IgG subclass antibodies to human and bacterial HSP60 are not associated with disease activity and progression over time in axial spondyloarthritis

Introduction

Spondyloarthritis (SpA), an interrelated group of rheumatic diseases, has been suggested to be triggered by bacterial infections prior to the development of an autoimmune response that causes inflammation of the spinal and peripheral joints. Because human heat shock protein 60 (HSP60), recently renamed HSPD1, and bacterial HSP60 are highly homologous, immunological cross-reactivity has been proposed as a mechanism of disease initiation. However, previous investigations of the humoral immune response to HSP60 in SpA patients have lacked determination of immunoglobulin G (IgG) subclasses and patient follow-up. In this study, we have focused on these parameters in a cohort of axial SpA patients with a well-established set of clinical characteristics, including MRI changes and human leukocyte antigen B27.

Methods

IgG subclass antibodies (IgG1, IgG2, IgG3 and IgG4) against recombinant HSP60 of three reactive arthritis-related bacteria; human HSP60; and the microorganisms Chlamydia trachomatis and C. pneumoniae were determined by ELISA. Serum samples collected from 2004 to 2006 and in 2010 and 2011 from 39 axial SpA patients were analyzed and compared with samples from 39 healthy controls. The Mann-Whitney U test and Wilcoxon matched pairs test were used to compare the antibody levels in different and paired groups, respectively. P < 0.01 was considered significant. The Spearman nonparametric correlation was used to determine correlation between antibody levels and between antibody levels and the disease parameters.

Results

Elevated levels of IgG1 and IgG3 to human HSP60 and IgG1 to HSP60 of Salmonella enterica Enteritidis were observed in SpA patients compared with healthy controls at both time points. The antibody levels were almost constant over time for IgG1, whereas high levels of IgG3 to human HSP60 tended to decrease over time. The antibody response to human HSP60 was predominantly of the IgG3 subclass, and patients with high levels of IgG3 to this antigen had low levels of IgG1, indicating an inverse association. Different IgG subclasses were produced against bacterial and human HSP60 in the same serum sample, IgG1 and IgG3, respectively, indicating that there was no cross-reaction.

Conclusions

A significant association was observed between axial SpA and the presence of IgG1/IgG3 antibodies to human HSP60 and of IgG1 to S. enterica Enteritidis and C. trachomatis. Generation of antibodies to human HSP60 was independent of the presence of antibodies to bacterial HSP60. No association was observed between clinical and MRI changes with antibodies over time. Altogether, such antibodies do not reflect the disease activity in these patients.This study has been approved by the Regional Research Ethics Committee of Central Jutland, Denmark. Trial registration numbers: 20050046 and 20100083     

Substantial Influence of ERAP2 on the HLA-B*40:02 Peptidome: Implications for HLA-B*27-Negative Ankylosing Spondylitis

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Highlights

• •HLA-B*40:02 and ERAP2 are risk factors for ankylosing spondylitis.
• •The effects of ERAP2 on the B*40:02 peptidome are defined.
• •ERAP2 has a major influence mainly due to alterations of N-terminal residues.
• •These effects provide a basis for the association of ERAP2 with disease.

     

Redundancy and Complementarity between ERAP1 and ERAP2 Revealed by their Effects on the Behcet's Disease-associated HLA-B*51 Peptidome,

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Highlights

• •HLA-B*51 and ERAP1, but not ERAP2, are risk factors for Behçet's disease.
• •The HLA-B*51 peptidome and the effects of ERAP1 and ERAP2 on it are analyzed.
• •ERAP1 and ERAP2 alter multiple features of the HLA-B*51 peptidome in distinct ways.
• •Both enzymes act independently with complementary and partially redundant functions.

     

用组合肽库技术分析HLA-B27的抗原提呈模式

HLA分子抗原表位提呈模式的分析,在自身免疫病和肿瘤的病因与治疗研究方面有重要意义。本研究采用组合肽库的策略合成19组ORX7型肽亚库,通过与荧光素标记肽的竞争结合试验,分析了与强直性脊柱炎有强相关的HLA-B27分子的抗原提呈模式。结果显示HLA-B27与P1为不同氨基酸残基的19种肽亚库有相近的结合率,提示P1为非锚定残基;中国人群最常见的二种HLA-B27亚型B*2704和B*2705,在提呈肽表位的P1模式方面存在一些小差异,P1为D或E的肽亚库与HLA-B*2704的结合能力要强一些,而P1为K的肽亚库则与HLA-B*2705的结合能力强一些。本研究为HLA-B27与强直性脊柱炎关联机制的研究提供了线索,为开展HLA分子的抗原提呈模式分析打下了基础。     

