Autoimmunity

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Anti-ribosomal P protein antibodies

Roberto Gerli & Laura Caponi

To cite this article: Roberto Gerli & Laura Caponi (2005) Anti-ribosomal P protein antibodies,
Autoimmunity, 38:1, 85-92, DOI: 10.1080/08916930400022699

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Published online: 07 Jul 2009.

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Autoimmunity, February 2005; 38(1): 85–92

Anti-ribosomal P protein antibodies

ROBERTO GERLI1, & LAURA CAPONI2

1
Department of Clinical and Experimental Medicine, Center for the Study of Rheumatic Diseases, University of Perugia, Perugia
06122, Italy, and 2Laboratory of Specialised Clinical Analysis, Department of Experimental Pathology, University of Pisa,
56100 Pisa, Italy

(Submitted 13 August 2004; Accepted 30 August 2004)

Abstract
Anti-ribosomal P protein antibodies (Abs) recognize three specific ribosomal proteins located in the large ribosome’s subunit.
The term anti-ribosomal P protein Abs, often shortened in anti-P Abs, is due to the fact that these three proteins, P0, P1 and
P2, of 38, 19 and 17 Kd molecular weight, respectively, are phosphorylated.
One of the major points of interest of these autoAbs derives from their high specificity for systemic lupus erythematosus
(SLE), their description in other connective tissue diseases (CTDs) being only occasional. In SLE patients, their association
with renal and hepatic involvement has been proposed, while the possible association with psychiatric and/or neurological
involvement is still a matter of debate. From a serological point of view, a preferential association of anti-P with anti-Sm and/or
anti-DNA Abs, possibly due, at least in part, to cross-reactivity, has been suggested. This observation is intriguing since all
these autoAbs are considered specific serological indicators of SLE.
This review will summarize clinical and serological data on anti-P Abs provided by the main studies published in the last few
years and the more recent findings about proteins constituting their targets.

Keywords: Anti-ribosomal antibodies, systemic lupus erythematosus, connective tissue diseases, anti-P proteins

Ribosomal P protein biology as already mentioned, phosphorylated serins in

AutoAbs reacting with either whole ribosomes or
ribosome fractions were initially described in CTD
about 40 years ago, when they were found in 23% of
patients with SLE [1], a percentage quite similar to
that detected in more recent years by using different
techniques and antigen targets. Subsequent studies
identified two main distinct species of autoAbs
reacting with either ribosomal RNA or ribosomal
proteins. In more recent years, it has been clarified
that proteins, rather than RNAs, are the main targets
of anti-ribosomal Abs.
Ribosome proteins, around 80 for both small
and large subunits, are highly conserved during
the phylogenesis. Their interaction with the four
ribosomal acidic ribonucleic chains is facilitated by
the fact that they are mainly basic. Three of them,
however, the P0, P1 and P2 are acidic and contain,
eukaryotes, while their prokaryotic counterparts,
L10 and L7/12 heterodimers, are not phosphory-
lated. Differently from all other proteins, they have
an isoelectric point located in the neutral (for P0) or
in the acid (P1 and P2) range [2]. These three
proteins are those identified as autoAb target in SLE
[3 – 5] and, importantly, most of the reactive sera are
able to bind all the three P proteins.
Beside the acidic properties, some other structural
and biochemical features of the P proteins have been
shown [6]. They are organized in a pentameric
complex with one copy of P0 and two copies of P1 and
P2 forming the ribosomal stalk on the large ribosomal
subunits. The stalk is a protuberance, where the
elongation step of protein synthesis takes place. More
precisely, one copy of P1 forms a heterodimer with
one copy of P2. Two of these heterodimers are
anchored to one copy of P0 protein, included into

Correspondance: R. Gerli, MD. Rheumatology Unit, Sect. of Internal Medicine & Oncological Sciences, Policlinico di Monteluce, I-06122
Perugia, Italy. E-mail: gerlir@unipg.it

