REVIEW

Anti-Ro(SSA) and Anti-La(SSB) Antibodies in Lupus

Erythematosus and Sjogren's Syndrome
Thomas T Provost

Department of Dermatology, The Johns Hopkins University, Baltimore, MD, USA

(Received for publication on June 4, 1991)

Abstract. Anti-Ro(SSA) and La(SSB) antibody determinations have become important serologic tests in
the evaluation of lupus erythematosus and Sjogren's syndrome patients. These antibodies appear to
identify a group of lupus patients with prominent skin diseases. Although much of the initial investigations
regarding the value of these antibodies has been performed in the United States and Europe, preliminary
studies suggest that the frequency of these antibodies in Japanese and other Oriental patients may be
double that seen in American patients. This article will briefly review our knowledge of the molecular,
immunogenetic and clinical features of the anti-Ro(SSA) and anti-La(SSB) antibody responses. (Keio J
Med 40 (2): 72-77, June 1991)

Key words: Ro(SSA), La(SSB), auto antibodies, connective tissue disease

Introduction significant antinuclear antibody activity when heterolog

Antibodies directed against the RNA particles,
Ro(SSA) and La(SSB), are major antibody systems found
in patients with lupus erythematosus and Sjogen's syn
drome patients. Extensive studies have demonstrated
that these autoantibodies are highly, but imperfectly
specific for these two connective tissue diseases. By gel
double diffusion techniques, approximately 30% of lupus
patients and 45% of Sjogren's syndrome patients are
anti-Ro(SSA) antibody positive. Approximately 10% of
systemic lupus erythematosus and Sjogren's syndrome
patients are also anti-La(SSB) positive. Approximately 5
in 1000 asymptomatic females during the childbearing
age are anti-Ro(SSA) antibody positive. Similar, in
depth studies of normal females have not been performed
with the anti-La(SSB) antibody system, but extensive
experience in our laboratory indicates that this antibody
system is rarely found in normal individuals and almost
always in the presence of anti-Ro(SSA) antibodies1.
Anti-Ro(SSA) antibodies are directed against human
epitopes. These antibodies frequently demonstrate vari
able degrees of cross-reactivity with Ro(SSA) auto
antigens from other species.2 This observation probably
explains to a great extent the fact that many patients
demonstrating anti-Ro antibodies fail to demonstrate
ous (mouse liver, rat liver and kidney, etc.) tissues are
employed as substrates for detection of antinuclear anti
bodies. In patients proported to have anti-La(SSB) anti
bodies in the absence of anti-Ro(SSA) antibodies,
examination for anti-Ro(SSA) antibodies with human
Ro(SSA) antigen almost always detects anti-Ro(SSA)
antibodies.
Most recent studies have indicated that the gel double
diffusion technique still remains the most cost effective
technology for the detection of anti-Ro(SSA) antibodies.
ELISA technologies have been employed to measure
anti-Ro(SSA) antibody activity. These studies have
demonstrated that on unusual occasions the ELISA
technologies will detect non-precipitating anti-Ro anti
bodies, but, in general, these technologies will detect
only approximately an additional 5-10% of anti-Ro
antibody positive patients.3
Ro(SSA) Complex
At the present time, evidence from a number of
laboratories indicate that the Ro(SSA) autoantigen is, in
reality, a complex composed of at least three distinct
polypeptides. Two of these polypeptides migrate on
sodium dodecyl sulfate (SDS) gel electrophoresis as 60

Reprint requests to: Dr Thomas T Provost, Department of Dermatology, The Johns Hopkins Hospital, 600 North Wolfe Street Blalock 920,
Baltimore, MD 21205, USA

