The Lupus Book: A Guide for Patients and Their Families, Third Edition (5 page)

IL-1

pro-inflammatory, stimulated by TNF-alpha. Blocked by Kineret.

IL-2

T cell growth factor

IL-4

anti-inflammatory

IL-6

increased in rheumatoid arthritis, polymyalgia rheumatica. Drugs

which block it are in clinical trials

IL-8

promotes chemotaxis (a chemokine) and inflammation, increased

with autonomic nervous dysfunction

IL-10

anti-inflammatory

IL-12, 15, 17, 18

pro-inflammatory, drugs which block these are in development

Interferon-alpha

blocks B cells, antiviral; used to treat hepatitis, leukemia, dysregu-

lated in lupus

Interferon-beta

made by fibroblasts; used to treat multiple sclerosis

Interferon-gamma

antiviral made by T helper cells, dysregulated in lupus

TGF-beta

partly responsible for tight skin in scleroderma, but may help lupus

(TNF ϭ tumor necrosis factor, IL ϭ interleukin, TGF ϭ transforming growth factor) They are consumed (serum levels decrease) during inflammation, and low complement levels are an important indicator of lupus activity. (See Chapter 11.)

THE INFLAMMATORY PROCESS

We have described the key fighters in the body’s defensive army against im-

munologic and inflammatory attack. We can imagine them as a highly disci-

plined force, each member of which carries out a specialized task in the course of battling against foreign invaders. Neutrophils, lymphocytes, and macrophage-monocytes are all involved in the body’s inflammatory and immune process in

critical but distinct ways.

Neutrophils and Inflammation

In healthy people, neutrophils have only one known function: they kill foreign

invaders such as bacteria. If the level of neutrophils in the blood is low, we

know this decreases our ability to fight infection and increases our risk of contracting it. In rheumatic diseases such as gout, neutrophils can ingest or swallow immune complexes and crystalline material. Neutrophils are part of the acute

(early, initial) inflammatory process, whereas lymphocytes are part of a chronic (later, ongoing) inflammatory process.

The process by which neutrophils kill foreign material occurs in several

stages, which can be visualized in Figure 5.2. First, try to imagine neutrophils or antibodies as guns and cytokines or complement as bullets, which cause tissue destruction. By adhering to the surface of veins and emigrating through them,

neutrophils turn on a system of attractants that includes activated complement,

The Body’s Protection Plan

[23]

Fig. 5.2.
How Granulocytes Kill Bacteria

adhesion molecules, chemokines, histame leukotrienes, prostaglandins, nitric oxide, reactive oxygen intermediates, and cytokines, which are important for cell destruction and inflammation. These mediators generate chemicals that can be

suppressed by lupus medicines such as steroids and nonsteroidal anti-

inflammatories (e.g., Advil, Naprosyn). The end result is the coating of bacteria with IgG and activated complement, which then adheres to the neutrophil. Finally, the neutrophil discharges its granules, thus completing the killing process.

The Monocyte-Macrophage and Antigen-Presenting System

The monocyte-macrophage network is an important member of the immune

surveillance force; it is central because regulation of this network is what goes awry in autoimmune disease. It includes our lymph nodes and dendritic cells.

The monocyte-macrophage network has several functions: it destroys microor-

ganisms and tissue debris that result from inflammation; it clears dead and dying red cells, denatured plasma proteins, and microorganisms from the blood; it

plays a role in the recognition of foreign substances; and it also promotes the secretion of cytokines.

Antigens, or foreign materials, do not generally activate T cells directly. They are usually presented to the T cells by macrophages. Antigens are present on

the macrophage surface, but in order to respond to their presence, the T cell

must recognize a code on the surface of the macrophage, called the HLA class

[24]

Inflammation and Immunity

II (or D) determinant. The HLA (or human leukocyte antigen) system is re-

sponsible for recognizing antigens. See Chapter 7 for a review of this system.

This system acts in combination with a T-cell surface marker, which can then

activate T cells. Class II determinants recognize surface antigens for CD4, or

helper cells; class I (HLA-A, B, or C) determinants recognize markers for CD8

or suppressor cells. Figure 5.3 illustrates these complex interactions.

Let’s summarize what happens when something foreign (e.g., a virus) enters

the body. It is recognized as something that must be eliminated. The foreign

body (known as the antigen) is recognized by macrophages, which roam the

bloodstream keeping watch for foreign antigens. A macrophage engulfs the an-

tigens, and that may be the end of the story. However, in some instances, the

antigens are broken into small pieces known as “antigenic peptides.” If addi-

tional help is needed to destroy it, the antigenic peptide unites with an HLA

molecule inside the macrophage. The HLA molecule then moves to the outside

of the macrophage bound to the peptide, forming a “complex.” T cells and their

receptors interact with the antigen-peptide complex. T cells send chemical sig-

nals called cytokines which bring in more T cells and alert B cells to produce

antibody. Ultimately, phagocytes remove the antigen from the body.

Fig. 5.3.
How Antigens Stimulate Antibody Production

The Body’s Protection Plan

[25]

Activation of Lymphocytes

The T lymphocytes are made in the bone marrow and processed in the thymus.

