The Cusp theory: is there more to HLA-disease association?
The Cusp theory: is there more to HLA-disease association?
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Cusp 理论：HLA 与疾病之间还有更多关联吗？
DOI：
10.1093/rheumatology/keab624
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Holoshitz,Joseph
中科院分区：
文献类型：
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作者：
vanDrongelen,Vincent;MiglioranzaScavuzzi,Bruna;Holoshitz,Joseph
About half of disease risk of RA has been attributed to predisposing genes, of which the HLA region, particularly the HLA-DRB1 locus, is the most significant susceptibility factor currently known [1]. Most Caucasian RA patients carry at least one HLA-DRB1 allele encoding a five-amino-acid sequence motif called the ‘shared epitope’(SE)[2]. The SE is associated with RA severity in an allele-dose manner in which individuals carrying two SE alleles are at greatest risk of developing RA and present greater disease severity [3]. The mechanism by which SE-coding HLA alleles contribute to RA development and disease severity has been subject of many hypotheses of which most proposed an association through aberrant presentation of antigenic peptides. Hypotheses in this category postulate that reactivity to self-antigens due to molecular mimicry with foreign antigens, skewed T cell repertoire selection, reactivity to altered self-antigens, or association through linkage disequilibrium (and more) are the culprits. However, antigen presentation alone is difficult to reconcile with several observations, including:(i) certain HLA alleles associate with various unrelated (autoimmune and non-autoimmune) diseases;(ii) for most HLA-associated diseases the target antigen (s) remain unidentified; and (iii) some of the strongest class II HLA–disease associations occur in disorders not known to involve antigen presentation, such as narcolepsy. Because of these inconsistencies, an alternative hypothesis ‘the MHC Cusp theory’, has been proposed [4]. This hypothesis postulates that besides their role in antigen presentation, HLA molecules encode ligands in one of their hypervariable regions, designated a ‘cusp’based on its tri-dimensional cusp-like conformation. Certain environmental and background gene conditions allow these cusp-ligands to interact with non-major histocompatibility complex (MHC) receptors causing aberrant cell signalling events that lead to disease development [4](Fig. 1A). In this editorial we provide a brief overview of published findings that support the Cusp theory and indicate several opportunities for future research.Formulation of the Cusp theory was partly based on observations that cell lines carrying SE-coding HLA-DRB1 alleles showed higher spontaneous nitric oxide production compared with SE-negative cells [4]. Subsequent studies mapped the active region to amino acid residues 70–74 of the DRb chain, a region known as the SE. Further studies identified the SE-binding receptor as cell surface calreticulin, mapped the SE
