The Lupus Book: A Guide for Patients and Their Families, Third Edition (6 page)

If you are a lupus patient, your doctor is likely at some time to test your

blood for many if not most of these antibodies. Therefore the following para-

graphs endeavor to explain what they are. Doctors have been accused of creating their own vocabulary in order to make themselves indispensable. Consider this

chapter a foreign language class. The next time Dr. Jones excitedly tells you

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Inflammation and Immunity

that your anti-Ro (SSA) antibody is highly positive, ask him or her if it was

measured using immunodiffusion or by ELISA!

ANTIBODIES TO NUCLEAR CELLULAR COMPONENTS

Since its description in 1957, the
antinuclear antibody
, or ANA (antibody to the cell nucleus) has become the most widely known autoantibody in SLE. It

is hard to imagine having lupus without it, although a person can have a positive ANA test without having systemic lupus. For many years, the test for ANA was

conducted using animal cells. Human serum was placed over kidney or liver

cells of the mouse, rat, or hamster, and if ANA was present, human antibody

would attach to the animal cell’s nucleus. Fluorescent staining of the antibody bound to animal cell nuclei was used to document these findings. Now, however,

testing involves human cells in place of animal cells; as a result, the test more accurately predicts the presence of lupus. As recently as the late 1980s, 10

percent of lupus patients had false-negative results (in other words, people with lupus had a negative ANA test) and might have been told they did not have the

disease. The rate of negatives at present is as low as 2 percent; however, more people now have positive ANAs without evidence for lupus.

ANA tests are analyzed according to the amount of antibody present and the

pattern seen in cells recognized by antibodies in the sample. Although this is a crude measure, the amount of antibody can suggest the degree of seriousness of

the disease. The patterns of antibody are classified as follows:

1. The
homogeneous
pattern is seen primarily in SLE but also in other illnesses as well as in older adults. This pattern indicates the presence of

antibodies to chromatin (part of the chromosomes), histone, and/or deoxy-

nucleoprotein.

2. The
peripheral
or
rimed
patterns are seen primarily in SLE and represent antibodies to DNA (see below). Often, the concurrence of a homogenous

pattern makes the peripheral pattern undetectable, since a stain that covers

all the nucleus may include its rim or margin.

3. The
speckled
pattern is seen in SLE, numerous other autoimmune diseases, and in some healthy individuals who show low amounts of antibody.

‘‘Speckled’’ suggests a spotty uptake of the fluorescent stain.

4.
Nucleolar
(a part of the nucleus) patterns are not often seen in SLE and suggest scleroderma.

5.
Centromere
patterns detect the central part of the chromosome. They are rarely seen in lupus and their presence suggests a form of scleroderma

called the CREST syndrome.

As many as 10 million Americans may receive a positive ANA test result,

but fewer than a million probably have SLE. Positive ANAs (even in large

The Enemy Is Our Cells

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amounts) can be found in healthy relatives of SLE patients, patients with other autoimmune diseases, and in normal people, especially those over the age of

60. In addition, infections with certain viruses and bacteria can stimulate the production of ANA.

Deoxyribonucleic acid
, or
DNA
, is a molecule located in the control center of each of our cells and is responsible for the production of all the body’s

proteins. Antibodies to single-stranded DNA are found in many normal individ-

uals. However, the presence of
antibodies to double-stranded DNA
may suggest a serious form of SLE; these antibodies, if positively charged, may damage

tissue directly. Throughout, I will refer to these antibodies as
anti-DNA
. Approximately half of SLE patients possess anti-DNA. By tracking their specific

levels, I can assess my patient’s response to therapy. More than 90 percent of

patients with anti-DNA have SLE, especially those with serious organ-

threatening (e.g., kidney) disease.

Anti-Sm
stands for a Mrs. Smith, in whom it was first described. Antibodies to the Sm antigen are very specific for lupus (present in 20 to 30 percent of

those with SLE) and are rarely observed in any other disease. These antibodies

interfere with the ability to transcribe RNA (ribonucleic acid) from DNA.

