Faculty Opinions recommendation of Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis.

Author(s):  
Toshihiro Nakajima ◽  
Naoko Yagishita
2005 ◽  
Vol 88 (3) ◽  
pp. 157-202 ◽  
Author(s):  
Anthony K. Campbell ◽  
Jonathan P. Waud ◽  
Stephanie B. Matthews

A staggering 4000 million people cannot digest lactose, the sugar in milk, properly. All mammals, apart from white Northern Europeans and few tribes in Africa and Asia, lose most of their lactase, the enzyme that cleaves lactose into galactose and glucose, after weaning. Lactose intolerance causes gut and a range of systemic symptoms, though the threshold to lactose varies considerably between ethnic groups and individuals within a group. The molecular basis of inherited hypolactasia has yet to be identified, though two polymorphisms in the introns of a helicase upstream from the lactase gene correlate closely with hypolactasia, and thus lactose intolerance. The symptoms of lactose intolerance are caused by gases and toxins produced by anaerobic bacteria in the large intestine. Bacterial toxins may play a key role in several other diseases, such as diabetes, rheumatoid arthritis, multiple sclerosis and some cancers. The problem of lactose intolerance has been exacerbated because of the addition of products containing lactose to various foods and drinks without being on the label. Lactose intolerance fits exactly the illness that Charles Darwin suffered from for over 40 years, and yet was never diagnosed. Darwin missed something else – the key to our own evolution – the Rubicon some 300 million years ago that produced lactose and lactase in sufficient amounts to be susceptible to natural selection.


Author(s):  
Robert M. Plenge ◽  
Michael E. Weinblatt

2005 ◽  
Vol 34 (1) ◽  
pp. 14-21 ◽  
Author(s):  
F. Buttgereit ◽  
K. G. Saag ◽  
M. Cutolo ◽  
J. A. P. da Silva ◽  
J. W. J. Bijlsma

1997 ◽  
Vol 75 (11-12) ◽  
pp. 772-785 ◽  
Author(s):  
C. M. Weyand ◽  
J�rg J. Goronzy

2021 ◽  
pp. 4-10
Author(s):  
Eliseo Ruiz Bedolla ◽  
Briceida Lopez Martinez ◽  
Israel Parra Ortega

Rheumatoid arthritis (RA) is the most common form of inammatory arthropathy sustained by autoimmune responses. This review has the objective of updating the knowledge about RA especially its molecular pathogenesis. We examine here the current knowledge of tryptophan, arginine, homoarginine and histidine metabolism and the main immunoregulatory pathways in amino acid catabolism in both RA patients and experimental models of arthritis. Of the characteristic autoantibodies of RA, those that appear earlier, are those that recognize cyclic citrullinated peptides. (CCP) and/or citrullinated brinogen. Therefore our analysis would indicate that amino acids metabolism represents a fruitful area of research for new drug targets for a more effective and safe therapy of RA.


2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Jurgen van Heemst ◽  
Diahann T. S. L. Jansen ◽  
Savvas Polydorides ◽  
Antonis K. Moustakas ◽  
Marieke Bax ◽  
...  

2019 ◽  
Vol 20 (17) ◽  
pp. 1235-1245 ◽  
Author(s):  
Biljana Jekic ◽  
Nela Maksimovic ◽  
Tatjana Damnjanovic

For many decades, methotrexate (MXT) has remained the drug of choice in the treatment of rheumatoid arthritis (RA). Unfortunately, a considerable number of patients do not achieve an appropriate therapeutic response. Pharmacogenetics studies do not give usable results regarding differences in MTX response among RA patients. The mechanism of MTX action in RA is not completely understood. We present and discuss data regarding the molecular basis of folate and adenosine pathways, the most obvious MTX targets, to explain possible causes of therapy failure. The molecular basis of the disease could also have an impact on therapy outcomes and in this review we explore this. Finally, we make a short review of available pharmacogenetics study results.


2014 ◽  
Vol 70 (a1) ◽  
pp. C253-C253
Author(s):  
Stephen Scally ◽  
Jan Petersen ◽  
Soi Cheng Law ◽  
Nadine Dudek ◽  
Hendrick Nel ◽  
...  

Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease, characterized by inflammation of synovial tissue, joint pannus and bone erosion. The human leukocyte antigen (HLA) locus plays a vital role in immunity, encoding highly polymorphic molecules that present peptides to T cell lymphocytes. RA has a strong association with a region of the HLA-DRB1 locus known as the `shared epitope' (SE) and the presence of autoantibodies specific for citrullinated proteins. The SE maps to a highly polymorphic N-terminal region of the HLA-DRβ chain around amino acids 70-74. This region encodes a positively charged residue at position 71 that is thought to dictate the amino acid that is accommodated in the P4 pocket of the antigen-binding groove. Citrullination, the conversion of positively charged arginine to polar citrulline, is a physiological process catalyzed by peptidyl arginine deiminase. Previous studies have shown that citrullination of self-antigens can significantly increase the affinity of epitopes for SE alleles. Here we provide a molecular basis for how citrullinated vimentin and aggrecan epitopes can be presented by the SE alleles, HLA-DRB1*0401 and HLA-DRB1*0404. Citrulline was accommodated in the electropositive P4 pocket of HLA-DRB1*0401/04, whilst arginine was not. In addition, the RA resistant HLA-DRB1*0402 allomorph was capable of binding both arginine and citrulline in its electronegative P4 pocket. Peptide elution studies revealed that arginine was presented by HLA-DRB1*0402 but not by HLA-DRB1*0401/04. Moreover, citrullinated vimentin showed a greater sensitivity to proteolysis by cathepsin L, when compared to unmodified vimentin, indicating that citrullination can impact the repertoire of self-antigens presented. Using HLA Class II tetramers, we identified citrullinated vimentin and aggrecan specific CD4+ T cells from both HLA-DRB1*0401+ RA patients and healthy controls. In RA patients, the number of autoreactive T cells correlated with disease activity and were deficient in regulatory T cells compared to healthy controls. Together these findings provide significant insight into the role citrullination plays in the pathogenesis of RA[1].


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