Document Detail

Ways forward to identify new ACPA targets in RA.
Jump to Full Text
MedLine Citation:
PMID:  23025589     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
ABSTRACT: Anti-citrullinated protein antibodies (ACPAs) of the IgG subtype have become a critical hallmark of HLA-associated rheumatoid arthritis (RA) and point to important contributions from the adaptive immune system. To dissect the contributing autoimmune reactions, investigators must not only identify the protein targets of ACPA but also define the precise peptides recognized by the immune system. Several possible approaches could be used to achieve this goal, and sensitive mass spectrometry of relevant tissue is a promising way forward in advancing our detailed understanding of autoimmune immune reactions involved in RA pathogenesis.
Authors:
A Jimmy Ytterberg; Vivianne Malmström
Related Documents :
23569139 - Expression of dendritic cell lysosome-associated membrane protein and dendritic cell-sp...
21267569 - Polyethylene and metal wear particles: characteristics and biological effects.
23405029 - Expression of innate immune genes, proteins and micrornas in lung tissue of pigs infect...
17203169 - Immortalized ovarian surface epithelial cells acquire tumorigenicity by acrogranin gene...
9396739 - Role of membrane-anchored heparin-binding epidermal growth factor-like growth factor an...
21518319 - Chondrocyte death by apoptosis is associated with the initiation and severity of articu...
21160069 - Cytokine signature profiles in acquired aplastic anemia and myelodysplastic syndromes.
3304809 - Interleukin 1, tumour necrosis factor-alpha (cachectin) and the pathogenesis of cancer ...
20510339 - Resistance of neonatal primary astrocytes against fas-induced apoptosis depends on sile...
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-24
Journal Detail:
Title:  Arthritis research & therapy     Volume:  14     ISSN:  1478-6362     ISO Abbreviation:  Arthritis Res. Ther.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-10-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101154438     Medline TA:  Arthritis Res Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  124     Citation Subset:  -    
Affiliation:
Rheumatology Unit, Dept Of Medicine, CMM L8:04, Karolinska University Hospital Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden. Vivianne.Malmstrom@ki.se.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Arthritis Res Ther
Journal ID (iso-abbrev): Arthritis Res. Ther
ISSN: 1478-6354
ISSN: 1478-6362
Publisher: BioMed Central
Article Information
Download PDF
Copyright ©2012 BioMed Central Ltd
Print publication date: Year: 2012
Electronic publication date: Day: 24 Month: 9 Year: 2012
pmc-release publication date: Day: 24 Month: 3 Year: 2013
Volume: 14 Issue: 5
First Page: 124 Last Page: 124
PubMed Id: 23025589
ID: 3580505
Publisher Id: ar4031
DOI: 10.1186/ar4031

Ways forward to identify new ACPA targets in RA
A Jimmy Ytterberg1 Email: Vivianne.Malmstrom@ki.se
Vivianne Malmström1 Email: Vivianne.Malmstrom@ki.se
1Rheumatology Unit, Dept Of Medicine, CMM L8:04, Karolinska University Hospital Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden

In a recent issue of Arthritis Research & Therapy, Raijmakers and colleagues [1] use an unbiased approach via mass spectrometry to identify candidate citrullinated peptides that have the potential to be involved in rheumatoid arthritis (RA). By sampling synovial fluid from a number of patients with RA as well as from non- RA disease control subjects, the authors demonstrate that it is possible to broaden the arsenal of potential autoantigenic peptides that deserve further investigation as candidate B- or T-cell epitopes in the setting of anticitrullinated protein antibody (ACPA)-positive RA disease.

Why citrullination, a common physiological protein modification, is regarded as such a threat to the immune system in patients with RA and causes more than 60% of patients to mount autoantibody titers (ACPA) remains an enigma. One underlying reason is the strong bias toward a certain set of HLA class II alleles that are very capable of presenting this altered amino acid [2,3], but that is not enough. In fact, most individuals carrying the HLA shared epitope alleles do not develop RA. Clearly, these autoimmune reactions must be triggered, and here environmental provocations (smoking, bacterial infection in the gum, and so on) have become an intriguing hypothesis (reviewed in [4]).

A central function of citrullination is to contribute to structure (for example, in the skin, hair follicles, central nervous system, and histones). Another, partly related, function is to destabilize proteins and mark them for degradation. In most cases, the regulated step in degradation of proteins is initial cleavage followed by rapid removal of the degradation products. The commonality of ACPAs in patients with RA suggests that citrullinated proteins are readily exposed to the immune system. Indeed, citrullinated proteins are found and even abundant at many sites of inflammation [5]. ACPA targets are probably a mix of degradation products and secreted or cell-bound proteins [6,7]. In their study, Raijmakers and colleagues demonstrate that synovial fluid of patients with RA and, to lesser degree, that of disease control subjects accumulate fibrinogen degradation products and that the peptides thereof are citrullinated (to a small but significant degree).