ISSN 0891-6934 print/ISSN 1607-842X online q 2005 Taylor & Francis Ltd
DOI: 10.1080/08916930400022699
86 R. Gerli & L. Caponi
the ribosomal particle. Comparison of protein
sequences pointed out that they share the aminoacid
sequence at carboxy terminus. This sequence is highly
conserved, with minimal changes in various species,
and represents the specific target of most anti-P Abs.
This explains the finding that the same Ab specificity
could bind three distinct proteins.
Considerably more information has been
discovered in these recent years on these peculiar
ribosomal proteins representing the antigenic target of
anti-P Abs. Among these, it is of interest to underline
that most of the ribosomal proteins are synthetized in
the cytoplasm and, through a nuclear localization
signal represented by a short stretch of amino acids
recognized by specific carriers, they are subsequently
transported into the nucleus, where the ribosome is
built within the nucleoli [7]. Recent studies, however,
have demonstrated that human P proteins seem to be
incorporated into the forming ribosome according to a
specific pathway. P1 and P2, indeed, seem to be
incorporated in the ribosomal particles in a very late
stage, after their moving to the cytoplasm, rather than
transported into the nucleus. Conversely, P0 appears
to be located in the nucleus, but not in the nucleolar
fraction [8], probably because its incorporation occurs
in the nucleus but not in the nucleoli. This suggests
that the ribosome stalk formation is a final step in the
maturation of the ribosome particles.
Moreover, it has been early demonstrated that, in
addition to those bound to the ribosome, there is a
pool of free cytoplasmic P proteins [9], namely P1 and
P2, and that there is an exchange between cytoplasmic
and ribosome-bound P proteins. These observations
raised the question of the meaning of both different
locations and exchange on ribosomal functionality.
Differently from the three ribosomal P proteins, the
P proteins free in the cytoplasm are not phosphory-
lated. Phosphorylated P1 and P2 can be removed from
ribosomes. The viability of eukariotic cells, containing
ribosomes not expressing these proteins, does not
seem to be reduced, although cell growth appears to
be impaired [10]. Ribosomes can recover their full
functionality when removed phosphorylated proteins,
but not dephosphorylated P proteins, are let to
rebound to P-deficient particles [11,12]. More
importantly, phosphorylation affects the interaction
between P proteins (namely P2) and elongation factor
EF-2, one of the molecules involved in the protein
synthesis, since only phosphorylated P2 protein are
able to interact with EF-2 [13]. It has been shown that
this interaction induces a conformational change of
EF-2 [14]. Moreover, phosphorylation of ribosomal
stalk proteins is able to modify the pattern of
translated mRNAs [15].
All together, these data suggest that phosphoryla-
tion of ribosomal proteins may be one of the
regulatory mechanisms able to influence polypeptide
synthesis, as occurs for factors involved in mRNA
translation, perhaps influencing translation efficiency
[16]. However, the phosphorylation “question” is far
from being fully clarified: more than one enzyme is
able to phosphorylate P proteins, since at least four
protein kinases display phosphorylating activity on P
proteins [15]. In addition, mechanisms about dephos-
phorylation activity are completely unknown.
Anti-P Ab binding
Anti-P Abs are able to bind P proteins on their natural
location. As initially demonstrated in vitro [16,17], they
recognize their natural target, the stalk of ribosome,
and the binding seems to block protein synthesis.
There are some more recent investigations suggesting
that this might occur also in vivo [18]. It has been
demonstrated, indeed, that the penetration of anti-P
Abs into living cells leads to the inhibition of protein
synthesis [19 – 21]. This observation is of great
relevance, of course, since it suggests a possible
pathogenic mechanism for these autoAbs. However,
although it has been postulated that the binding on P
proteins exposed on the cell surface may be important,
the mechanisms implicated in the transmigration of the
autoAbs into the cell remain an open question. In fact,
P proteins have been demonstrated on the membrane of
several type of viable cells [22,23]. Ribosomal proteins,
moreover, have been demonstrated on ribosomal blebs
exposed by apoptotic cells [24]. On the other hand,
there is in vitro evidence that anti-P Abs are able to bind
protein target on the cell surface [25 –27], although this
observation, albeit intriguing and likely, has not been
yet confirmed in human diseases.
Other Ab specificities against ribosomal proteins
have been detected over years. In SLE, sera reacting
with ribosomal proteins located either in the small
subunit, such as the S10 [28 –30], or in the large
subunit, such as the L14 [31], the L12 [30,32] and the
L7 [33], have been recognized. Some of them, such as
the anti-L14, display high specificity for, but low
prevalence in SLE; others, such as the anti-L7, have
high prevalence, but a specificity not so restricted to
SLE; others again are preferentially described in