72

Keio J Med 40 (2): 72-77, 1991
kD proteins, and the third as a 52 kD protein. These
three polypeptides have been cloned and sequenced and
are distinct from one another. It appears that one of the
60 kD polypeptides is, in reality, approximately 47 kD
(by amino acid determination). This 47 kD Ro poly
peptide migrates anonymously on SDS gels. Additional
data indicates this 47 kD polypeptide shares a great deal
of homology with murine and rabbit calreticulin and that
Drosophila melanogaster, Onchocerca volvulus and a
snail, Aplysia californica, also possess a polypeptide,
sharing a great deal of homology to this 47 kD human
Ro(SSA) protein. McCauliffe, et al, have also demon
strated that this 47 kD Ro(SSA) polypeptide is encoded
by alleles on human chromosome 19.4The exact function
of this 47 kD Ro protein is unknown at the present time,
but it may play a part in calcium binding.
The other 60 kD Ro polypeptide (as determined by
SDS gel electrophoresis) has also been cloned and
sequenced.5 The cDNA sequence of this 60 kD Ro(SSA)
polypeptide demonstrates both the presence of RNA
binding protein consensus sequences and a single zinc
binding finger motif. The exact function of this poly
peptide is unknown at the present time. However, since
this 60 kD Ro(SSA) protein contains putative RNA
binding domains designated RNP1 and RNP2, as well as
a single zinc binding finger motif, it is conceivable that
this Ro polypeptide might be able to bind both DNA and
RNA and, therefore, play a role in transcriptional
regulation.
In addition to these two polypeptides migrating at 60
kD on SDS gel electrophoresis, a third protein com
ponent of the Ro(SSA) complex has been described.
This 52 kD polypeptide has recently been cloned and
sequenced by three groups, including our own.6 This
polypeptide possesses a zinc binding finger and a leucine
zipper sequence which conceivably confers on this poly
peptide the ability to bind DNA.
Recent data indicates that isomorphic forms of the Ro
complex exist. Rader, et al, have demonstrated that red
blood cells, compared to lymphocytes, possess two anti
genically different forms of Ro(SSA) polypeptides.7 For
example, the 60 kD red blood cell and lymphocyte
Ro(SSA) 60 kD show partial immunologic identity.
These Ro polypeptides are complexed with 5 distinct
RNAs (83-112 bases) termed hyl-5-RNAs.
La(SSB) Macromolecule
The La(SSB) macromolecule is 48-50 kD in size.
This polypeptide is composed of two distinct regions; a
28 kD and a 23 kD domain. The larger domain contains
an RNA binding site. The La(SSB) binds transiently to
all RNA polymerase III transcripts including Ro associ
ated hY-RNAs; the precursors of tRNA; and 5.0S
RNA. In addition, this protein also binds the adenovirus
73
encoded RNA (VA-RNA); Epstein-Barr encoded KNA;
4.53 RNA; 4.51S RNA; 7S RNA and U6RNA.
The exact interrelationship between Ro and La auto
antigens is a source of a great deal of interest. The linked
anti-Ro(SSA) and anti-La(SSB) antibody responses in
some lupus and Sjogren's syndrome patients has provided
the stimulus for this interest. Most recent work by
Mammula, et al, indicates that the La protein resides on
a subset of Ro particles.8 RNA studies indicate that the
La protein is not present on hY-RNA in the absence of
the Ro polypeptide. Further studies by Boire and Craft,
using biochemical techniques to examine "native" Ro
ribonuclear protein particles from Hela cells, have
demonstrated that these particles segregate into three
distinct physical chemical groups.9 One Ro particle con
tains the hY5-RNA, one contains only hY4-RNA and
one contains hY1, hY3, and hY4-RNAs. These investi
gators found that purified Ro hY5 particles contained
the La polypeptide.
The La(SSB) polypeptide appears to function as a
transcription, as well as a termination factor in all RNA
polymerase III transcripts. Gottlieb and Steitz have
demonstrated that cell extracts depleted of the La(SSB)
polypeptide lose more than 99% of the transcription
activity of RNA polymerase III.10,11 Additionally, the
La(SSB) depleted extracts demonstrated that the few
transcripts synthesized were truncated (ie, were small in
length; had fewer uridylate residues at the 3' end). The
addition of purified La(SSB) protein to these extracts
reconstituted the transcription activity and resulted in
the production of full length transcripts. Thus, it has
been reasoned by these investigators that the La(SSB)
protein is both a transcription and termination factor for
all RNA polymerase III transcripts.
Whether or not the Ro polypeptide plays a role in the
transcription of RNA polymerase III transcripts is an
intriguing speculation based upon the recent data sug
gesting the stable association of Ro(SSA) and La(SSB)
polypeptides. At present, however, there is no direct
evidence establishing a role for the Ro(SSA) polypeptide
in transcriptional activity of RNA polymerase III
transcripts.
Cellular Localization of Ro(SSA) and La(SSB)
Polypeptides
The exact localization of these RNA particles has
been a source of controversy for years. It now appears
that the cellular localization of the La(SSB) polypeptide
is the nucleus. However, it appears that the polypeptide
constituents of the Ro polypeptide may exist in both the
cytoplasm and the nucleus.
Most important, however, are the observations that
have been made in the series of publications by David
Norris' group at the University of Colorado.12 These
74
investigators have determined that the perturbation of
keratinocytes in vitro with either estrogens or sublethal