The antibody directed against ribonuclear protein,
anti-RNP
, is essential for the diagnosis of mixed connective tissue disease, a lupus look-alike. However,

it is not specific to this disease, since 20 to 30 percent of lupus patients and a small number with scleroderma or rheumatoid arthritis also have the antibody. Anti-RNP interferes with the ability of RNA to bind in the cytoplasm of

cells.

Histones are structural proteins in the cell nucleus. They can be autoantigens

and are observed in SLE, rheumatoid arthritis, certain cancers, and liver diseases.

Histones are thought to be responsible for the LE cell phenomenon, the first

immune abnormality reported in lupus.
Antihistone antibodies
are of particular interest because they are present in 95 percent of patients with drug-induced

lupus.

ANTIBODIES TO CYTOPLASMIC COMPONENTS

Four autoantibodies to cytoplasm (if a cell looks like an egg, it is the egg white) are important in SLE and are discussed here. The true prevalence of many of

these antibodies, however, is not known, since the levels vary according to the methods of detection employed. Although the technology is not relevant to this

discussion, it is important to know that older, less sensitive methods such as

immunodiffusion detect fewer positive patients than the newer ELISA and im-

munoblotting tests. But whereas the older tests rarely if ever gave false-positive readings, newer methods of evaluation occasionally produce misleading results.

These methods nevertheless detect 30 to 50 percent more patients with the auto-

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antibody than traditional testing. The percentages listed below for anti-Sm, anti-RNP, anti-Ro, and anti-La were derived from older methods.

Antiphospholipid antibodies
react against phospholipids, which are components of the cell membrane. There are several antiphospholipid antibodies,

the most important of which is anticardiolipin. These antibodies are frequently seen with the lupus anticoagulant and are discussed in detail in Chapter 21.

Antiphospholipid antibodies are present in about one-third of patients with

SLE and are less frequently found in other autoimmune diseases.

Anti-Ro (SSA)
is present in most patients with Sjo¨gren’s syndrome (dry eyes, dry mouth, and arthritis) and 20 to 30 percent of those with SLE. As one of

the few autoantibodies that crosses the placenta, it may induce neonatal lupus

and congenital heart block. Anti-Ro can impart increased sun sensitivity to

its carriers and is seen in nearly all patients with a skin disorder called subacute cutaneous lupus erythematosus. It is associated immunogenetically with

HLA-DR2 and HLA-DR3. Anti-Ro may interfere with the cell’s ability to

process RNA.

Anti-La (SSB)
is almost always seen with anti-Ro. Rarely present by itself, it coexists with anti-Ro 40 percent of the time and may make anti-Ro less

pathogenic, or dangerous. This statement especially applies to kidney disease.

La may function as a waystation on the road to where RNA transcripts are

carried from the nucleus to the cytoplasm.

Antiribosomal P
antibodies are observed in 20 percent of known patients with SLE. Found only in the cytoplasm, antiribosomal P may correlate with psychotic behavior or depression in lupus and its levels may decrease with re-

sponse to therapy.

ANTIBODIES TO CELLS

Lupus patients can have antibodies to red blood cells, white blood cells, platelets, and nerve cells.

Antierythrocyte antibodies
are directed against the surface of red blood cells.

One lupus patient in 10 develops autoimmune hemolytic anemia, or the destruc-

tion of red blood cells due to antierythrocyte antibodies. The true prevalence of these antibodies is not known, but there are probably two to three lupus patients with this antibody for every one who becomes seriously anemic.

Antineutrophil antibodies
are occasionally observed. Antibodies that act against the cytoplasmic component of neutrophils, called
ANCA (antineutrophil
cytoplasmic antibodies)
, indicate the presence of one of two types of non-lupus vasculitis (inflammation of the blood vessels) called Wegener’s granulomatosis

(which is characterized by the c-ANCA subset) and microscopic polyangiitis.

