Altered levels of complement components associated with non-immediate drug hypersensitivity reactions

Abstract

2020) Altered levels of complement components associated with nonimmediate drug hypersensitivity reactionsABSTRACT Nonimmediate drug hypersensitivity reactions (niDHRs) range from mild-type maculopapular exanthema (MPE) to severe type Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with unentirely clarified pathogenesis. This study sought to explore whether complement components participated in niDHRs. The participants comprised of three groups as follows: MPE (n ¼ 65), SJS/TEN (n ¼ 13, contains 7 SJS, 2 SJS-TEN overlap and 4 TEN), and equal healthy controls (n ¼ 78). Skin pathological changes were confirmed by hematoxylin and eosin staining. The mRNA and protein levels of complement components were assessed. In the MPE group, there were no alterations in complement components at the protein and mRNA levels found except for a decrease in factor H mRNA. In the SJS/TEN group, up-regulated levels of C3aR and C5aR mRNA and down-regulated factor H mRNA levels in blood were noted. A lower plasma protein level of C3, Factor H and a higher level of C3a, C5, C5a, C5b-9, Factor B (p < 0.05) were found in the SJS/TEN group compared with in the control (p < 0.05). In SJS/TEN skin lesions, indirect immunofluorescence assays showed positive specific staining for C5b-9, but not C3. Both C3aR and C5aR were positive staining in the SJS/TEN samples, while staining for C1q, mannose-binding lectin (MBL), Factor B, and Factor H were only weak or negative. The findings reported here are the first to define the expression profiles/extent of the presence of various complement components at the mRNA and protein levels in niDHRs, especially in SJS/TEN. These altered complement components might, at least in part, be integral to the mechanisms underlying the pathogeneses of SJS and TEN. ARTICLE HISTORY

Association between HLA alleles and sub-phenotype of childhood steroid-sensitive nephrotic syndrome

“…Haplotype analysis shows that HLA-B*44:03-HLA-C*07:01 is a potential risk factor for CM-SJS/TEN combined SOC in Thai population [ 55 ]; In 2020, the research results reported by Wang et al clarified the expression profile and expression degree of several complement components in niDHRs, especially SJS and TEN, at the mRNA and protein levels for the first time. To a certain extent, it indicates that the abnormality of complement system may be a part of the pathogenesis of SJS and TEN [ 56 ]. Combined with the results showing the impact of HLA alleles on the complement system of other diseases, we speculate that there may be LD between HLA-B*15:11, B*44:03 & C*07:06 and C4 or C4-related complement genes.…”

Extracellular Vesicles from Human Plasma Show a Distinctive Proteome and miRNome Profile in Patients with Severe Cutaneous Adverse Reactions

“…Recent studies measured complement proteins obtained from plasma and peripheral blood mononuclear cells of SJS/TEN patients and found differential expression of the C3a, C5, C5a, and C5b-9 proteins at the mRNA and protein level. 6 However, the presence and role of complement proteins in DRESS have not been investigated previously. It is possible that not only complement circulating proteins in the plasma of SCARs patients but also those contained in EVs directly or indirectly enhance the activation of the complement classic pathway, contributing to the generalized inflammatory environment observed in SCARs.…”

“…The three subunits of the C1q subcomponent were more abundant in vesicles from DRESS and SJS/TEN when compared with the MPE and tolerant groups. Recent studies measured complement proteins obtained from plasma and peripheral blood mononuclear cells of SJS/TEN patients and found differential expression of the C3a, C5, C5a, and C5b-9 proteins at the mRNA and protein level . However, the presence and role of complement proteins in DRESS have not been investigated previously.…”

“…Upregulated expression of several plasma inflammatory markers is observed in SCAR patients; these include C-reactive protein (CRP), procalcitonin, and immunoglobulins, and more recently the presence of complement proteins, − although none of them are used as a validated biomarker. CRP levels are significantly higher in SJS and TEN patients compared with erythema multiforme majus, but direct comparative studies with DRESS are missing.…”

Disease severity and status in Stevens–Johnson syndrome and toxic epidermal necrolysis: Key knowledge gaps and research needs

“…There have been much fewer studies focusing on biomarkers to monitor severity, progression, and response to therapy during the acute stages of SJS/TEN and how these correlate with long-term morbidity and delayed mortality. Biomarkers that have been studied either singly or in combination in SJS/TEN include procalcitonin ( 32 ); granulysin ( 123 ); IFN-g ( 124 ); interleukin (IL)-8 and granzyme B ( 125 ); endocan, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein; serum IL-17 ( 126 ); complement components ( 127 ); alarmins like the heterodimeric form of S100 calcium-binding protein A8 and S100 calcium-binding protein (A9 S100A8/A9) ( 123 ); chemokines like CXCL9/MIG and CXCL10/IP-10 ( 124 ); antimicrobial peptides like LL-37 ( 128 ); exosomal nucleic acids like miR-375-3p ( 129 ); plasma lipid profiles ( 130 ); renal functions ( 78 , 79 ); neutrophil:lymphocyte ratio; and C-reactive protein:albumin ratio ( 131 ).…”