doses of ultraviolet light can induce the de novo synthesis
of the Ro polypeptide in the cytoplasm and nucleus.
However, time lapsed studies have detected that the Ro
polypeptide is subsequently expressed on the plasma
membrane of the cell. Similar studies have indicated that
in addition to the Ro polypeptide, La(SSB) is also ex
pressed on the plasma membrane. (This localization to
the plasma membrane conceptually means that these
polypeptides can be exposed to an immunologic assault,
either by antibodies or various subsets of T cells.)
In vivo studies by the Colorado group, employing the
nude mouse model, have also provided some potentially
important information regarding the plasma membrane
localization of the Ro polypeptide.13 These investigators
have demonstrated that anti-Ro(SSA) antibodies injected
into nude mice containing a human skin explant will
demonstrate the deposition of the anti-Ro(SSA) antibody
in a speckled pattern over the basal cell layer of the
human, but not mouse skin. This staining pattern is
similar to the direct immunofluorescence examination of
the cutaneous lesions of subacute cutaneous lupus ery
thematosus and neonatal lupus. This staining pattern can
be blocked by preabsorbing the human anti-Ro(SSA)
sera with purified Ro(SSA) antigen.
The exact composition of the Ro complex
expressed on the plasma membrane is unknown
present time, but is an area of active research
in several laboratories.
In addition to these studies, which strongly suggest
that cytoplasmic and nuclear Ro(SSA) polypeptides can
be synthesized de novo by keratinocytes and, with time,
expressed on their plasma membrane, there is a good
deal of evidence to indicate that the Ro(SSA) polypeptide
is found as early as the tenth week of gestation in the
neonatal myocardium and conduction system. The exact
localization of these RNA particles in the neonatal myo
cardium is unknown at the present time. However, recent
studies in our laboratory, attempting to develop an in
vitro heart model for the neonatal lupus syndrome using
neonatal rabbits, have provided some evidence that may
be germane to this localization question.14 Using isolated
neonatal rabbit papillary heart muscles bathed with
Tyrode's solution, we have measured the action po
tential. Our studies have determined that if the isolated
papillary muscle is bathed in anti-Ro(SSA) antibody
containing sera, the repolarization phase of the myo
cardial action potential in the neonatal heart is pro
longated. This effect upon the repolarization phase of
the action potential was not seen when the isolated
papillary muscle was bathed with anti-native DNA, anti
U1RNP/Sm, anti-cardiolipin antibodiesor an anti-La(SSB)
containing sera. (These studies, because of the rapidity
of onset of the effect upon the repolarization phase, can
Provost TT: Anti-Ro and Anti-La
be used as evidence that in the neonatal myocardium, as
in the keratinocytes perturbated with estrogens or sub
lethal doses of ultraviolet light, there may also be
a plasma membrane localization of the Ro(SSA)
polypeptide.)
These series of experiments, as recounted above,
provide a good deal of evidence indicating that under
certain circumstances, and possibly during the ontogeny
of skin and heart development, that RNP particles, in
this case, Ro(SSA) and La(SSB), may be translocated
from what has been thought to be their normal localiz
ation in the cytoplasm and the nucleus to the plasma
membrane. As indicated above, on the plasma mem
brane, these polypeptides would be exposed to an
immunologic mediated assault.
Immunogenetics
A great deal of evidence indicates that the Ro(SSA)
and La(SSB) antibody responses in Caucasian patients
are found in association with a greatly enriched frequency
of specificalleles of the major histocompatibility complex
on the short arm of chromosome 6. Specifically, the anti
Ro(SSA) antibody response in both lupus erythematosus
and Sjogren's syndrome is associated with an approxi
mately 90% frequency of either HLA-DR2 or HLA
being DR3. The anti-La(SSB) antibody response is associated
at the with the HLA-DR3 phenotype. Our studies indicate that
occurring the week association of HLA-DR2 and DR3 with lupus
erythematosus (relative risk, 2-3) and the HLA-DR3
phenotype in Sjogren's syndrome is most likely associated
with the anti-Ro(SSA) antibody response.15,16If one
subtracts the anti-Ro(SSA) antibody positive lupus and
Sjogren's syndrome patients from the total lupus ery
thematosus and Sjogren's syndrome patient population,
the statistically significant increased frequency of HLA
DR2 and DR3 with lupus erythematosus and HLA-DR3
with Sjogren's syndrome disappears. Furthermore, those
HLA-DR3 positive Sjogren's and lupus erythematosus
patients appear to have an increased magnitude of anti
Ro(SSA) antibody response compared to non-HLA
DR3 patients. Other studies have demonstrated that the
enhanced anti-Ro(SSA) and anti-La(SSB) antibody
responses may be more closely associated with alleles
localized to the DQ locus.17The highest anti-Ro and La
antibody titers have been seen in those patients heter
ozygote DQ1/DQ2 at the DQ locus. Most recent studies
have proported to demonstrate restriction fragment
length polymorphism at the DQ locus associated with
the enhanced anti-Ro(SSA) antibody responses.
Orientals generally lack the HLA-DR3 phenotype.
At the present time, extensive HLA typing has not been
performed on anti-Ro(SSA) antibody positive Oriental
patients. Such a study, in light of studies in American
white and black anti-Ro(SSA) antibody positive patients,
Keio 3 Med 40 (2): 72-77, 1991 75

