 cases with functional, immunologic and ultrasonographic data

Fine needle aspiration provided material for detailed cytomorphologic study in 51 cases of thyroiditis, 40 of which were diagnosed as Hashimoto's (autoimmune) thyroiditis. Of these 40 cases, 22 were found to be euthyroid on clinical examination and radioimmunoassay (RIA), 10 were hyperthyroid and 8 were hypothyroid. Of the 11 cases of subacute thyroiditis, 4 were thyrotoxic and 7 were euthyroid. Radioactive iodine uptake (RAIU) showed decreased to negligible uptake in ten and normal uptake in one case of subacute thyroiditis, whereas all of the thyrotoxic cases of Hashimoto's thyroiditis showed markedly increased RAIU. Echography showed a hypoechoic or anechoic pattern in most of the cases. Antimicrosomal and/or antithyroglobulin antibodies were positive in 25 cases of Hashimoto's thyroiditis and in 1 case of subacute thyroiditis. The cytologic features that characterized subacute thyroiditis were the presence of multinucleated giant cells and a polymorphonuclear and lymphocytic population associated occasionally with epithelioid-cell granulomas. Hashimoto's thyroiditis was characterized by Hürthle-cell changes and a significant lymphoid population consisting of mature and transformed lymphocytes, often impinging on follicular cells. There was an overlap in the cytomorphologic features between some cases of Hashimoto's and subacute thyroiditis. In such cases, the final diagnosis was arrived at by an integrated approach incorporating all of the diagnostic parameters available.     

Fine Needle Aspiration Cytodiagnosis of Subacute (De Quervain's) Thyroiditis In an Endemic Goitre Area

Between 1977 and 1989 252 fine needle aspirates (FNAs) of the thyroid from patients with a clinical suspicion of subacute granulomatous (de Quervain's) thyroiditis were examined in the Department of Pathology of the University of Innsbruck, Austria. In the same period 31 cases with preoperative FNA were diagnosed histologically as subacute thyroiditis. Only in three of these cases were the cytological features of de Quervain's thyroiditis found in the preoperative FNA. However, in 13 of these 31 cases a cytological suspicion of malignancy was obtained. Subsequent histological examination revealed an acute phase inflammation of de Quervain's thyroiditis in most of these cases. We conclude that an accurate FNA diagnosis of de Quervain's thyroiditis, particularly in the acute stage, may cause difficulties due to a lack of typical features and the appearance of atypical thyroid follicular cells. For the cytopathologist, accurate clinical information relating to the possibility of de Quervain's thyroiditis is essential if unnecessary surgery is to be avoided.     

Disseminated cryptococcosis presenting as thyroiditis. Fine needle aspiration and autopsy findings

A 47-year-old diabetic ethanol and intravenous drug abuser presented with symptoms and signs indistinguishable from subacute thyroiditis. After cultures of cerebrospinal fluid grew Cryptococcus neoformans, the organism was recognized in a review of a fine needle aspirate of the thyroid. Postmortem examination documented extensive thyroid inflammation and fibrosis secondary to involvement by widely disseminated C. neoformans. Fungal infection is an uncommon cause of thyroiditis, and the need for a clinical awareness of fungal thyroiditis is emphasized, as is the need to utilize special stains to detect opportunistic infections when examining cytologic preparations from immunocompromised patients.     

Sulfisoxazole Chemoprophylaxis and Recurrent Otitis Media

Sulfisoxazole, 75 mg per kg per day, was administered for 13 weeks to all children with otitis media recurring at a rate of at least once every other month. The first 26 patients began prophylaxis during the months of January and February of 1979. To compare rates of otitis media with those in children not receiving concurrent prophylaxis during the same season, a matched control was randomly chosen as a child who began prophylaxis on the day nearest that when a study patient completed prophylaxis. The rates of otitis media during this same period were determined as the number of episodes per patient-month. Of the 26 treated patients, 11 had 16 episodes of otitis media in 72 patient-months (0.22 episodes per patient-month), in contrast to the 26 untreated patients who had 63 episodes in the same period (0.88 episodes per patient-month). This 75% reduction in incidence was statistically significant by X² analysis (P<.005). The two groups of children were comparable in age, sex, nursery school attendance, family history of allergy and number of episodes in the three months preceding chemoprophylaxis. These findings support the short-term chemoprophylactic use of sulfisoxazole for recurrent otitis media.     

HLA Class I and Class II Associations with ESRD in Saudi Arabian Population

Background

Chronic renal failure (CRF) leads in the majority of instances to end stage renal disease (ESRD) requiring renal replacement therapy. Our interest was to evaluate the possible associations of HLA class I and class II antigens with ESRD independent of other factors, in Saudi Arabia population.

Methodology

A retrospective study to determine the HLA class I and class II polymorphisms and their association with ESRD, was performed on 350 patients with ESRD, and 105 healthy unrelated control. Patients and control groups were typed by SSOP lumenix techniques. The alleles positively associated to the ESRD were: HLA-B*15, B*18, B*49 - DRB1*03, negatively associated alleles were A*26, HLA-B*39, B*50. The haplotypes positively associated with ESRD were: HLA-A*01-DRB1*13 and HLA-A*30-DRBI*03. The negatively associated haplotypes were: HLA-A*02-B*39, A*02-B*50, A*24-B*35, A*24-B*58, A*24-DRB1*16, A*68-DRB1*04, A*02-DQB1*03, A*29-DQB1*02, A*29-DOB1*05 and B*27-DRB1*07 and the last one is the most significant protective haplotypes.

