Anti-Sm antibodies in the classification criteria of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus is characterized by autoantibodies and immune complex deposition. Several autoantibodies against mainly nuclear autoantigens have been described. One of these nuclear autoantigens is the Smith antigen. In this review, we focus on the position of autoantibodies against the Smith antigen in the classification criteria, the characteristics of the antigen, the production of anti-Smith antibodies in SLE and we discuss the different test methods available, together with their pitfalls, to detect these autoantibodies.

Keywords: Classification criteria; Smith antigen; Systemic lupus erythematosus.

Fig. 1

The U1 small nuclear ribonucleoprotein complex. The U1 small nuclear ribonucleoprotein (U1-snRNP) complex consists of the Sm protein complex, which includes 9 different proteins (B1, B2 and B3, D1, D2, D3, E, F and G), ribonucleoproteins (RNP 70 KDa, RNP A and RNP C) and U1 ribonucleic acid (U1 RNA). RNA: ribonucleic acid; RNP: ribonucleoproteins; Sm: Smith protein.

Fig. 2

B-cell development is subjected to different checkpoints. During normal B-cell development several checkpoints (indicated by the arrows) are present to limit the loss of self-tolerance, in the bone-marrow (central tolerance) as well as in the periphery and secondary lymphoid tissue (peripheral tolerance).

Fig. 3

Checkpoints can either stimulate or inhibit B-cell development. B-cells express a broad range of stimulatory (A) and inhibitory (B) checkpoints, of which a selection is depicted in this figure. In SLE, different checkpoint molecules can be modulated (e.g. due to genetic modifications) leading to altered B-cell activation. BAFF(R): B-cell activating factor belonging to TNF family (receptor); BCR: B-cell receptor; DAMPs: danger-associated molecular patterns; IFNAR: interferon-α/β receptor; LAIR1: Leukocyte-associated immunoglobulin-like receptor 1; LIR1: leukocyte immunoglobulin-like receptor-1; PAMPs: pathogen-associated molecular patterns; PD-1(L): programmed cell death (Ligand) 1; TLR: Toll-like receptor.

Fig. 4

Anti-Smith antibodies give rise to a speckled ANA staining. When performing IIFT on HEp-2 cells or variants of this cell line, antibodies against the Sm antigen will lead to a nuclear (large, course) speckled pattern (AC-5) [42]. Nucleoli in the nucleoplasm may be stained or may not be stained. The chromatin is typically not stained. Note: image is taken at the laboratory of Medical Immunology of the department of Immunology at the Erasmus Medical Center in Rotterdam, The Netherlands.

Fig. 5

Post-translational modifications lead to SmD peptides with increased specificity for SLE. Arginine can be converted into a symmetrical dimethylarginine by methyltransferases (A). This post-translational modification leads to more SLE specific SmD1 and SmD3 epitopes (B). These epitopes range from amino acid position 95 until 119 for the SmD1 antigen and amino acid position 108 until 122 for the SmD3 antigen. Symmetrical dimethylargine residues are underlined and depicted in red. PRMT = Protein Arginine MethylTransferases.