juvenile rather than in adult disease (anti-L12).
Another important finding is worth to note: P proteins
are immunogenic in several ways. They represent,
indeed, an antigenic target not only for autoAbs in SLE,
but also for immune responses against some parasitic
infections. In this setting, the Ab response triggered by
the Trypanosoma Cruzi, the protozoa inducing Chagas
disease, includes the production of Abs directed against
protozoan P proteins. As anti-P Abs in SLE do, these
Abs bind the carboxy terminus which is very similar to
the P proteins of other species. Anti-P Abs developed in
patients with Chagas disease, however, display a
functional activity on cardiomyocites that anti-P Abs
from SLE patients do not show [34,35]. Similar
humoral responses can be elicited by other intracellular
 Determination of autoantibody in rheumatic syndromes
parasites, including Leishmania. Moreover, it is inter-
esting to note that P proteins are also involved in the
allergic response to fungal allergens [36]. P2 protein, for
example, is one of the target of the allergic response to
Aspergillus Fumigatus, Alternaria Alternata and Clado-
sporium Herbarum [37].
Isotype and subclasses
A limited number of studies examined the isotype
moiety of anti-P. Beside IgG, the presence of IgM anti-
P has been reported in some works [38,39]. A specific
study was conducted in order to verify the develop-
ment of anti-P response [40]. A limited number of
SLE patients followed during the disease developed
IgG anti-P Abs after a transient IgM response.
Animals immunized with the immunodominant P
peptide developed an IgM anti-P response then
switched to IgG. These evidences, though limited in
humans, suggested that the anti-P response may be
antigen-driven. Other studies suggest that cell
destruction entailing ribosomal protein exposition is
not sufficient to elicit anti-P response [41].
Studies focused on IgG subclasses showed that
IgG1 and IgG2 were equally represented in SLE
patients [42,43], while IgG2 were shown to be the
most represented in MRL mice [44].
Assays for anti-P Ab detection
Various tests have been set up since the discovery of
these Abs. Gel immunoprecipitation, immunofluo-
rescence and radioimmunoassay (RIA) were the first
techniques that allowed their detection [45 –49].
These assays were subsequently substituted by the
introduction of immunoblot on electrophoretically
separated ribosomal proteins that became the best
technique to show antibody binding to ribosomal
proteins (3). To date, it is still the gold standard
technique to detect such a specificity. In the mid-80s,
the employment of other techniques was favoured by
some new findings. First of all, the analysis of the
sequences of the three P proteins revealed that they
share the last C-terminal aminoacid sequence and
an epitope mapping study revealed that such a shared
C-terminus was the target of the anti-P Abs. This
allowed to perform a new form of tests based on the
peptide synthesis of the sequence, although the length
of the synthetized peptides employed was not the
same in the various studies. The first one was
a 22 aminoacid peptide [50], but a subsequent epi-
tope mapping study revealed that a shorter sequence,
represented by the last 11 amino acids, contained the
minimum number of amino acids sufficient to ensure
a good binding [51]. On the basis of this observation,
shorter peptide chains, of 17 and 13 amino acids,
respectively [52,53], were fruitfully used as antigen
targets in order to set up anti-P evaluations.
87
Despite the importance of the phosphorylation on P
proteins for their function in the ribosomes, this post-
translational modification does not seem to affect the
binding capacity of spontaneously produced anti-P
Abs. Indeed, the binding of anti-P Abs, found in the
serum of SLE patients, to purified ribosomal proteins
appears to be equal to that to recombinant proteins or
synthetic peptides, where minimal discrepancies may
be due to technical differences in assays or to the
binding ability of Abs (see below).
Solid-phase techniques became the assays of choice
with the availability of the target sequence. As
variation of liquid-phase tests, RIA was initially
employed, but rapidly abandoned, since enzyme-
linked immunosorbent assays (ELISAs) offered quite
similar performances without the problems linked to
the use of radioactive reagents. ELISAs based on
antigen peptides, therefore, are actually the simplest
and most used assay to evaluate anti-P Abs.
It is likely that P proteins, as all proteins of
considerable molecular weights, may have other
epitopes other than those located onto the
carboxy terminus. In fact, Abs against P proteins
which bind other regions of the protein, have been
described [54]. This evidence is obtained when
techniques based on whole proteins, such as immuno-
blot on separated ribosomal proteins, are employed:
if the binding is restricted to only one or two of the
three P proteins, it is likely that in these cases the
epitope target may be different.
The fine specificity may represent a key point in
ELISAs, where the target antigenic protein(s) can be
native purified or recombinant. This technique does not
allow to distinguish if the binding of the Ab is towards
