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Abstract Number: 1078

Highly Reactive anti-Jo1 Autoantibodies to Distinct HisRS Variants and Domains Associate with Lung and Joint Involvement in Patients with Myositis

Antonella Notarnicola1, Charlotta Preger2, Susanna L. Lundström2, Nuria Renard2, Edvard Wigren2, Eveline Van Gompel2, Angeles S. Galindo-Feria2, Helena Persson3, Maryam Fathi4, Johan Grunewald2, Per-Johan Jakobsson2, Susanne Gräslund2, Ingrid Lundberg5 and Cátia Fernandes-Cerqueira2, 1Karolinska Institutet, Stockholm, Stockholms Lan, Sweden, 2Karolinska Institutet, stockholm, Sweden, 3Science for Life Laboratories, KTH, Stockholm, Sweden, 4Karolinska University Hospital, stockholm, Sweden, 5Division of Rheumatology, Department of Medicine, Karolinska Institutet,, Stockholm, Sweden

Meeting: ACR Convergence 2020

Keywords: Autoantibody(ies), autoantigens, interstitial lung disease, Myositis, Synovitis

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Session Information

Date: Sunday, November 8, 2020

Session Title: Muscle Biology, Myositis & Myopathies Poster

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: To address the reactivity and affinity against histidyl-transfer RNA synthetase (HisRS) autoantigen of anti-Jo1 autoantibodies from serum and bronchoalveolar lavage fluid (BALF) and associations with clinical data in patients with idiopathic inflammatory myopathies/anti-synthetase syndrome (IIM/ASS).

Methods: Samples and clinical data were obtained from: i) 25 anti-Jo1+ (19 sera and 6 BALF/matching sera at diagnosis, 16/19 sera at follow-up); ii) 29 anti-Jo1– (25 sera and 4 BALF/matching sera at diagnosis) patients; iii) 24 age/gender matched healthy controls. Reactivity towards HisRS full-length (HisRS-FL), two HisRS domains, and two HisRS splice variants (WHEP and SV) was tested. Anti-Jo1 IgG reactivity was evaluated by ELISA and western blot in IgG purified from serum by affinity chromatography. In paired serum-BALF, anti-Jo1 IgG and IgA reactivity was analyzed by ELISA. Autoantibodies affinity was measured by surface plasmon resonance. Correlations between autoantibody reactivity and clinical data were evaluated.

Results: Anti-Jo1 IgG from serum and BALF bound HisRS-FL, WHEP and SV with high reactivity, already at diagnosis and recognized both conformation-dependent and -independent HisRS epitopes (Figure 1). Levels of autoantibodies (against HisRS-FL, -domains and -splice variants) generally decreased over time (Figure 2). Individuals with interstitial lung disease, arthritis and less skin involvement presented higher autoantibody levels against HisRS-FL (Figure 3). IgG with anti-WHEP reactivity in BALF correlated with poor pulmonary function. Anti-HisRS-FL IgG displayed high affinity early in the disease.

Conclusion: High levels and high affinity of anti-Jo1 autoantibodies towards HisRS early in disease in sera and BALF support the hypothesis that autoimmunity against HisRS is most likely initiated before IIM/ASS diagnosis.

Serum and BALF-derived anti-Jo1 autoantibodies display high reactivity against HisRS variants/domains already at IIM/ASS diagnosis. (A) The reactivity towards HisRS-FL, WHEP, CD, ABD, and SV as conformational epitopes was measured by ELISA in IgG purified from serum of 19 anti-Jo1+, 25 anti-Jo1-, and 24 healthy controls (HC). Higher reactivity corresponds to stronger blue color. (B) Anti-Jo1 reactivity against linear HisRS antigens was addressed by WB in IgG purified from serum of 12 anti-Jo1+, 1 anti-Jo1-, and 1 HC. Stronger band intensity denotes higher anti-Jo1 reactivity. Some patients also showed an additional band, correspondent to HisRS dimer. (C-D-E-F) Anti-Jo1 IgG and IgA reactivity in BALF and paired serum was measured by ELISA in 6 anti-Jo1+. Autoantibody levels were normalized to total values of IgG and IgA (Y-axis). Kruskal-Wallis (A) and Friedman’s tests (C-D-E-F) corrected for multiple comparisons by Dunn’s test was applied. P < 0.05 was assumed as significantly different.

Reactivity of anti-Jo1 autoantibodies towards HisRS variants decreases over time but remains high against HisRS-FL. (A-B) Reactivity against HisRS-FL, -splice variants (WHEP and SV), and -domains (CD and ABD) displayed by total IgG purified from the first available anti-Jo1+ sera close to diagnosis (T = -0.25 – 0 years) and 2.1 – 3 years after diagnosis. (C-D-E) Anti-Jo1 reactivity of 3 anti-Jo1+ patients (P7, P6, P11) displayed by total IgG purified from sera collected longitudinally. Y-axis represents anti-Jo1 antibody levels against HisRS, measured in the total IgG isolated from anti-Jo1+ IIM/ASS sera. X-axis represents disease duration in years. Dark grey sentences provide information on rituximab introduction and/or follow-up on interstitial lung disease/arthritis. Concentration (ng/mL) of anti-Jo1 antibodies was calculated based on a standard curve derived from anti-Jo1 IgG isolated from a sera pool of 38 anti-Jo1+ IIM/ASS individuals. Total anti-Jo1+ IgG from different patients present distinct binding capacity to HisRS proteins (note the different scale which goes from 100, 200, 400 up to 1200 ng/mL). The letter P (Patient) followed by a number in each graph represents an anti-Jo1+ IIM/ASS individual.

IIM/ASS patients diagnosed with ILD and arthritis and less skin involvement harbor more reactive anti-Jo1 autoantibodies. (A-B-C-D-E-F) Percentage of IIM/ASS patients distributed according to anti-HisRS full-length (HisRS-FL) reactivity levels, clinical diagnosis and clinical manifestations. The anti-HisRS-FL reactivity displayed was measured in total anti-Jo1+ IgG purified from serum. Numbers on top of the bars represent the percentage of patients in the group. Jo1-, anti-Jo1 IIM/ASS negative patients; Jo1+ +, anti-Jo1 IIM/ASS positive patients with low to moderate reactivity (0.52 – 72.59 ng/mL); Jo1+ ++, anti-Jo1 IIM/ASS positive patients with moderate to high HisRS reactivity (97.29 – 322.41 ng/mL). IIM, idiopathic inflammatory myopathies. ILD, interstitial lung disease; ASS, anti-synthetase syndrome.


Disclosure: A. Notarnicola, None; C. Preger, None; S. Lundström, None; N. Renard, None; E. Wigren, None; E. Van Gompel, None; A. Galindo-Feria, None; H. Persson, None; M. Fathi, None; J. Grunewald, None; P. Jakobsson, None; S. Gräslund, None; I. Lundberg, Bristol Myers Squibb, 2, Astra Zeneca, 2; C. Fernandes-Cerqueira, None.

To cite this abstract in AMA style:

Notarnicola A, Preger C, Lundström S, Renard N, Wigren E, Van Gompel E, Galindo-Feria A, Persson H, Fathi M, Grunewald J, Jakobsson P, Gräslund S, Lundberg I, Fernandes-Cerqueira C. Highly Reactive anti-Jo1 Autoantibodies to Distinct HisRS Variants and Domains Associate with Lung and Joint Involvement in Patients with Myositis [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/highly-reactive-anti-jo1-autoantibodies-to-distinct-hisrs-variants-and-domains-associate-with-lung-and-joint-involvement-in-patients-with-myositis/. Accessed May 26, 2022.
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