Conclusion

The high Relative Risk (RR) observed and its statistical correlation reflect the strength of the described association between HLA antigens and ESRD.     

Association of different pathologic processes of the thyroid gland in fine needle aspiration samples

OBJECTIVE: To evaluate the possible significant association between different pathologic processes of the thyroid gland. STUDY DESIGN: From a series of 10,039 fine needle aspiration biopsies of the thyroid gland, a total of 1,330 cases were aspirated involving two or more palpable nodules. In 103 (1%) cases, two different pathologic processes were cytologically diagnosed. Statistical analysis was performed through four two-tailed chi 2 tests to evaluate the following events: (1) mononodularity and multinodularity vs. neoplasms, (2) colloid goiter and neoplasms, and (3) all neoplasms vs. colloid goiter and lymphocytic thyroiditis. All tests were performed using < .05 as the probability level. RESULTS: Simultaneous pathologic processes observed were: goiter and chronic lymphocytic thyroiditis (32), goiter and Hashimoto's thyroiditis (21), goiter and subacute granulomatous thyroiditis (8), goiter and follicular neoplasm (9), and goiter and papillary carcinoma (14). In 12 cases we found goiter and Hürthle cell tumor, goiter and medullary thyroid carcinoma (2), papillary thyroid carcinoma and Hashimoto's thyroiditis (2), Graves' disease and lymphocytic thyroiditis (2), and follicular neoplasm and lymphocytic thyroiditis (1). Statistical analysis showed significant association between multinodularity and neoplasms (P < .001), while the association between goiter and any type of neoplasia was not statistically significant. All the neoplasms taken together were associated with lymphocytic thyroiditis and goiter (P < .005). CONCLUSION: While there may be no statistically significant associations between the individual pathologies, it seems that having one pathology increases the risk of developing another. All the palpable nodules in the same gland should be investigated by fine needle aspiration in order to improve diagnostic sensitivity and to identify occult neoplasms.     

Beh?et’s disease in HLA-B*51 negative Germans and Turks shows association with HLA-Bw4-80I

Introduction

Behçet’s disease (BD) as systemic vasculitis of unknown etiology is associated with HLA-B*51 in European and Asian populations. HLA-A*26 was claimed as an additional BD susceptibility marker in Japanese and Greek patients. This study was performed to test for HLA associations in HLA-B*51 negative German and Turkish BD populations.

Methods

In total, 65 German and 46 Turkish patients lacking HLA-B*51 were analyzed in comparison to healthy HLA-B*51 negative Germans (n = 1500) and Turks (n = 130). HLA-A/B genotypes were determined by SSOP. P-values with correction for multiple testing (p_c), χ2-test and odds ratio (OR) were used for statistical evaluation.

Results

HLA-A*26 was significantly more frequent in HLA-B*51⁻ German patients [p_c = 0.0076, OR = 3.23, 95% CI 1.63 to 6.39] than in respective controls. HLA-A*26 was also elevated in a smaller group of Turkish patients versus the controls. Significant association of HLA-Bw4 with isoleucine at amino-acid position 80 (HLA-Bw4-80I) was found in the HLA-B*51⁻ German cohort of BD patients [p_c = 0.0042, OR = 2.35, 95% CI 1.41 to 3.93) and in the Turkish patients in comparison to the respective controls [p = 0.025, OR = 2.17, 95% CI 1.09 to 4.31]. On the contrary, HLA-Bw4-80 T was reduced in both HLA-B*51⁻ BD patient cohorts.

Conclusions

The study shows a significant association of HLA-Bw4-80I present on HLA-B*51 as well as on other B-locus molecules with BD. This indicates that distinctive Bw4 epitopes on HLA-B locus molecules could play a role in BD pathogenesis. The study also indicates an association with HLA-A*26 in German and Turkish BD patients as a genetic risk factor independent of HLA-B*51.     

HLA anchor optimization of the melan-A-HLA-A2 epitope within a long peptide is required for efficient cross-priming of human tumor-reactive T cells

The uptake and long-term cross-presentation of tumor Ag long peptides (LP) by dendritic cells (DC) make them attractive cancer vaccine candidates. However, it remains to be established whether LP can prime long-lived tumor-reactive CTL and whether other cell types are able to cross-present them. Using HLA-A2 healthy donor and melanoma patient-derived PBMC, we studied the in vitro cross-priming potential of Melan-A 16-40 LP bearing the HLA-A2-restricted epitope 26-35 or its analog 26-35(A27L) and compared it to the priming capacity of the short analog. We then addressed LP priming capacity in vivo using HLA-A2 mice. We also studied LP cross-presentation by monocyte-derived DC, plasmacytoid DC, monocytes, and B cells. We showed that the modified LP gave rise to high and sustained cross-presentation by monocyte-derived DC. This led to cross priming in vitro and in vivo and to expansion of long-lived tumor-reactive cytotoxic T cells. In contrast, the LP containing the natural 26-35 epitope primed specific T cells poorly, despite its long-lived cross-presentation, and T cells primed against the short analog were short-lived. We further showed that LP cross-presentation is restricted to monocytes and conventional DC. These results document for the first time, to our knowledge, the strong immunogenicity of a human tumor Ag LP. Of note, they underscore that this property is critically dependent on sufficient HLA binding affinity and/or TCR ligand potency of the cross-presented epitope. We conclude that LP fulfilling this requirement should be used as tumor vaccines, together with DC maturating agents, especially the Melan-A 16-40(A27L) LP, for the treatment of HLA-A2(+) melanoma patients.