Autoimmunity Reviews 10 (2011) 123–125

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Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev

Review

The meaning of anti-Ro and anti-La antibodies in primary Sjögren's syndrome

Gabriela Hernández-Molina ⁎, Gustavo Leal-Alegre, Martha Michel-Peregrina
Immunology and Rheumatology Department, Instituto Nacional de Ciencias Médicas y Nutrición SZ, Vasco de Quiroga 15. Colonia Sección XVI, CP 14000, Mexico City, Mexico

a r t i c l e i n f o a b s t r a c t

Article history: Anti-SSA/Ro and anti-La/SSB are the hallmark antibodies in primary Sjögren's syndrome (pSS), being present
Received 2 September 2010 in 60–70%. These antibodies have been associated with an earlier disease onset, glandular dysfunction and
Accepted 6 September 2010 extraglandular manifestations as well as with other B cells activation markers. In addition an immunogenetic
Available online 15 September 2010
background is important for the autoantibody formation, having a stronger association with HLA-DR2 and
HLA-DR3. Anti-Ro/SSA and anti-La/SSB antibodies are useful in the diagnosis of pSS and help to identify more
“active” patients, however their association with response to treatment is unclear. Herein we review the
evidence regarding the association of these antibodies with HLA background, demographic, clinical, glandular
dysfunction, other serologic features and response to treatment in patients with pSS.
© 2010 Elsevier B.V. All rights reserved.

Contents

1. Association with HLA class II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

2. Association with demographic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
3. Association with clinical course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
4. Association with glandular dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
5. Association with other serologic markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
6. Association with treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
7. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Primary Sjögren´s syndrome (pSS) is a chronic autoimmune
disorder mainly affecting the exocrine glands whose serologic
hallmark is the presence of anti-Ro/SSA and/or anti-La/SSB antibodies
[1]. Anti-Ro/SSA may be found in isolation (50–70%) or concomitantly
with the presence of anti-La/SSB antibodies (30–60%), whereas
positivity for exclusively anti-La/SSB is rare [2]. These antibodies are
part of the current classification criteria for pSS [3]. Briefly, the Ro/SSA
antigen is a RNP complex containing hY-RNAs and at least two
proteins (Ro 52 kD and Ro 60 kD), while the La/SSB antigen consists of
a 48 kD protein [4]. The La protein works as a transcription
termination factor of the RNA polymerase III transcripts and recently
the Ro protein has been identified as an E3 ligase that regulates
negatively cytokine production induced by the IFNγ pathway [5]. The
coexistence of both autoantibodies has been explained in the context
of autoimmunity spreading between components of the Ro/La
⁎ Corresponding author. Tel.: + 52 11 5255 54850766; fax: + 52 11 5255 55732096.
E-mail addresses: gabyhm@yahoo.com (G. Hernández-Molina), gztvo@hotmail.com
(G. Leal-Alegre), martha-lizzetmp@hotmail.com (M. Michel-Peregrina).
ribonucleoprotein, finding also suggested by animal models [6]. The
stability of the antibody profile is fixed at an early stage of disease and
hardly changes. In this context, Davidson et al. described that the
serological pattern of 100 pSS patients remained constant throughout
a follow up period of 10 years. Only in two patients who were positive
for Ro/La antibodies: one became Ro and La negative but DNA positive
and the other became serological negative after local radiotherapy
and chemotherapy for associated lymphoma [7].
The aims of our review were to evaluate the association of these
antibodies with HLA background, demographic, clinical, glandular
dysfunction, other serologic features and response to treatment of
patients with pSS.
1. Association with HLA class II
Studies to date have showed that levels of anti-Ro/SSA and anti-La/SSB
antibodies are higher in HLA-DR3 and HLA-DR2 positive patients [8,9]
Davidson et al., found that DR3 was present in 79% of the Ro/La positive
pSS patients comparing with 20% of seronegative group and 25% of

