The Lupus Book: A Guide for Patients and Their Families, Third Edition (7 page)

Lupus Specificity

Antinuclear

Nucleus

98

5–10

Fair

Anti-DNA

Nucleus

50

Ͻ1

Excellent

Antihistone

Nucleus

50

1–3

Fair

Anti-Sm

Nucleus

25

Ͻ1

Excellent

Anti-RNP

Nucleus

25

Ͻ1

Fair

Antiphospholipid

Membrane

33

5

Fair

Anti-Ro (SSA)

Cytoplasm

30

Ͻ1

Fair

Anti-La (SSB)

Cytoplasm

15

Ͻ1

Fair

Antiribosomal P

Cytoplasm

20

Ͻ1

Good

Antierythrocyte

Red cells

15–30

Ͻ1

Fair

ANCA

White cells

20

Ͻ1

Poor

Antilymphocyte

White cells

Most

20

Poor

Antiplatelet

Platelets

15–30

Ͻ5

Poor

Antineuronal

Nerve cells

20

Ͻ1

Good

Rheumatoid factor

Ag-Ab*

30

5–10

Poor

Immune complexes

Ag-Ab*

Most

Varies

Poor

* Ag-Ab is an abbreviation for antigen-antibody complexes. These immune complexes are elevated with many common bacterial and viral infections, not just with lupus.

The Enemy Is Our Cells

[33]

but these approaches have been abandoned. One laboratory has extensive ex-

perience inducing lupus in cats with an antithyroid preparation, but this has not been adopted as a research tool by other investigators. More than 95 percent of animal lupus research studies involve mice with lupus.

WHY SHOULD WE STUDY ANIMAL MODELS OF LUPUS?

Antivivisectionists loudly proclaim that animal research is inhumane and un-

necessary. They believe that computer modeling and tissue-culture work rule

out the need for animal studies. However, many of the advances in lupus over

the last 30 years would not have been possible without animal studies, and

thousands of human lives have been saved as a result of this work. The immune

system of a mouse is remarkably similar to that of a human. As hard as we try,

no satisfactory computer simulation of the mouse’s or human’s immune system

exists, in large part because there’s a lot we don’t know about it.

The breakthroughs resulting from mouse work in SLE include proof that

genetic factors are important determinants of autoimmune disease and have led

to the identification of genes important in lupus. Animal research has also proved that lupus can be influenced by environmental and hormonal factors. Therapy

has pushed forward because trials of multiple therapeutic interventions that never would have worked in humans have saved years of research and lots of misery

for patients. Furthermore, many of the drugs we use to treat lupus (e.g., cyclophosphamide) were first shown to be effective in mice. Three types of mice are

used by researchers: breeds which spontaneously develop lupus, those in whom

it can be induced, or mice missing a specific gene. There have even been strong suggestions from mouse work that ‘‘gene therapies’’ may become useful in the

treatment of lupus, as scientists have been able to develop breeds of ‘‘knock

out’’ mice missing a specific gene or chemical.

As long as investigators stick to well-established guidelines that mandate hu-

mane and ethical environments for animal research, these efforts can save bil-

lions of dollars and a lot of unnecessary trial and error in humans while accelerating the pace for establishing the efficacy of new treatments. For example,

since mice with lupus live 1 to 2 years and humans with lupus can live up to

100 years, the influence of different therapeutic or environmental interventions can be seen more easily in animals with lupus.

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Part III

WHAT CAUSES

LUPUS?

Now that we have seen how our complex immune system works, we can return

to the question of what causes lupus. Researchers now believe that SLE probably results from multiple factors. It begins when certain genes predisposing an individual to lupus interact with environmental stimuli. These interactions result in immunologic responses that make autoantibodies (antibodies to one’s self)

and form immune complexes (antigens combined with antibodies). Certain au-

toantibodies and immune complexes are capable of causing the tissue damage

typically seen in lupus.

This part briefly outlines the causes of lupus and the immunologic responses

typically seen in lupus patients; subsequent chapters review these concepts in

more detail.

THE GENETICS OF LUPUS

Several different single genes increase the relative risk for lupus by increasing the body’s ability to promote certain autoantibodies. These are called HLA (human

leukocyte antigen) class II genes (there are class I, II, and III genes), and they are present on the surface of all cells that present foreign material, called antigens, to white blood cells, which are central in the body’s immune system. A defect in

HLA class III genes results in low complement levels (an important protein that plays a role in inflammation), which are commonly observed in SLE. Outside the

HLA system, genes that help program the structure of immunoglobulin or the re-

ceptors on the surface of T cells are important as well. And as one might deduce from the much greater number of female SLE patients, sex hormones also play a

role in the unique immunologic response of lupus patients. In fact, female sex hormones are more compatible with lupus activity than are male hormones.

[36]

What Causes Lupus?

ENVIRONMENTAL FACTORS

Environmental factors such as ultraviolet light, certain prescription drugs, and some chemicals can promote lupus. They either act like antigens that react

against the body or introduce new antigens to the immune system. Viruses

and other microbes can also alter cellular DNA or RNA (the essential structural material of chromosomes) and make them respond as if they were antigens.

For still unknown reasons, non-Caucasians are more susceptible to these

events.

ABNORMALITIES OF B LYMPHOCYTES

One-third of the human white blood cells are called lymphocytes. They are

divided into B and T cells. B cells are the body’s ‘‘humoral’’ response; their

job is to produce immunoglobulins and ultimately antibodies. The B lympho-

cytes in lupus patients are overactive; that is, they produce abnormally large

amounts of immunoglobulin and autoantibodies.