The Enemy Is Our Cells

[31]

The p-ANCA subset, which characterizes microscopic polyangiitis, is also pos-

itive in 20 percent of those with SLE.

Another white blood cell antibody called
antilymphocyte antibody
is present in most lupus patients. It is a natural autoantibody; large amounts indicate

greater severity of the disease, and it is responsible for the low white blood cell counts seen in many lupus patients. Most antilymphocyte antibodies are IgM

antibodies that coat the surface of lymphocytes and result in the depletion of T

cells.

Antiplatelet antibodies
are present in approximately 15 percent of lupus patients and account for most thrombocytopenia (a condition in which platelet

counts drop below 100,000 per cubic millimeter) seen in lupus patients. Al-

though there are many other reasons for thrombocytopenia (they are discussed

in detail in Chapter 20), the majority of patients have platelets coated with IgG, which assures their premature destruction. Unfortunately, the methods for detecting antiplatelet antibodies are technically difficult and not always reproducible. Antiplatelet antibodies are often seen in association with antiphospholipid antibodies.

Antineuronal antibodies
react to nerve cell membranes, or coverings. Nerve cells, or neurons, look like a series of electrical wires and are responsible for storing and transmitting nerve responses throughout the body. Autoantibody

reactivity to nerve cell components is not observed in healthy people, but if

tested correctly can be detected in 5 percent of patients with rheumatoid arthritis, 5 to 20 percent of all lupus patients, and in up to 90 percent of patients with active central nervous system inflammation from lupus or autoimmune nervous

disorders. Although blood levels may indicate the presence of central nervous

system lupus, spinal fluid is a more reliable source than serum for measuring

neuronal antibodies.

ANTIBODIES THAT FORM AGAINST

CIRCULATING ANTIGENS

Remember that antigens are foreign materials to which cells react. Sometimes

the body makes antibodies to antigens expressed by its own cells.

In rheumatoid arthritis, it is probable that antigenic material to the synovium (the lining of the joint) induces an antibody response. The body then makes

antibody to this antigen-antibody complex which is called
rheumatoid factor
.

Rheumatoid factor, in turn, may release a chain of biochemical events that con-

tributes to joint and cartilage destruction. As many as one-third of lupus patients may have rheumatoid factor. Rheumatoid factor in lupus can exacerbate the

inflammation of joints but may be protective of other tissues such as the kidneys.

Circulating immune complexes
are the combination of antibody and antigen

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circulating in the bloodstream. These complexes contain everything from rheu-

matoid factor to complement mixed with antigen and immunoglobulins. The

true incidence of circulating immune complexes in lupus is unknown, since the

variety of methods capable of assessing them detect only certain types of com-

plexes. Circulating immune complexes can activate complement which, in turn,

can promote inflammation. In lupus, some complexes cannot be cleared from

the body by the monocyte-macrophage system, and when they settle in tissues

either directly or indirectly, they induce inflammation.

Table 6.1 summarizes these antibodies and compares their presence in normal

individuals and lupus patients.

LESSONS LEARNED FROM ANIMALS

What is fascinating about animal research is that we have found similarities

between the immune systems of animals and those of humans. Much of the

information presented here was derived from animal research. In addition to

affliciting nearly a million Americans, lupus is also found in many animals. It has been reported to occur spontaneously in dogs (including a presidential one—

George Bush’s Millie), cats, rabbits, rats, mice, guinea pigs, pigs, monkeys,

goats, hamsters, and Aleutian minks. One of the best described is canine lupus, which is very similar to human lupus in its presentation and management. In

the 1950s and 1960s, occasional research studies utilized guinea pigs and rabbits,
Table 6.1.
Important Autoantibodies and Antibodies in Lupus

Percent

Percent

Autoantibody

Antibody to

in Lupus

in Normals