1568-9972/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2010.09.001
124 G. Hernández-Molina et al. / Autoimmunity Reviews 10 (2011) 123–125
controls [7]. In addition, the HLA DR5 has been linked to higher levels of
anti-La/SSB antibody [10]. Further, as there is a linkage disequilibrium
among DR3 with DQ2, and DR2 with DQ1, both DQ1 and DQ2 have also
been associated with elevated binding of antibodies to Ro/SSA and La/SSB.
The allelic combination DQ1/DQ2 has been also associated with a higher
concentration of these autoantibodies [11]. In addition, studies have
found that specific HLA haplotypes are linked to the autoantibody profile
[12–16]. Table 1 shows diverse haplotypes and the associated antibody.
Thus according to the previous studies, the HLA class II may
participate in the perpetuation and initiation of an autoimmune
response, however a clear association between HLA and clinical
manifestations has not been established so far.
2. Association with demographic features
Cross sectional studies have shown an earlier disease onset in pSS
patients with anti-Ro/SSA and anti-LA/SSB antibodies than in
seronegative patients [17,18]. For instance, patients with younger
onset (defined as b35 years old), presented a higher prevalence (45%
vs. 12%) of anti-Ro/SSA antibody than those patients with an elderly
onset [17], whereas when groups were defined as N70 and b70 years
old, the prevalence of antibodies were similar [18]. Regarding the
gender, some works have showed that male patients have a lower
frequency of anti-Ro/La antibody compared with female population
whereas others have not [19–21].
3. Association with clinical course
Overall, multiple studies have showed that patients with positive
results for these antibodies have more frequent parotiditis and
extraglandular complications than those with negative results
[16,22–24]. An analysis of 321 patients with pSS showed that those
with organ involvement had in 65% anti-Ro52 and antiRo60
antibodies, whereas the non-organ group had 57%. The occurrence
of anti-La/SSB was also greater in the organ-affected group (48% vs.
13% OR 6, 95% CI 3–12) [24].
Finally, the link between positive antibodies and lymphoma was
explored in a cohort of 100 patients followed up by 10 years, where
the three of them who developed lymphoma were anti-Ro/La positive
[7]. This result contrasts with the finding of an Italian population
where of those with pSS and non-Hodgkin lymphoma only 37% were
Ro/SSA and 50% La/SSB positive [25].
4. Association with glandular dysfunction
Serum anti-Ro/SSA and anti-La/SSB concentrations have been associ-
ated with dry eye symptoms, Shirmer-I test and rose Bengal staining
scores [26,27]. An abnormal sialogram has been also more frequently
found in patients with positive anti-Ro antibodies [27]. For instance,
Tsuzaka et al. found that the accumulation rate in the parotid glands of
patients anti-Ro/SSA was lower than those who had anti-La/SSB
antibodies. In addition this rate was significantly lower in patients who
Table 1
HLA haplotypes in pSS according the anti-Ro/SSA and anti-La/SSB profile.
Author Population
Rischmuller 1998 Australian
Miyagawa 1998 Japanese
Guggenbuhl 1998 French
Tzioufas 2002 European
Guttenberg 2003 French
were positive for each antibody than out of patients negative for either
antibody [28].
Regarding the correlation of lip salivary gland infiltration and
autoantibodies, it has been described that subjects with anti-La/SSB
exhibited higher infiltration than subjects with Ro/SSA alone or those
who were negative for both autoantibodies [29,30]. Halse et al.
showed a correlation between focus score and Ro 52 kd and La 48 KD
in saliva indicating a strong relation between local inflammation and
autoantibody production [30]. In addition a strong correlation was
reported between the presence of autoantibodies in sera and localized
Ro 52-kD, Ro 60 kD and La/SSB producing cells in salivary glands [31].
This description was supported by the MRL-lpr/lpr mice sialoadenitis
model where animals that produced serum anti-Ro/SSA also had anti-