ABNORMALITIES OF T LYMPHOCYTES

The T cells are our body’s ‘‘memory’’ lymphocytes. They remember what is

foreign (or antigenic) and signal us to respond to this stimulus. Different types of T cells have various functions: they suppress immune response (suppressor

cells), promote the immune response (helper cells), destroy cells (natural killer cells), or promote chemicals (e.g., cytokines) that modulate or signal other immune cells to do certain things.

In SLE, the abnormalities observed include increased helper function, de-

creased suppressor function, an alteration of the lymphocytes that promote au-

toantibody formation, and increased B-cell responses. CD8 cells and NK cells

end up promoting inflammation rather than suppressing it.

ALTERATIONS IN CELL SIGNALING

Antigen-presenting cells, or macrophages, normally process antigen and make

peptides (specialized protein components) which stimulate T lymphocytes. In

lupus, some T-cell surface receptors are altered structurally or functionally, and the normal two-step co-stimulatory ‘‘handoff’’ of information is bobbled. Further down the road, altered receptors on the B-cell surface mishandle signals

from T cells.

ABNORMALITIES OF IMMUNOGLOBULIN RESPONSE

B cells make immunoglobulins, which destroy foreign material and protect the

body. In lupus, the regulation of this process goes awry when autoantibodies

What Causes Lupus?

[37]

form or when immune complexes are deposited in tissue and produce inflam-

mation. Autoantibodies that target different parts of cells, such as anti-DNA,

anticardiolipin, or anti-Ro (SSA), are capable of damaging tissues directly.

ABNORMALITIES IN DECREASING IMMUNE RESPONSES

In a healthy body, antigenic or foreign material combines with antibodies to

form immune complexes that vary in size, shape, charge, and binding properties.

Circulating immune complexes are usually cleared and dispersed through a fil-

tering system in which the spleen plays a prominent role. In SLE, this clearance is defective because certain important receptors have lost their binding ability and these complexes are unusually large or small in size or too plentiful.

Moreover, in the lupus patient, the body’s ability to control inflammation is

hampered because T-suppressor cells develop helper functions and natural killer cells promote B cells instead of killing certain invaders. Indeed, the body’s

system of ‘‘tolerance’’ (its ability to distinguish what is self from what is foreign) is altered. The regulation of cytokines is also altered in lupus.

ABNORMALITIES IN APOPTOSIS

Apoptosis
, the Greek word for falling or dropping off, refers to programmed cell death. Normally, cells die by two mechanisms: they are either killed or are genetically programmed to die. Apoptosis genes activated in a pregnant woman

ensure that their baby will not have 3 arms, 8 legs, or 4 hearts. In adults,

Environmental factors,

drugs, infectious

agents

Loss of regulating

cells which control

autoreactivity

Disease progression, Epitope spreading

Tissue Injury

Fig. III.1.
Factors Promoting the Development of SLE

[38]

What Causes Lupus?

damaged or old cells are genetically selected to die. When this fails to occur

normally, studies have suggested that the persistence of debris from damaged

cells in lupus patients may promote autoantibody formation. Nucleosomes are

chromatin complexes generated during apoptosis that are phagocytized by B

cells which activate T cells.

LOSS OF TOLERANCE

“Bad” cells can be eliminated by the thymus, spleen, lymph glands, and mac-

rophages. In SLE, evidence of loss of tolerance occurs whereby “self” or slightly altered self is recognized as being foreign. This occurs by several mechanisms

including loss of T cell tolerance (by the thymus centrally or peripherally; cells without HLA markers escape thymic deletion) and loss of B cell tolerance. B

cell tolerance is lost via failed elimination in the spleen, lymph nodes, bone

marrow through clonal deletion, receptor editing, or passive transfer which re-

sults in defects in our surveillance mechanisms. These inhibit, delete, suppress or ignore which leads to autoreactive cells “breaking through” and ultimately

autoantibodies are produced.

Summing Up

Genetic, environmental, T-cell, B-cell, and antibody factors combine to produce what we recognize as lupus. We still don’t know which factors are the cart and

which the horse. And we don’t yet know why event A leads to event B. We do

know that lupus results in alterations of immune regulation that cause the body to become sensitive to its own tissues. Figure III.1 summarizes some of these

concepts. In the next few chapters, we explore some of the factors that induce

lupus.

7

The Genetic Connection

Is lupus a genetic disorder? Does it run in families? How can it be passed on

or be inherited? These questions are commonly asked. The answer is not simple,

but researchers now believe that various genes that predispose people to lupus

are inherited, among them the
major histocompatibility complex
, or
MHC
, which includes the
human leukocyte antigen (HLA)
region, a specific area of the genes.

Along with HLA, we also inherit T-cell receptor genes and other genes relevant

to SLE, such as immunoglobulin genes. Each of us inherits a unique chemical

signature, just as we inherit our blood type.

All this probably seems a little like alphabet soup, but in the next few pages

we take a closer look at how the principles of genetics apply to our understanding of lupus.

THE MAJOR HISTOCOMPATIBILITY COMPLEX:

A GENE SYSTEM

Every human cell that contains a nucleus (or center) also contains 23 pairs of

chromosomes
. We inherit one member of every pair from each of our parents.

These chromosomes store the genetic material responsible for determining

whether you are a male or female, have red hair, are color blind, might develop cystic fibrosis, among other characteristics. In mapping human chromosomes,

geneticists have referred to the ‘‘short’’ and ‘‘long’’ arms of the chromosomes, which have been numbered for convenience. On the short arm of the sixth

chromosome lie a series of specific sites, called genetic markers, that determine what an individual’s HLA system will look like. First described in the early

1970s, the HLA region contains genes that may predispose one to a remarkable

number of diseases, especially rheumatic disorders.