is of considerable interest. of anti-La, frequently have a concomitant presence of

anti-single stranded DNA antibodies, whereas in the
Clinical Significance of Anti-Ro(SSA) and Anti-La(SSB) anti-Ro and La positive patient population, there is
Antibodies a decreased frequency of anti-single stranded DNA
antibodies.
These antibody systems have been found to occur In addition to lupus erythematosus, anti-Ro(SSA)
with increased frequency in a group offfcy
ina group
ofAmerican
lupus and anti-La(SSB) antibodies are detected in Sjogren's
patients.1 Various subsets of lupus patients have been syndrome patients.1 Our studies indicate those patients
recognized to be associated with anti-La(SSB) and/or who are anti-Ro(SSA) antibody positive have an
anti-Ro(SSA) antibody responses. These include; sub increased frequency of extraglandular manifestations
acute cutaneous lupus erythematosus, the lupus disease characterized by seroreactivity (i.e. positive antinuclear
process associated with homozygous C2 deficiency and antibodies, rheumatoid factor, a general tendency to be
homozygous C4 deficiency, late onset lupus erythemato hypocomplementemic), cytopenia (i.e. lymphopenia,
sus and the neonatal lupus erythematosus syndrome. In anemia, and neutropenia), and have evidence of peri
the studies that have been performed in the United pheral and central nervous system disease, as well as an
States involving predominantly white patients of increased frequency of pulmonary disease. These patients
European ancestry, but also black patients, it has been also frequently will demonstrate evidence of cutaneous
recognized that these various subsets have in common vasculitispresenting clinically as either palpable purpuric
the presence of photosensitive skin disease, mild systemic lesions over the lower extremities or urticaria-like vas
features including myalgias, fatigue and arthralgias, but culitic lesions.20
generally an absence of significant renal disease. Ap The peripheral and central nervous system disease

