How RAGE turns in rage | Genes & Immunity

The genetic background strongly contributes to susceptibility and clinical outcome of inflammatory diseases. The genetics of many of these diseases is complex, involving multiple genes. In

the case of rheumatoid arthritis (RA), a chronic inflammatory joint disease, estimates suggest that at least 10 different genetic regions may be linked to susceptibility.1 Parametric linkage

analysis suggests that the major histocompatibility complex (MHC) region may contribute up to 30% of overall inherited susceptibility in RA.2 Good evidence exists that RA is associated with

HLA-DRB1 alleles, in particular alleles that share a short amino acid sequence QKRAA, QRRAA or RRRAA at position 70–74 in the binding groove of the MHC molecule found in HLA-DR1

(HLA-DRB1*0101 and 0102), DR4 (HLA-DRB1*0401, 0404, 0405), DR6 (HLA-DRB1*1402) and DR10 (HLA-DRB1*1001) specificities named shared epitope alleles.3 Thus besides HLA, additional regions

contribute to disease whereby differences in the constitution of these factors may relate to variability in clinical presentation with a spectrum ranging from mild to severe disease. In this

issue Hofmann _et al_4 provide evidence for a role of the gene encoding the receptor for advanced glycation end products (RAGE), implicated in the amplification of immune responses, as good

candidate for a genetic factor that contributes to RA.4 Previous studies already suggested a pivotal role of RAGE activation in the pathogenesis of diabetic vascular disease and

Alzheimer.5,6 RAGE is a multiligand member of the immunoglobulin superfamily of cell surface receptors that binds advanced glycation end products (AGE)—the products of non-enzymatic

glycoxidation of protein/lipids—and amyloid-β peptide, a cleavage product of the β-amyloid precursor protein.5,6,7 Subsequent studies revealed that RAGE was also implicated as a receptor of

proinflammatory ligands, the so-called _e_xtracellular _n_ewly identified RAGE binding proteins (EN-RAGEs) and related members of the S100/calgranulins family, that accumulate at sites of

chronic inflammation.8 Signaling studies revealed that ligation of cell surface RAGE activates cell signaling pathways such as p21Ras, ERK1/ERK2 kinases and NF-κB, thereby activating an

inflammatory gene expression profile that typifies chronic inflammatory disorders.9 The EN-RAGEs S100A8 (myeloid related protein 8 (MRP)) and S100A9 (MRP14) are specifically secreted by

monocytes upon interaction with inflammation activated endothelium.10 Hence, the subsequent interaction of the secreted EN-RAGEs with cell surface RAGE is expected to further amplify the

inflammatory response and suggests a pivotal role for EN-RAGEs and RAGE in chronic cellular activation. The observation that the levels of MRP8 and 14 were elevated in juvenile RA and

correlated with disease activity is in support for a role of EN-RAGEs in chronic inflammation.11 It is in this context that the authors performed studies in a collagen-induced murine

arthritis model, which demonstrated that blockade of RAGE suppressed clinical, molecular and histological evidence of arthritis, thereby supporting a functional role for RAGE in arthritis.4

These findings made the RAGE gene an attractive candidate to study for the existence of allelic variations that might be important in the pathogenesis of inflammatory disease. The RAGE gene

is located in the MHC locus on chromosome 6p21.3, which contains multiple genes involved in inflammatory and immune responses and is known for its multifold disease associations. Most

interestingly, the search for heterogeneity within the RAGE gene uncovered several polymorphisms.12,13 However, since polymorphic genes within the MHC display a high degree of linkage

disequilibrium, disease-associations found do not necessarily direct to a functional variation but could well be the consequence of a nearby disease-causing allele. In fact, most

disease-associated polymorphisms are functionally inert or lack information on the functional relevance. For those reasons it is specially noteworthy that in the same paper Hofmann _et al_4

elegantly provide evidence for a functional difference between the naturally occuring RAGE protein variants, ie, the wild-type with a glycine at position 82 and the variant with a serine in

that position. The studies revealed significant differences in (i) the Kd between RAGE 82G (Kd∼122+/−31 nM) and RAGE 82S (Kd∼77+/−21 nM) receptors, (ii) the EN-RAGE induced phosphorylation

of MEK1/2 and p44/42 MAP kinases and NF-κB induction (RAGE 82S>G), and (iii) EN-RAGE induced production of the pro-inflammatory cytokines TNF-α and IL-6, and the metalloproteinases (MMP)

3, 9 and 13 (RAGE 82S>G). These results demonstrate a significant functional difference in binding, signalling and gene expression between the allelic RAGE 82S and 82G receptors. In a

previous study Hudson _et al_12 reported on the functional relevance of RAGE promoter polymorphisms at position −429, −374 and −63, suggesting that also genetically determined differences at

the level of RAGE production may exist.12 Together these data suggest that polymorphism within the RAGE gene affect RAGE signalling and may influence disease susceptibility and/or outcome.