Ro/SSA antibody producing cells in salivary gland, spleen and lymph
nodes [32].
Summing up, the positivity of these antibodies correlates with the
salivary gland lymphocytic infiltration and abnormal oral and ocular
tests performed to assess glandular dysfunction in Sjögren's
syndrome.
5. Association with other serologic markers
It is well known the serological abnormalities in patients with pSS
such as hypergammaglobulinemia [23,33], hypocomplementemia
[2,34] as well as high rheumatoid factor (RF), high serum levels of
IgG and IgA [7,9], mixed monoclonal IgM cryoglobulins (found in one
third of the patients) [35] and positive ANA titers [9,36]. Studies have
showed that absolute levels of Ro/SSA and La/SSB antibodies correlate
with levels of gammaglobulins, β2 microglobulin [37], κ free light
chains of immunoglobulins and recently with serum levels of BLys, a
member of the TNF-ligand family linked to B cell maturation and
survival [35,37,38]. The presence of anti-Ro/SSA or anti-La/SSB
antibodies has not been associated with other antibodies described
in SS such as α-fodrin antibodies [37].
Although anti-Ro and anti-La antibodies correlates with other
biomarkers previously mention, it is noteworthy to say that when B cell
depletion therapy with rituximab has been used, there is no change in the
levels of Ro/SSA and La/SSB antibodies has been found, whereas there is a
dramatic decrease in RF, IgG and β2 microglobulin [39].
6. Association with treatment
Recent evidence indicates a major role of B cells in the pathophys-
iology of pSS. A treatment that eliminates these abnormal B cells
(preventing the appearance of extraglandular manifestations and
progression toward malignancy) promises as a disease-modifying
drug in primary Sjögren's syndrome. Until now, patients enrolled in
these trials need to be positive to anti-Ro/SSA antibodies and/or
rheumatoid factor [40].Nevertheless, as previously mention the posi-
tivity and the titers of anti-Ro/SSA antibody do not change after the
treatment. Thus, the anti-Ro/SSA antibody helps in selecting patients
Haplotype Antibody
DR2-DQA1*0102DQB1*0602 Anti-Ro/SSA or anti-La/SSB
DR3DQA1*0501-DQB1*02 Coexistance of anti-Ro/SSA anti-La/SSB
DRB1*08032/DQA1*0103/DQB1*0601 Coexistance of anti-Ro/SSAS anti-La/SSB
DRB1*1501/DQA1*0102DQB1*0602 Anti-Ro/SSA alone
DRB1*1501-*0301 Anti-Ro/SSA or anti-La/SSB
DRB1*03-DQA1*0501-DQB1*02 Anti-Ro/SSA or anti-La/SSB
DRB1*01/DQB1*02 heterozygosity Coexistance of anti-Ro/SSA anti-La/SSB
DRB1*15/DQB1*01 Anti-Ro/SSA or anti-La/SSB
DRB1*03/DQB1*02 Coexistance of anti-Ro/SSA anti-La/SSB
 G. Hernández-Molina et al. / Autoimmunity Reviews 10 (2011) 123–125
who are most likely to benefit, however it is not used as a serologic
outcome.
7. Conclusion
The anti-Ro/SSA and anti-La/SSB antibodies have a wide-spread
occurrence in patients with Sjogren´s Syndrome. Their presence has
been associated with glandular and extraglandular manifestations, as
well as other features also indicating B cells disturbances. Studies have
showed that a specific immunogenetic background is important for
anti-Ro/SSA and/or anti-La/SSB autoantibody formation; suggesting
that the HLA class II may participate in the perpetuation and initiation
of an autoimmune response.
Until now, evidence suggest that anti-Ro/SSA and anti-La/SSB
antibodies are useful in the diagnosis of pSS and help to identify more
“active” patients in whom we should be concern about their clinical
behavior, although they are not used as a biomarker outcome. Studies
to explore their association with survival and accrual damage are still
lacking.
Take-home messages
• Anti-Ro and anti-La antibodies are useful in the diagnosis of primary
Sjögren´s Syndrome and help to identify more “active” patients.
• Specific HLA-II haplotypes are associated with the presence of anti-
Ro and anti-La antibodies.
• Anti-Ro and anti-La antibodies are not serological parameters to
assess response to B depleting cells treatment.
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