the carboxy terminus or another protein fragment.
When whole proteins are used, the binding, of course,
can be due to Abs against the carboxy terminus as well as
other epitopes [55]. As a consequence, the prevalence of
anti-ribosomal P protein Abs evaluated in adults with
whole proteins is usually higher than that found with the
employment of the C-terminus [56]. Comparative
studies of different techniques did not often specify if the
anti-P reactivity, usually ascertained by immunoblot,
was assigned only to those sera reacting with all three
proteins. In fact some studies considered as anti-P
positive those sera binding the sole P0 protein at 38 Kd
in immunoblot [57]. However, the results showed that
the majority of anti-P Abs bound to all three P proteins.
On the contrary, ELISA based on specific sequences as
antigens are easily interpreted.
The various techniques used in the different studies
could justify, at least in part, the different prevalence
of anti-P Abs found. When this specific point has been
examined in SLE patient populations, the majority of
P-reactive sera were directed against all the three P
proteins [54,55,57]. Taken together, these data appear
to suggest that the employment of anti-C terminus
peptide as antigen, although it does not allow
88 R. Gerli & L. Caponi
the recognition of some anti-ribosomal specificities,
namely those against epitopes different from the C-
terminus of P proteins, is able to identify the majority
of anti-P Abs.
Serological test performance
Comparative analysis of the efficiency of various tests
for anti-P Abs may be influenced by many factors,
including, of course, antigen and technique differ-
ences. Performance of anti-P tests is mainly depen-
dent on the technique used. To date, solid phase
assays, such as immunoblot and ELISA, are thought
to provide the most reliable results.
In this setting, it is well known that ELISA methods
display very high sensitivity, although this property
can lead to inexact results due to possible nonspecific
reactivity. For this reason, optimal set-up conditions,
such as choice of plates with optimal characteristics,
efficacious saturation step, parallel tests on uncoated
plates and cut-off obtained with a large number of
normal human sera, are crucial. However, a grey zone
on the edge of the cut-off may remain with possible
uncertain results. In other words, some quantitative
results at low titre provided by ELISA tests could be
located in an “equivocal” range, that may give doubts
on the true anti-P positivity of the serum.
A key point in the comparison of the results
obtained by immunoblot with those obtained with
other techniques is the definition of a positive serum
for anti-P. Only sera binding all three bands
corresponding to the P proteins in immunoblot
should be compared to sera reactive with the
C-terminus peptide, independently from the length
of the peptide chain used as antigen. In this way, the
number of positive sera are almost equivalent and the
few discrepancies found are usually due to differences
in technique sensitivity [58].
As mentioned above, several studies have compared
results obtained with immunoblot and ELISA, usually
home-made. Recently, the performance of different
commercial kits using different kinds of antigens for
anti-P detection, i.e. purified or recombinant proteins,
synthetic peptides or a combination of them, has been
evaluated and compared to immunoblot results [59].
All tests provided quite good performance associated
with optimal specificity, although the sensitivity
varied. In addition, nonoptimal correlations were
found between the various tests, including those
employing the same antigen (see below). It is possible
that the affinity of Abs may influence the quality of the
binding, as suggested by the authors, but it is also
conceivable that the binding may be influenced by
many other factors, only partially due to methodology.
For example, differences may be due to different
availability of the antigen in the different tests. In one
of the our studies, the comparison of anti-P reactivity
with two ELISA peptide-based techniques, one using
a single 13 aminoacid long C-terminus peptide, the
other using a multiple antigen peptide carrying four
copies of the same 13-mer peptide, showed a better
sensitivity of the latter, possibly due to the greater
availability of the antigen for Ab binding onto the plate
[53]. The importance of these factors has been
confirmed in this study by the observation that the
same antigen, namely the C-22 terminus, used in
different assays may give a concordance of the results
lower than that expected.
Although the authors did not specify whether the
anti-ribosomal protein positive sera bound all the three
P proteins, they suggest that optimal results can be
obtained with a combination of P proteins and
C-terminal peptide as antigen. This raises the already
mentioned question if Abs against epitopes different
from that located in the C-terminus have to be
considered as anti-P positive sera. For these reasons,
we agree with the authors’ suggestion that an
international standardization of laboratory tests for
anti-P Abs may be the best tool to definitively clarify
this topic.
Serological associations
