Autoantibodies in Systemic Lupus Erythematosus

Introduction and Historical Perspective

Systemic lupus erythematosus (SLE) is a multi-
systemic autoimmune disease that can involve almost
any organ of the human body.
 The diverse clinical manifestations of SLE are
accompanied by a huge number of autoantibodies.
 The number of antibodies associated with SLE was
recently reported to be 116
No other autoimmune disease is similar to SLE with
regard to the vast number of autoantibodies linked
with it.
SLE autoantibodies can react with nuclear,
cytoplasmic, and surface cellular antigens as well as
with complement components and coagulation system
factors.
In 1948, Malcom Hargraves, Helen Richmond, and
Robert Morton from the hematology laboratory of the
Mayo Clinic in Rochester noted the presence of
previously unknown cells in the bone marrow of a
patient with acute SLE.
 These cells,which they called LE cells, were described
as mature neutrophilic polymorphonuclear leukocytes
that phagocytose Feulgen-stained nuclear materiall
This historic finding ultimately led to the discovery of
a broad variety of autoantibodies directed against
nuclear antigens, which are now known as antinuclear
antibodies (ANAs).
In 1949, Haserick and Bortz made the important
observation that, when incubated with normal bone
marrow, serum from SLE patients was able to induce
the formation of LE cells.
The inducing factor, called LE factor, was found to be
associated with the gamma-globulin fraction of SLE serum,
which was suspected to be an antibody.
 For the next 10 years, the detection of LE cells in the
peripheral blood remained the most popular laboratory
test for the diagnosis of SLE.
In 1953, Peter Miescher observed that the sera from rabbits
immunized with cell nuclei were able to induce LE cell
formation using normal human leukocytes.
One year later, Miescher demonstrated that absorption of
SLE serum by cell nuclei isolated from calf thymus cells
made the serum incapable of inducing LE cell formation.
Based on these experiments, the LE factor was confirmed
to be an ANA
These pivotal findings resulted in the simultaneous
reporting of antibodies to DNA in the sera of SLE patients
by at least four different groups in 1957
Antinuclear Antibodies
Since ANAs are present in almost all patients with SLE,
the ANA test is the most sensitive test for lupus.
However, ANAs are not specific for SLE because they
occur in a variety of autoimmune, rheumatic, and
infectious diseases.
Moreover, ANAs are sometimes detected in healthy
individuals, especially in the elderly.
In any case, the absence of ANAs makes the diagnosis of
SLE much less likely, although still possible.
Indirect immunofluorescence with tissue or cell culture
substrates is the most widely used method for detection
of ANAs
Because of their large nucleus and prominent
nuclear constituents, human esophageal tumor
cells (HEp-2) are most commonly used for this
purpose.
The ANA test is interpreted both by titer and by
pattern.
Higher titers loosely correlate with pathologic
significance.
Since the ANA test is dependent upon
immunologic reagents and laboratory conditions,
there is substantial interlaboratory variation .
The different antigenic targets bound by the
autoantibody lead to different ANA
immunofluorescence patterns,
depending on their location within the cell and
on the specific changes caused by fixation
but more sensitive techniques have now been developed,
for instance, enzyme-linked immunosorbent assays
(ELISA)
and line immunoassays (LIA) using whole cell nuclei,
affinity-purified antigens,recombinant proteins, or
synthetic peptides.
 Immunoblotting and immunoprecipitation are valuable
tools for characterizing many autoantibodies that react
with nuclear and cytoplasmic antigens.
 Sensitivity
Target antigen ANA type
Inflammatory Sjögren Limited Diffuse systemic
Drug-induced LE SLE
myopathy syndrome Scleroderma sclerosis

Antinuclear antibodies
40-60 50-80 70-90 70-90 >95

Sensitivity
>95 Various
All ANAs
(by indirect IF)

- - - Diffuse- - 40-60
Target antigen DNA ANAAnti-dsDNA
type
Inflammatory Sjögren Limited Drug-induced
systemic SLE
myopathy syndrome Scleroderma LE
sclerosis
Core proteins of
- - - - - 20-30 All ANAsAnti-Sm
40-60 50-80 70-90 70-90 >95 >95 VarioussnRNPs
(by indirect IF)
- - - - - 40-60 DNA Anti-dsDNA
- - - - >95 50-70 Histones Anti-histone
Core proteins of
- - - - - 20-30 Anti-Sm
snRNPs
- - - - 10 - 15- >95 - 30-40
50-70 HistonessnRNPAnti-histoneU1 RNP

- - 10 15 - 30-40 snRNP U1 RNP

Type I
- - 10-18 28-70 - - Type I Scl-70
- - 10-18 28-70 - - topoisomerase Scl-70
topoisomerase
Centromeric
Centromeric Anti-
- - - - 9090 22-26
22-26 - - - - Anti-centromere
proteins
proteins centromere
10 70-95 - - - 30-50 RNPs SS-A (Ro)
10 - 70-95
60-90 - - -- - - 30-50
10-15 RNPs RNPs SS-B (La)
SS-A (Ro)

Histidine-tRNA
25 - - - - - Jo-1
ligase
- 60-90 - - - 10-15 RNPs SS-B (La)

Histidine-tRNA
25 - - - - - Jo-1
ligase