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Clinical Significance of Antinucleolar Antibodies: Biomarkers for Autoimmune Diseases, Malignancies, and others

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Abstract

Nucleolar staining is one of the standard patterns in immunofluorescence antinuclear antibodies (ANA), seen in 5–9% of ANA in various conditions. Antinucleolar antibodies (ANoA) are classified into 3 patterns in the International Consensus on ANA Patterns (ICAP) classification; AC-8 homogeneous pattern, AC-9 clumpy pattern, and AC-10 punctate pattern. Specificities known to show AC-8 include anti-Th/To, -PM-Scl, -nucleophosmin/B23, -nucleolin/C23, -No55, and others. AC-9 is seen by anti-fibrillarin/U3RNP and AC-10 by anti-RNA polymerase I and hUBF/NOR-90. ANoA has been classically known to be associated with scleroderma (SSc) and the characterization of nucleolar antigens identified several autoantigens recognized by SSc autoantibodies. The clinical association of anti-Th/To, PM-Scl, fibrillarin/U3RNP, and RNA polymerase I with SSc or SSc-overlap syndrome is well established, and commercial assays are developed. Anti-hUBF/NOR90, nucleophosmin/B23, and nucleolin/C23 are known for decades and reported in systemic autoimmune rheumatic diseases (SARDs), malignancies, graft versus host disease (GVHD), and others; however, their clinical significance remains to be established.

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Abbreviations

ACA:

Anticentromere antibodies

AFP:

Alpha fetoprotein

AH:

Autoimmune hepatitis

ALCL:

Anaplastic large cell lymphoma

ALK:

Anaplastic lymphoma kinase

AMA:

Anti-mitochondria antibodies

ANA:

Antinuclear antibodies

ANoA:

Antinucleolar antibodies

APS:

Antiphospholipid syndrome

BC:

Breast cancer

BMT:

Bone marrow transplant

BPH:

Benign prostatic hypertrophy

CADM:

Clinically amyopathic dermatomyositis

cGVHD:

Chronic graft versus host disease

CH:

Chronic hepatitis

CI:

Confidence interval

CIA:

Chemiluminescence immunoassay

CL:

Cardiolipin

CLD:

Chronic liver disease

CTDs:

Connective tissue diseases

CTNE:

Calf thymus nuclear extract

dcSSc:

Diffuse cutaneous SSc

DB:

Dot blot

DID:

Double immunodiffusion

DLE:

Discoid lupus erythematosus

DM:

Dermatomyositis

ELISA:

Enzyme-linked immunosorbent assay

ENA:

Extractable nuclear antigen

GAVE:

Gastric antral vascular ectasia

GVHD:

Graft versus host disease

HCC:

Hepatocellular carcinoma

HR:

Hazard ratio

hUBF:

Human upstream binding factor

ICAP:

International Consensus on Antinuclear Antibody Patterns

IIF:

Indirect immunofluorescence

IIM:

Idiopathic inflammatory myopathy

ILD:

Interstitial lung disease

IP:

Immunoprecipitation

IP-NB:

Immunoprecipitation-northern blot

IPF:

Idiopathic pulmonary fibrosis

ITP:

Idiopathic thrombocytopenic purpura

lcSSc:

Limited cutaneous SSc

LC:

Liver cirrhosis

LIA:

Line immunoassay

mAbs:

Monoclonal antibodies

MCTD:

Mixed connective tissue disease

NCM:

Nailfold capillary microscopy

NHANES:

National Health and Nutrition Examination Survey

NHC:

Normal human controls

NHS:

Normal human serum

NOR:

Nucleolar organizer regions

NPM:

Nucleophosmin

NSCLC:

Non-small cell lung cancer

OA:

Osteoarthritis

OL:

Overlap syndrome

PAH:

Pulmonary arterial hypertension

PCa:

Prostatic carcinoma

PH:

Pulmonary hypertension

PM:

Polymyositis

PMR:

Polymyalgia rheumatica

PSA:

Prostate-specific antigen

RA:

Rheumatoid arthritis

RD:

Rheumatic diseases

RHA II:

Nucleolar RNA helicase II

RIA:

Radioimmunoassay

RNAP:

RNA polymerases

RNP:

Ribonucleoproteins

RP:

Raynaud’s phenomenon

SARDs:

Systemic autoimmune rheumatic diseases

SclMy:

Scleromyositis

SjS:

Sjӧgren’s syndrome

SLE:

Systemic lupus erythematosus

snoRNP:

Small nucleolar RNP

SRC:

Scleroderma renal crisis

SRD:

Systemic rheumatic diseases

SSc:

Scleroderma, systemic sclerosis

ssSSc:

Systemic sclerosis sine scleroderma

TCAD:

Transplant-related coronary disease

TnT:

In vitro transcription and translation

TSS:

Total skin score

UCTD:

Undifferentiated connective tissue disease

WB mice:

(NZW × BXSB) F1 mice

WB:

Western blot

β2GPI:

Beta2 glycoprotein I

2D-WB:

Two-dimensional western blot

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Acknowledgements

This work was supported by JSPS KAKENHI (Grants-in-Aid for Scientific Research) grant number 19K08617 (for MS).

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Satoh, M., Ceribelli, A., Hasegawa, T. et al. Clinical Significance of Antinucleolar Antibodies: Biomarkers for Autoimmune Diseases, Malignancies, and others. Clinic Rev Allerg Immunol 63, 210–239 (2022). https://doi.org/10.1007/s12016-022-08931-3

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