Anti-P Abs are more frequently found in sera
containing peculiar Ab specificities. A first observation
pointed to a higher frequency of anti-P in anti-Sm
positive sera [44,60]. More recent findings suggested
an association of anti-P with anti-nDNA Abs in the
serum of SLE patients with renal involvement [61,62].
It is intriguing to note that anti-Sm, anti-nDNA and
anti-P are all specific markers of SLE because of their
very high disease specificity.
The hypothesis of a cross-reactivity between anti-P
and these two different specificities has been tested in
a number of investigations. Although the results have
not been conclusive in some of these [63], inhibition
studies, i.e. inhibition of the binding of specific Abs to
their corresponding target antigen obtained with
another antigen, provided some evidence of anti-P
cross-reactivity with both Sm proteins [64] and nDNA
[65,66]. It is conceivable, therefore, that the simul-
taneous presence of these autoAbs in the serum of the
same subject may be due, at least in part, to a family of
Abs able to react with various antigens.
The possible association of anti-P with anti-
phospholipid Abs has been investigated by some
studies [67– 69], but this hypothesis needs further
clinical and experimental studies to confirm it and to
test possible cross-reactions between such families of
auto-Abs [70].
Clinical studies
After early discovery in SLE, anti-P Abs have been
searched in other CTDs, including RA, Sjögren’s
syndrome, mixed connective tissue disease (CTD),
 Determination of autoantibody in rheumatic syndromes
scleroderma and others. However, they have been
detected only occasionally in disorders different
from SLE or SLE overlapping and transitional
conditions [71,72]. The high specificity for SLE of
anti-P Abs makes them a marker potentially useful
for the diagnosis of SLE, although the low
prevalence in the disease represents a limit for
their utilization as new diagnostic and/or classifi-
cation serological criterion for the disease. Anti-P
frequency in SLE, indeed, ranges around 15 – 20%,
but it may be dependent from the antigen used, i.e.
whole protein(s) or peptides, or the detection
method employed. Moreover, it has been shown
that the prevalence of these autoAbs in SLE is
higher in subjects with active disease [68,73 – 76], in
Asiatic patient populations [38,73,77] and in
patients with early disease onset [68,74,75]. The
observation of some influence of age and race on
anti-P production fits with the findings showing that
the synthesis of these autoAbs can be affected by
certain MHC class II alleles [78 –80].
Despite circulating anti-ribosome autoAbs in SLE
having been described for the first time many years ago,
a clinical relevance of anti-ribosomal P protein Abs was
suggested in 1987, when Bonfa et al. observed high
titres of anti-PAbs in lupus patients with psychosis [81].
Since then, multiple investigations have been published
on the possible association between anti-P and
psychiatric and/or neurological manifestations of
SLE and the results did not always confirm this
finding [38,67,68,73,74,76 – 78,80,82 – 86]. Several
problems, including the low number of patients studied
and the methodological approaches adopted to
diagnose the neuropsychiatric disease, impaired a
precise evaluation of this topic [56]. In brief, however,
the data seems to suggest that anti-P are not clearly
associated with lupus neurological involvement, but
they may be associated with certain psychiatric
manifestations of the disease [87]. In this setting, the
demonstration in longitudinal studies of anti-P titer
peaks corresponding to lupus psychotic crisis may
further support this hypothesis [77,81].
Other associations of anti-P have been proposed in
a number of studies [56,88]. Among these, skin,
kidney and liver involvement appear to be the most
frequent and interesting. The first one has been
essentially demonstrated in 3 different series of
European patients [68,76,82], thereby underscoring
the already mentioned role of the genetic background
in anti-P production. The second one has been
proposed more recently [61,89,90] and it could be
linked to cross-reactivity of anti-P with anti-nDNA
Abs [62,66]. Finally, the association with lupus
hepatitis, which has been described in the subjects
with such a rare disease manifestation [88,91,92],
represents an intriguing finding also on the basis of
experimental evidence of hepatocyte damage induced
by these autoAbs [19,93].
89
Conclusions
After early discovery of P proteins as the main targets
of autoAbs recognizing ribosomal autoantigens in
subjects with SLE, great interest emerged recently
about the possible clinical significance of these Abs
and their possible pathogenic role in SLE as well as the
best methodology to detect them. Several studies
tackled these topics and, although some problems are
still being debated and remain unsolved, the strong
specificity of these autoAbs for SLE and their
correlation with disease activity, young age of disease
onset, race and some particular clinical manifestations
of SLE, make anti-P Abs of particular interest from
both speculative and clinical point of view.
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