In the last few years, several studies that present either improved methods for the identification of citrullinated peptides or new citrullinated targets present in biological tissues have been published (reviewed in [8]). Citrullination of arginines can easily be confused with deamidation of asparagine or glutamine, and this potential confusion makes correct assignments of citrullinated peptides very important. The present study illustrates several characteristics that are diagnostic for citrulline species, such as a decrease in the precursor charge state, shifts in retention time when reverse-phase chromatography is used, and changes in the relative abundance of the ions in tandem mass spectrometry. With this approach, citrullinated peptides from a variety of sources [9,10] can be identified and validated.

The next step is to evaluate whether these 'suspects' are indeed involved in immune reactions and, if so, the nature of these responses. Understanding the chronic autoimmune reactions in affected joints may hold critical clues toward ways of reversing them and re-establishing a tolerogenic state.

An even broader vision of current RA research entails preventive measurements toward disease development. Dissecting disease-initiating events (since ACPAs appear before clinical onset) will require access to different material from subjects at risk of disease. Time will tell what technical platforms will help us dissect ACPA targets in this setting. Clearly, unbiased approaches such as the one described in the present study are very attractive.


Abbreviations

ACPA: anti-citrullinated protein antibody; RA: rheumatoid arthritis.


Competing interests

The authors declare that they have no competing interests.


References
Raijmakers R,van Beers JJ,El-Azzouny M,Visser NF,Bozic B,Pruijn GJ,Heck AJ,Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patientsArthritis Res TherYear: 201214R11410.1186/ar384022584083
Hill JA,Southwood S,Sette A,Jevnikar AM,Bell DA,Cairns E,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 moleculeJ ImmunolYear: 200317153854112847215
Snir O,Rieck M,Gebe JA,Yue BB,Rawlings CA,Nepom G,Malmström V,Buckner JH,Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patientsArthritis RheumYear: 2011632873288310.1002/art.3044521567378
Klareskog L,Malmström V,Lundberg K,Padyukov L,Alfredsson L,Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritisSemin ImmunolYear: 201123929810.1016/j.smim.2011.01.01421376627
Makrygiannakis D,af Klint E,Lundberg IE,Lofberg R,Ulfgren AK,Klareskog L,Catrina AI,Citrullination is an inflammation-dependent processAnn Rheum DisYear: 2006651219122210.1136/ard.2005.04940316540548
Bae S,Kim H,Lee N,Won C,KIm HR,Hwang YI,Song YW,Kang JS,Lee WJ,alpha-Enolase expressed on the surfaces of monocytes and macrophages induces robust synovial inflammation in rheumatoid arthritisJ ImmunolYear: 201218936537210.4049/jimmunol.110207322623332
Harre U,Georgess D,Bang H,Bozec A,Axmann R,Ossipova E,Jakobsson PJ,Baum W,Nimmerjahn F,Szarka E,Sarmay G,Krumbholz G,Neumann E,Toes R,Scherer HU,Catrina AI,Klareskog L,Jurdic P,Schett G,Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentinJ Clin InvestYear: 20121221791180210.1172/JCI6097522505457
De Ceuleneer M,Van Steendam K,Dhaenens M,Deforce D,vivo relevance of citrullinated proteins and the challenges in their detectionProteomicsYear: 20121275276010.1002/pmic.20110047822318877
Hermansson M,Artemenko K,Ossipova E,Eriksson H,Lengqvist J,Makrygiannakis D,Catrina AI,Nicholas AP,Klareskog L,Savitski M,Zubarev RA,Jakobsson PJ,MS analysis of rheumatoid arthritic synovial tissue identifies specific citrullination sites on fibrinogenProteomics Clin ApplYear: 2010451151821137068
Ytterberg AJ,Reynisdottir G,Ossipova E,Rutishauser D,Hensvold A,Eklund A,Sköld M,Grunewald J,Lundberg K,Malmström V,Jakobsson PJ,Zubarev RA,Klareskog L,Catrina AI,Identification of shared immunological targets in the lungs and joints of patients with rheumatoid arthritisAnn Rheum DisYear: 201271A19

Article Categories:
  • Editorial


Previous Document:  Aluminum-doped ceria-zirconia solid solutions with enhanced thermal stability and high oxygen storag...
Next Document:  Spatial and temporal variation of whirling disease risk in montana spring creeks and rivers.