The Bw4/Bw6 difference between HLA-B*0802 and HLA-B*0801 changes the peptides endogenously bound and the stimulation of alloreactive T cells

 HLA-B^*0801 is unique among HLA-B allotypes in having dominant amino acid anchors at positions 3 and 5 of the peptide-binding motif. HLA-B^*0802 is a variant of HLA-B^*0801 in which the Bw6 sequence motif is replaced by a Bw4 sequence motif. This change, involving substitutions at positions 77, 80, 81, 82, and 83 of the B^*08 heavy chain, is probably the result of a single evolutionary event of interallelic conversion. Moreover, the difference between B^*0802 and B^*0801 is sufficient to stimulate a cytotoxic T-cell response. To assess further the functional impact of the Bw4 motif on a B8 background, we compared the peptide-binding specificity of the B^*0801 and B^*0802 allotypes by sequencing the mixture of peptides endogenously bound to B^*0802 and 12 individual peptides purified from that mixture. The HLA-B^*0802 allotype, while able to bind some peptides bound by B^*0801, has a broader repertoire of endogenously bound peptides than B^*0801: the peptides bound by B^*0802 are more variable in length and exhibit greater diversity in the carboxyl-terminal amino acid which interacts with the F pocket. Received: 29 October 1997     

Gene frequency changes in Cepaea snails on the Marlborough Downs over 25 years

In 1985 we resurveyed the sites on the Marlborough Downs in southern England at which Cain and Currey in 1960/61 sampled Cepaea snails and thence introduced the term 'area effects' to describe large areas of uniform morph frequency. Some sites no longer harboured Cepaea and at others the species composition had changed, with a general spread of Cepaea hortensis at the expense of Cepaea nemoralis. The majority, however, permitted comparison of morph frequencies between the two surveys. In C. nemoralis, we detected a significant overall decrease in the frequency of the brown morph and estimate selection as 5–9% per generation. There was no apparent change in frequencies of banded morphs. In C. hortensis we detected a significant overall increase in the frequency of unbanded shells (1–3% selection per generation) and an almost significant decrease in the frequency of fusions within the banded class. There was insufficient colour polymorphism in C. hortensis to allow analysis of colour morph frequencies. These changes—all in the direction of reduced absorption of solar energy—resemble others detected in both species at other localities in southern England. Possible explanations include large-scale climatic effects and changes in vegetation.     

Structural modeling of HLA-B*1502/peptide/carbamazepine/T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis

Drug-induced adverse reactions are a significant problem in healthcare worldwide and are estimated to cost billions of dollars annually in the United States. A portion of such reactions is observed to strongly associate with certain human leukocyte antigen (HLA) alleles; one of the strongest associations is the HLA-B*1502 protein with carbamazepine (CBZ)-induced Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) – the odds ratio value can even be higher than one thousand. The particularly strong association in CBZ-induced SJS/TEN suggests that the HLA-B*1502 is not only a genetic marker but also a participant in the pathogenesis of the disease. In the current study, we attempt to computationally model the atomic-level structure of the complete HLA-B*1502/peptide/CBZ/T-cell receptor (TCR) complex architecture based on prior knowledge obtained from epidemiological investigations as well as in vitro and in vivo assays. The model tells a different story about the molecular mechanism of CBZ-induced SJS/TEN from that previously reported for abacavir (ABC)-induced hypersensitivity (HSR); the CBZ molecule is located at the interface between HLA-B*1502/peptide and TCR, directly contacts the P3–P6 residues of antigen peptide, and bound within a pocket region encompassed by two TCR CDR3 fingers. Molecular dynamics simulation and binding energy analysis further reveal that the CBZ shows considerably high affinity to TCR over HLA-B*1502/peptide, which can tightly interact with the former rather than the latter. From the model, two hypotheses are proposed that can well explain most previous observations and are expected to guide next wet-lab experiments. This study could help to promote our understanding of the molecular mechanism and pathological implication underlying CBZ-induced SJS/TEN.     

HLA-B27分子及其与强直性脊柱炎关联的研究进展简

HLA-B27是MHCI类分子,因而具有MHCI类分子的相关生物学特性。在正常免疫状态下,HLA-B27分子执行对内源性抗原如肿瘤及病毒的免疫监视及杀伤功能;但在机体免疫状态出现异常的情况下,它又可能成为引发自身免疫性疾病的主要相关因素,其中最为著名的是其与强制性脊柱炎（As）的关联研究。我们首先概述了HLA—B27分子正常免疫学功能的研究进展,然后对其在AS相关性研究中的进展进行了总结和分析。通过对上述两方面的综述与分析,全方位展示HLA-B27在执行免疫学功能和引发免疫病理性改变方面的作用,为全面认识和深入研究HLA-B27分子的生理与病理学作用提供坚实的基础。