{"id":22689,"date":"2022-10-19T04:51:00","date_gmt":"2022-10-18T20:51:00","guid":{"rendered":"http:\/\/csccm.org.cn\/?p=22689"},"modified":"2022-10-19T07:58:24","modified_gmt":"2022-10-18T23:58:24","slug":"nejm%e8%af%bb%e8%80%85%e6%9d%a5%e4%bf%a1%ef%bc%9a%e6%8e%a5%e7%a7%8d%e6%96%b0%e5%86%a0%e7%97%85%e6%af%92%e7%96%ab%e8%8b%97%e5%90%8e%e5%bf%83%e8%82%8c%e7%82%8e%e7%9a%84il-1ra%e6%8a%97%e4%bd%93","status":"publish","type":"post","link":"https:\/\/csccm.org.cn\/?p=22689","title":{"rendered":"[NEJM\u8bfb\u8005\u6765\u4fe1]\uff1a\u63a5\u79cd\u65b0\u51a0\u75c5\u6bd2\u75ab\u82d7\u540e\u5fc3\u808c\u708e\u7684IL-1RA\u6297\u4f53"},"content":{"rendered":"\n

CORRESPONDENCE<\/a><\/p>\n\n\n\n

IL-1RA Antibodies in Myocarditis after SARS-CoV-2 Vaccination<\/h1>\n\n\n\n

Lorenz Thurner, Christoph Kessel, Natalie Fadle, et al<\/h3>\n\n\n\n

N Engl J Med September 21, 2022
DOI: 10.1056\/NEJMc2205667<\/h3>\n\n\n\n

TO THE EDITOR:<\/h2>\n\n\n\n

Myocarditis associated with messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly affects male adolescents and young male adults (14 to <30 years of age) and typically occurs after receipt of the second vaccine dose.1,2<\/a><\/sup> In adults with critical coronavirus disease 2019 (Covid-19) and in cases of multisystem inflammatory syndrome in children (MIS-C), we recently discovered neutralizing autoantibodies targeting the endogenous interleukin-1 receptor antagonist (IL-1RA), which inhibits interleukin-1 signaling and inflammation.3,4<\/a><\/sup><\/p>\n\n\n\n

In this study, we evaluated the prevalence of antibodies neutralizing IL-1RA and progranulin, which inhibits tumor necrosis factor signaling, in 69 patients (14 to 79 years of age) who had clinically suspected myocarditis after SARS-CoV-2 vaccination. A total of 61 patients underwent endomyocardial biopsy.<\/p>\n\n\n\n

\"\"\/<\/figure>\n\n\n\n

Figure 1.\u00a0<\/strong>Autoantibodies Targeting IL-1RA in Myocarditis after SARS-CoV-2 Vaccination.<\/p>\n\n\n\n

Myocarditis was confirmed by biopsy in 40 of 61 patients (Figure 1A<\/a>). Among patients with histologically confirmed myocarditis, anti\u2013IL-1RA antibodies were found in 9 of 12 patients (75%) younger than 21 years of age, as compared with 3 of 28 patients (11%) 21 years of age or older. Anti\u2013IL-1RA antibodies were not detectable in the 21 patients in whom biopsy ruled out the diagnosis of myocarditis (Figure 1B and 1C<\/a>). IL-1RA antibody\u2013positive patients with biopsy-confirmed myocarditis had an early onset of symptoms, which occurred mostly after receipt of the second vaccine dose, and a milder course of myocarditis than patients with biopsy-confirmed myocarditis but without anti\u2013IL-1RA autoantibodies (Tables S1 through S6 and Figs. S1 through S6 in the Supplementary Appendix<\/a>, available with the full text of this letter at NEJM.org).1,2<\/a><\/sup><\/p>\n\n\n\n

IL-1RA antibodies were observed in 2 of 214 vaccinated control participants (1%) and in 2 of 125 participants (2%) who had histologically proven myocarditis that had been diagnosed before the Covid-19 pandemic. Previous data that had been obtained from patients with critical Covid-19 did not support the cross-reactivity of purified IL-1RA antibodies with structural proteins of SARS-CoV-2, including the spike protein,3<\/a><\/sup> which argues against virus- or vaccine-driven molecular mimicry.<\/p>\n\n\n\n

Current evidence points toward a transient hyperphosphorylation of IL-1RA preceding a breakdown of peripheral immune tolerance.3,4<\/a><\/sup> In Western blots of total plasma protein, antibodies to IL-1RA coincided with weaker bands of free IL-1RA, but prominent immune (IgM or IgG)\u2013complexed protein with an atypical IL-1RA isoform occurred exclusively in patients who were seropositive for anti\u2013IL-1RA antibodies (Figure 1D<\/a>). This additional IL-1RA isoform was hyperphosphorylated at threonine position 111, which had been observed previously in adult patients with critical Covid-19 and in patients with MIS-C.3,4<\/a><\/sup> In contrast to our observations in patients with myocarditis after SARS-CoV-2 vaccination, IL-1RA was not hyperphosphorylated in any of the samples that had been obtained from control participants.<\/p>\n\n\n\n

At the time of acute myocarditis, the mean (\u00b1SD) free IL-1RA plasma level in 15 patients who were seropositive for anti\u2013IL-1RA antibodies was 236\u00b182 pg per milliliter, whereas the level was 1736\u00b1312 pg per milliliter in 33 patients without anti\u2013IL-1RA antibodies and 1599\u00b1277 pg per milliliter in 21 patients in whom histologic testing ruled out the diagnosis of myocarditis (Figure 1F<\/a>). IL-1RA plasma levels correlated with markers of cardiac damage (troponin T, creatine kinase, creatine kinase MB, or pro\u2013B-type natriuretic peptide), cardiac-tissue infiltration of CD3+ T cells and CD68+ macrophages, and systemic inflammation (C-reactive protein). There was a negative correlation between markers of cardiac damage and IL-1RA plasma levels in patients with anti\u2013IL-1RA antibodies (Figure 1E<\/a>). Interleukin-1 signaling reporter assay experiments showed direct impairment of IL-1RA bioactivity after the addition of anti\u2013IL-1RA antibodies from patients\u2019 plasma (Figure 1G<\/a>).<\/p>\n\n\n\n

Our study of SARS-CoV-2 vaccination\u2013associated myocarditis and anti\u2013IL-1RA antibodies should be interpreted within the context that the transiency of hyperphosphorylation (as previously reported in patients with critical Covid-19 or MIS-C3,4<\/a><\/sup>) and patients\u2019 HLA haplotypes were not known. In our study, neutralizing antibodies against IL-1RA and a hyperphosphorylated IL-1RA isoform were observed in young male patients with biopsy-confirmed myocarditis after the receipt of SARS-CoV-2 mRNA vaccine. These antibodies impaired IL-1RA bioactivity in vitro, were associated with low circulating levels of IL-1RA, and were found in patients with biomarker evidence of cardiac damage and inflammation.<\/p>\n","protected":false},"excerpt":{"rendered":"

CORRESPONDENCE IL-1RA Antibodies in Myocarditis after S […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[32,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/22689"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=22689"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/22689\/revisions"}],"predecessor-version":[{"id":22690,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/22689\/revisions\/22690"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=22689"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=22689"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=22689"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}