proximately 50% of these patients will satisfy the appears to be the result of a diffuse vasculopathy in
American Rheumatism Association's (ARA) criteria for which small to medium size vessels are involved with an
the diagnosis of systemic lupus erythematosus. inflammatory infiltrate characterized in some cases by a
Photosensitivity is by far the dominant clinical picture classic leukocytoclastic angiitis and, in other cases, by a
seen in these patients. Our experience, as well as the lymphocytic vasculopathy.
experience of rheumatologists dealing with anti-Ro(SSA) We have developed evidence that there may be a
positive patients, have detected that approximately 90% much closer relationship between anti-Ro(SSA) antibody
of their patients are photosensitive. Many of these positive lupus disease patients and anti-Ro(SSA) positive
patients will develop a severe phototoxic eruption in Sjogren's syndrome patients.21 We have detected a
which the classic features of lupus erythematosus may number of anti-Ro(SSA) antibody patients who have
not be present. Many of these patients burn through both Sjogren's syndrome and lupus erythematosus. These
window glass indicating that ultraviolet light wavelengths patients (generally women) frequently are also anti
greater than 320 nanometers are capable of activating La(SSB) antibody positive, have rheumatoid factor,
their disease. A recent study in Germany has documented various cytopenias, pulmonary disease, cutaneous vas
that in some of these patients, UVA is capable of inducing culitis, peripheral and central nervous system disease,
a lupus lesion in these patients.18 Heavy pigmentation and most commonly have widespread photosensitive
does not appear to protect anti-Ro(SSA) positive lupus cutaneous lupus lesions. In addition to sharing common
patients from the deleterious effects of ultraviolet light clinical and serologic features, these American Caucasian
irradiation. In our experience, some of the most photo patients also share a statistically significant increased
toxic anti-Ro(SSA) antibody positive patients have been frequency of the HLA-B8, DR3, DQ2, DRw52 pheno
black. types.
While renal disease is an uncommon finding in anti Other studies indicate an immunogenetic relationship
Ro(SSA) antibody positive patients, it does occur. One between anti-Ro positive subacute cutaneous lupus ery
study, performing classic acid elution methodologies upon thematosus, neonatal lupus erythematosus , Sjogren's
kidneys obtained at autopsy, has demonstrated, in two syndrome, and Sjogren's/LE overlap patients. These
anti-Ro(SSA) positive patients, an enriched concentra patients all share in common a statistically significant
tion of anti-Ro(SSA) antibodies in the kidneys.19 This increased frequency of the HLA phenotypes B8, DR3 ,
has been interpreted as indicating a direct role of these DQ2, and DRw52.
antibodies, most likely in the form of immune complexes These studies suggest a significant proportion of
in the pathogenesis of the renal disease. patients described under the headings Sjogren's syn
There is also evidence to indicate that anti-Ro pa drome, neonatal lupus erythematosus mothers , subacute
tients, in the absence of anti-La(SSB) antibodies, may be cutaneous lupus erythematosus, and the lupus/Sjogren's
more susceptible to renal disease. Studies also indicate overlap may, in fact, have the same disease process with
that the anti-Ro(SSA) antibody patients, in the absence the phenotypic features (Sjogren's syndrome versus lupus
76 Provost TT: Anti-Ro and Anti-La

erythematosus) changing strikingly over the years. antibodies are frequently found in lupus and Sjogren's
Although much work has been done in the United syndrome patients. These antibodies have prognostic
States and Western Europe regarding the value of anti implications; they seem to be closely regulated, at least
Ro and anti-La antibody determination in the investiga in the Caucasian patient, by alleles on the major histo
tion of lupus erythematosus and Sjogren's syndrome compatibility complex, and evidence in the neonatal
patients, recent evidence suggests that these antibodies lupus syndrome suggests these antibodies may cause
may be of great significance in the evaluation of Japa specific features of disease. For these reasons, studies of
nese, as well as other Oriental lupus and Sjogren's these antibodies will continue to fascinate dermatologists,
syndrome patients. There is a good deal of evidence to immunologists and rheumatologists in the future.
suggest that the frequency of these antibody systems in
Oriental patients is much higher than American investi References
gators have seen in their patient populations. Several
studies have reported a frequency of between 50 and 1. Provost TT, Ratrie H: Autoantibodies and autoantigens in lupus
60% of anti-Ro positivity in their Oriental lupus patient erythematosus. Curr Probl Dermatol 2: 151-208, 1990
2. Reichlin M, Reichlin MW: Autoantibodies to the Ro(SSA)
populations.22,23
Although data is still being collected, preliminary particle react preferentially with the human antigen. In: Second
International Symposium on Sjogren's Syndrome, Talal N, ed,
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is not a prominent feature of these patients. Also Japa Detection of anti-Ro(SSA) antibodies by gel double diffusion
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positive lupus patients have failed to detect the increased 1991
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