When they leave the thymus, they are able to respond selectively to environ-

mental stimulation. Upon exposure to a foreign body or antigen and after a

series of steps, T cells transform; they become larger in appearance and start to divide. This occurs in part as a result of the production of the cytokine

interleukin-2 (also called T-cell growth factor). T cells then differentiate into helper cells, suppressor cells, effector cells (which make cytokines), and cytotoxic or killer cells, and they promote the production of B cells. Some B cells become plasma cells and make immunoglobulin, or antibody. A small number

of T cells live for many years and act as memory cells for the immune system.

They are capable of initiating effective and rapid immunologic responses if the body is re-exposed to the antigen.

Summing Up

Whole blood consists of red blood cells, white blood cells, platelets, and plasma.

There are five types of white blood cells. These include the neutrophils, which are important in acute inflammation; lymphocytes, which help regulate chronic

inflammatory processes; and monocytes, which are responsible for helping the

body recognize foreign material. All these cells are derived from the bone mar-

row. In a normal immune response, these elements all work together. Lympho-

cytes migrate to the thymus, where they are ultimately recognized as T cells or B cells. The T cells read antigenic signals present in monocytes or macrophages and are thus able to promote or turn off inflammation and the killing of specific cells. Some B cells transform themselves into plasma cells that make immunoglobulin, which then circulates in the plasma. Immunoglobulins G, A, M, D,

and E also help to destroy foreign materials. All these processes are promoted

and amplified by cytokines, complement, and other mediators that constitute our normal immune surveillance network.

6

The Enemy Is Our Cells

Chapter 5 reviewed the normal inflammatory and immune response network.

Several features unique to lupus and other autoimmune processes alter this sys-

tem to produce tissue injury that is not observed by the body’s normal immu-

nological surveillance system. These features will be summarized briefly here

in order to help us understand the many antibodies that play an important role

in lupus.

Lupus results when genetically susceptible individuals are exposed to certain

environmental factors, and in my opinion, only 10 percent of those who carry

lupus genes will ever develop the disease. These environmental factors create a setting where things happen that normally shouldn’t.
Neutrophils
(the white blood cells responsible for mediating acute inflammation) can increase inflammation in the body of lupus sufferers because of the way their blood plasma

interacts with cytokines, complement, and adhesion molecules (the chemicals

that draw cells closer to the site of inflammation).
Lymphocytes
, the white blood cells responsible for chronic inflammation, also have their function altered in lupus. The T-helper cells become more active, and the body becomes less responsive to T-suppressor cells. Natural killer lymphocytes promote inflammation and are not able to suppress or contain it. As a result, the body’s system of

tolerance is disrupted so much that B cells are signaled to make antibodies to

the patient’s own tissues, which are called
autoantibodies
. In other words, the normal immune surveillance system is altered in lupus, resulting in accelerated inflammatory responses and autoantibody formation; the autoantibodies, in turn, attack the body’s own cells and tissues. It is as if our body’s police force found itself unable to tolerate healthy, law-abiding cells and schemed to undermine

them.

AUTOANTIBODIES GALORE!

Autoantibodies are the hallmark of lupus. They represent antibodies to the

body’s own tissue—to parts of the cells or the cells themselves. In addition to
The Enemy Is Our Cells

[27]

having a positive result on an antinuclear antibody (ANA) test, the typical SLE

patient has at least one or two other autoantibodies. These antibodies distinguish lupus patients from others without the disease, since few healthy people have

significant levels of them.

Sixteen important autoantibodies in lupus are described and defined in this

chapter. In Chapter 11, the clinical importance of some of these autoantibodies is discussed in more detail; there, we will look at the blood tests your doctor will order so that your disease can be diagnosed and treated. In other words,

this section defines and categorizes autoantibodies.

WHERE DO AUTOANTIBODIES COME FROM?

Autoantibodies are triggered by antigens in the environment (e.g., foods, dyes, tobacco smoke), autoantigens (self-driven), and
idiotypes
. Idiotypes are regions of immunoglobulin that are recognized as being foreign, or antigenic. They

promote the formation of
anti-idiotypic antibodies
.

Even though immunologists know that B cells are critical in the formation of

autoantibodies, several important issues regarding autoantibodies remain unre-

solved. Namely, which B cells can make autoantibodies? And what is the defect

in immune response that permits the expression of pathologic or injurious au-

toantibodies?

In nature, autoantibodies are often produced that do not have any clinical or

pathologic significance (mostly IgM antibodies). In lupus, IgG autoantibodies

often correlate with disease activity. Autoantibody responses can be general or on occasion quite specific. Both phenomena are observed in lupus.

WHAT KINDS OF AUTOANTIBODIES ARE THERE?

The autoantibodies important in lupus can be broken down into four categories.

These include
antibodies that form against materials in the nucleus or center
of the cell
, such as antinuclear antibody, anti-DNA, anti-Sm, anti-RNP, and antihistone antibody;
antibodies that form against cytoplasm or cell surface
components
, such as anti-Ro (SSA), anti-La (SSB), antiphospholipid, and antiribosomal P antibodies;
antibodies to different types of cells
, such as red blood cells, white blood cells, platelets, or nerve cells; and
antibodies that form against
circulating antigens
, such as rheumatoid factors and circulating immune complexes.