These observations raise the possibility that a predisposition to a vigorous RAGE responsiveness may be associated with chronic inflammatory diseases like RA and other autoimmune diseases.

In the same study Hofman _et al_4 reported that the genetic variant that correlates with the expression of the more active RAGE 82S receptor, confers increased susceptibility for the

development of RA. However, the picture is more complicated as it seems due to the high degree of linkage disequilibrium within the MHC. Two major extensive HLA class II haplotypes

associated with the 82S variant, HLA-DRB1*0401-DQA1*0301-DQB1*0301 and HLA-DRB1*1501-DQA1*0102-DQB1*0602, are described.13 When corrected for the contribution of HLA-DRB1*0401 in RA the

association did not reach statistical significance. However, the inclusion of RAGE polymorphisms within HLA-DRB1*0401 haplotypes could well affect the severity of disease. Assignment of

functional RAGE gene variants that predict outcome will be helpful to stratify patients for clinical studies and tailor treatment. Therefore, further studies are necessary to explore the

association of functional RAGE polymorphisms with outcome measures of laboratory parameters, such as TNF-α, IL-6 and MMPs, and clinical severity. REFERENCES * Cornelis F, Faure S, Martinez M

_et al_. New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study _Proc Natl Acad Sci USA_ 1998 95: 10746–10750 Article  CAS  Google Scholar  * Gregersen

PK, Silver J, Winchester RJ . The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis _Arthritis Rheum_ 1987 30:

1205–1213 Article  CAS  Google Scholar  * Wordsworth P, Bell J . Polygenic susceptibility in rheumatoid arthritis _Ann Rheum Dis_ 1991 50: 343–346 Article  CAS  Google Scholar  * Hofmann MA,

Drury S, Hudson BI _et al_. RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response _Genes Immun_ 2002 3 Article  CAS  Google Scholar  * Schmidt AM, Vianna M, Gerlach

M _et al_. Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface _J Biol Chem_

1992 267: 14987–14997 CAS  Google Scholar  * Yan SD, Chen X, Fu J _et al_. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease _Nature_ 1996 382: 685–691 Article  CAS  Google

Scholar  * Brownlee M . Advanced protein glycosylation in diabetes and aging _Annu Rev Med_ 1995 46: 223–234 Article  CAS  Google Scholar  * Hofmann MA, Drury S, Fu C _et al_. RAGE mediates

a novelproinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides _Cell_ 1999 97: 889–901 Article  CAS  Google Scholar  * Kislinger T, Fu C, Huber B _et al_.

N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression _J Biol

Chem_ 1999 274: 31740–31749 Article  CAS  Google Scholar  * Rammes A, Roth J, Goebeler M _et al_. Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are

secreted by activated monocytes via a novel, tubulin-dependent pathway _J Biol Chem_ 1997 272: 9496–9502 Article  CAS  Google Scholar  * Frosch M, Strey A, Vogl T _et al_. Myeloid-related

proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile

rheumatoid arthritis _Arthritis Rheum_ 2000 43: 628–637 Article  CAS  Google Scholar  * Hudson BI, Stickland MH, Grant PJ . Identification of polymorphisms in the receptor for advanced

glycation end products (RAGE) gene: prevalence in type 2 diabetes and ethnic groups _Diabetes_ 1998 47: 1155–1157 Article  CAS  Google Scholar  * Prevost G, Fajardy I, Fontaine P, Danze PM,

Besmond C . Human RAGE GLY82SER dimorphism and HLA class II DRB1-DQA1-DQB1 haplotypes in type 1 diabetes _Eur J Immunogenet_ 1999 26: 343–348 Article  CAS  Google Scholar  Download

references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Molecular Cell Biology, VU Medical Center, Amsterdam, 1081 BT, The Netherlands C L Verweij Authors * C L Verweij View

author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to C L Verweij. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Verweij, C. How RAGE turns in rage. _Genes Immun_ 3, 117–118 (2002). https://doi.org/10.1038/sj.gene.6363865 Download citation * Published: 21 May 2002 * Issue

Date: 01 May 2002 * DOI: https://doi.org/10.1038/sj.gene.6363865 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a

shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative