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Anti-SSA autoantibodies (anti–Sjögren's-syndrome-related antigen A autoantibodies, also called anti-Ro, or similar names including anti-SSA/Ro, anti-Ro/SSA, anti–SS-A/Ro, and anti-Ro/SS-A) are a type of
anti-nuclear autoantibodies
Antinuclear antibodies (ANAs, also known as antinuclear factor or ANF) are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human prote ...
that are associated with many autoimmune diseases, such as
systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
(SLE), SS/SLE overlap syndrome,
subacute cutaneous lupus erythematosus (SCLE),
neonatal lupus
Neonatal lupus erythematosus is an autoimmune disease in an infant born to a mother with anti-Ro/SSA and with or without anti-La/SSB antibodies. The disease most commonly presents with a rash resembling subacute cutaneous lupus erythematosus and ...
and
primary biliary cirrhosis
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build ...
.
They are often present in
Sjögren's syndrome (SS).
Additionally, Anti-Ro/SSA can be found in other
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s such as
systemic sclerosis
Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are two ...
(SSc),
polymyositis
Polymyositis (PM) is a type of chronic inflammation of the muscles (inflammatory myopathy) related to dermatomyositis and inclusion body myositis. Its name means "inflammation of many muscles" ('' poly-'' + '' myos-'' + ''-itis''). The inflammati ...
/
dermatomyositis
Dermatomyositis (DM) is a long-term inflammatory disorder which affects skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over time. These may occur suddenly or develop over months. Other symptoms may inc ...
(PM/DM),
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
(RA), and
mixed connective tissue disease
Mixed connective tissue disease, commonly abbreviated as MCTD, is an autoimmune disease characterized by the presence of elevated blood levels of a specific autoantibody, now called anti-U1 ribonucleoprotein (RNP) together with a mix of symptoms of ...
(MCTD), and are also associated with heart arrhythmia.
Anti-SSA/Ro autoantibodies are classified as extractable nuclear antigens. The Anti-SSA/Ro autoantibody targets Ro proteins, namely Ro52 and Ro60. Ro52 and Ro60 were originally thought to be one protein, however current findings show that they are two functionally distinct proteins encoded by genes on separate chromosomes.
Anti-SSA/Ro autoantibodies are used in clinical settings as a diagnostic tool to identify patients with SLE and Sjögren's syndrome. In clinical tests for
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
, Anti-Ro antibodies are some of the most consistently and frequently detected among autoantibodies.
Anti-Ro autoantibodies are often found in conjunction with a similar antibody, Anti-La/SSB (also called anti–SS-B or anti–SS-B/La), in patients with SS. These two antibodies share pathological characteristics.
History of discovery
In 1969, two separate labs simultaneously identified antigens in the sera of SLE and SS patients. Clark et al. referred to the antigen as Ro – named after the patient from which the antibodies were extracted
, while Alspaugh & Tanand used the term SSA. It was later found that the labs described the same antigen, hence the compound term for the antibody, Anti-SSA/Ro, Anti-Ro/SSA.
Methods of detection
In laboratory settings,
ELISA
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
and immunodiffusion assays are most commonly used to detect levels of Anti-Ro/SSA antibodies in patient sera.
Antibodies specific to Ro52 are difficult to detect via laboratory testing. Their low detectability may be attributed to several factors: the antibodies are
precipitin
A precipitin is an antibody which can precipitate out of a solution upon antigen binding.
Precipitin reaction
The precipitin reaction provided the first quantitative assay for antibody. The precipitin reaction is based upon the interaction of an ...
negative, lack
antinuclear antibody (ANA) specific fluorescence staining patterns, and have a low signature in ELISA assays. Furthermore, Ro52 can be masked by Anti-Ro60 antibodies in lab tests that simultaneously assess the two antibodies.
Mechanism
Anti-Ro/SSA can target Ro52 and Ro60 proteins. Most Anti-Ro/SSA activity occurs on the cell surface, wherein Ro proteins are expressed on the cell membrane and extracellular Anti-Ro/SSAs bind to Ro. There is some evidence that the
IgG isotype of anti-Ro/SSA antibody can enter the cell.
* Anti-Ro autoantibodies are typically
IgA,
IgM
Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...
, and IgG isotypes, though most is known about the five IgG subclasses. The antibody is inducible via immunization using Ro peptide.
The mechanism that induces Anti-Ro/SSA production in autoimmune disorders remains under study.
Some proposed factors that may stimulate production are viral infection, treatment of cells with
TNF-α
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, cellular
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, and exposure to
UV irradiation
Ultraviolet germicidal irradiation (UVGI) is a disinfection method that uses short-wavelength ultraviolet (ultraviolet C or UV-C) light to kill or inactivate microorganisms by destroying nucleic acids and disrupting their DNA, leaving them unabl ...
.
* Anti-Ro/SSA is produced in the cytoplasm of cells in the epidermal layer of the skin following UV irradiation. Ro antigens are simultaneously upregulated on the cell surface, resulting in the Anti-Ro/SSA antibody marking cells for destruction. Anti-Ro52 antibodies in particular have been tied to elevated photosensitivity.
Certain alleles of the human major histocompatibility complex (
MHC II
MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, ...
, called
HLA II in humans) have been associated with the presence of Anti-Ro antibodies and the spread of the immune response. Anti-Ro/SSA associates with the HLA II alleles
HLA-DR3
HLA-DR3 is composed of the HLA-DR17 and HLA-DR18 split 'antigens' serotypes. DR3 is a component gene-allele of the AH8.1 haplotype in Northern and Western Europeans. Genes between B8 and DR3 on this haplotype are frequently associated with autoi ...
and
HLA-DR2
HLA-DR2 (DR2) of the HLA- DR serotype system, is a broad antigen serotype that is now preferentially covered by HLA-DR15 and HLA-DR16 serotype group. This serotype primarily recognizes gene products of the HLA-DRB1*15 and HLA-DRB1*16 allele gro ...
, as well as some
HLA-DQ
HLA-DQ (DQ) is a cell surface receptor protein found on antigen-presenting cells. It is an αβ heterodimer of type MHC class II. The α and β chains are encoded by two loci, HLA-DQA1 and HLA-DQB1, that are adjacent to each other on chromos ...
alleles.
The
T-cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
response plays a role in the formation of Anti-Ro/SSA antibodies due to T-cell affinity for MHC class II.
Antigens
The specific pathogenic role of the Ro antigen in autoimmune disorders remains unknown.
Ro52
The Ro52 gene is officially termed
TRIM21
Tripartite motif-containing protein 21, also known as E3 ubiquitin-protein ligase TRIM21, is a protein that in humans is encoded by the ''TRIM21'' gene. Alternatively spliced transcript variants for this gene have been described but the full-length ...
, as it is a member of the tripartite motif protein (TRIM) family, qualified by its RING and B-box domains. The protein is typically located in the cytoplasm, though it can move to the nucleus in the presence of pro-inflammatory signals, and it can also be expressed on the cell surface.
There is evidence that Ro52 itself is a
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
ic Fc receptor.
Ro52 is a regulatory protein, and negatively moderates inflammatory response, such as the secretion of pro-inflammatory
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s in the
interleukin
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
and
INF families.
Ro52 can both regulate and be induced by INF cytokines. Loss of function or blockage of Ro52 results in uncontrolled inflammation at the onset of injury or disease. Patients with SLE and SS not only show elevated levels of Anti-Ro antibodies, but also elevated levels of Ro52.
Ro52 has one primary epitope to which anti-Ro/SSA binds, independent of the autoimmune disease. The most common domain anti-Ro52 targets is the coiled coil (cc) domain, as well as the RING and B-box domains.
Ro52 does not bind to small cytoplasmic
non-coding RNA
A non-coding RNA (ncRNA) is a functional RNA molecule that is not Translation (genetics), translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally im ...
strands (hY-RNA). The notion that Ro52 formed a complex with
Y RNA
Y RNAs are small non-coding RNAs. They are components of the Ro60 ribonucleoprotein particle which is a target of autoimmune antibodies in patients with systemic lupus erythematosus. They are also reported to be necessary for DNA replication thr ...
resulted from studies that suggesting that Ro52 and Ro60 formed a complex together.
Ro52 may impact the pathogenesis of autoimmune disease: patients with SLE and SS have been shown to express high levels of Ro52 transcripts.
Though Ro52 and Ro60 are often seen in elevated levels together in patients with autoimmune disease, Ro52 manifests without Ro60 in SS. Additionally, Anti-Ro52 antibody has been identified at elevated levels in patients with
interstitial lung disease
Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue and space around the alveoli (air sacs)) of the lungs. It concerns alveolar epithelium, pu ...
, as well as in autoimmune
hepatitis
Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pa ...
type 1.
Ro60
Ro60 is not part of the TRIM family. Ro60 is encoded by a gene 32 kb in length and acts to regulate the fate of misfolded RNA within the host cell.
Ro60 forms a ribonucleoprotein complex with one molecule of noncoding Y1, Y3, Y4, or Y5RNA, all of which are approximately 100 nucleotides in length, to form the epitope that Anti-Ro60 recognizes. The absence of Ro60 results in an elevated immune response and decreased resilience to immune-related stress.
The
epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
of the Ro60 protein is similar to that of the
Epstein-Barr virus, and the presence of the virus may enhance the autoimmune response to Ro60, as anti-Epstein Barr antibodies can target the protein.
Anti-Ro/SSA in systemic lupus erythematosus (SLE)
Anti-Ro/SSA antibodies are found in 40–90% of patients with systematic lupus erythematosus (SLE). The antibodies can be detected years before symptoms of SLE surface, making them an effective diagnostic tool.
In patients with SLE, high levels of Anti-Ro/SSA are correlated with elevated levels of IFN-α. The presence of Anti-Ro/SSA antibodies also correlates with symptoms of
photosensitivity Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light. In medicine, the term is principally used for abnormal reactions of the skin, and two types are distinguished, photoallergy and phototoxicity. ...
,
cutaneous vasculitis, and
hematological disorders
Hematologic diseases are disorders which primarily affect the blood & blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease & complications from chemotherapy or transfusions.
Myeloid
* Hemo ...
.
In individuals with
cutaneous lupus erythematosus
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different de ...
(CLE), a subcategory of lupus erythematosus, elevated levels of Ro52 are found regardless of expression of Anti-Ro autoantibodies.
Anti-Ro/SSA in neonatal lupus erythematosus (NLE)
The presence of Anti-SSA/Ro in pregnant women with SLE is associated with an increased risk of
neonatal lupus erythematosus which can be accompanied by
congenital heart block (CHB) in the fetus.
[James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. Page 160. .] SLE-related symptoms in infants that arise from Anti-Ro/SSA resolve in about 6 months as the mother's antibodies leave the baby's system.
Mothers of babies with NLE most often do not show signs of autoimmune disease.
The role of Anti-SSA/Ro in NLE is remains under study, as recent studies have suggested that CHB in neonates is more generally linked to instances of autoimmunity in the mother rather than the presence of Anti-Ro/SSA antibody.
References
{{DEFAULTSORT:Anti-SSA Ro autoantibodies
Chemical pathology
Autoantibodies