Mike Bambenek
MicB 5546 – Immunopathology
SLE Outline
3/22/10
Systemic Lupus Erythematosus (SLE) Section
Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that is characterized by
the presence of “self” antibodies that are synthesized by autoreactive B-cells. SLE is a chronic
disease that will never resolve itself. The presence of “self” antibodies leads to chronic
inflammation and damage of various tissues in the host body.
Autoreactive B-cells are created when a normal B-cells accidently present “self” antigen to
helper T-cells, which in turn give an inappropriate signal to the B-cell, allowing it to proliferate.
This presentation of “self” antigen by the B-cells it thought to be due in part to a clearance
deficiency in the germinal centers. Normally, when cells go apoptotic in the germinal center,
macrophages phagocytose the remaining debris. When there is a clearance deficiency,
macrophages fail to clean up this cellular debris and it is mistakenly taken up by B-cells. There is
no single gene or environmental factor that has been identified as the cause of lupus, but there are
several promising theories. One such theory suggests that lupus is caused by damage to the
enzyme DNaseI, which is responsible for degrading DNA and chromatin. If this enzyme is
damaged, it reduces the macrophages ability to phagocytose nuclear debris, allowing it to build up
in the extracellular matrix, increasing the chances of uptake of “self” antigen by B-cells. This
theory is further supported by the fact that almost all cancers are caused by some type of DNA
damage, usually instigated by a mutation in a critical DNA repair-associated protein such as
BRCA1 or p53. This damage to DNA repair-associated proteins could likely lead to increased rates
of mutation to critical enzymes like DNaseI.
The symptoms of lupus are commonly very vague, including fever, malaise, joint paints,
muscle pain, fatigue, and temporary loss of cognitive ability, making it a difficult disease to
diagnose. Clinically, SLE is usually diagnosed by the presence of specific, anti-nuclear antibodies
such as anti-dsDNA and anti-RNP. This production of “self” antibodies will cause chronic
inflammation throughout an individual’s lifetime.
SLE is thought to have played a critical role in the progression Julie’s cancer. Her SLE
caused the production of “self” antibodies by autoreactive B-cells, causing chronic inflammation.
The chronic inflammation caused a significant amount of damage to Julie’s cells, including damage
to their DNA. While her normal somatic cells could repair most of the DNA damage through
regular DNA repair pathways, her cancerous cells already had mutations to several critical DNA
repair-associated proteins (BRCA1, p53), rendering them incapable of repairing further DNA
damage. This increased rate of DNA damage coupled with her reduced ability to repair DNA
damage lead to an overall increase in the rate of mutation. This partially explains the rapid and
aggressive growth of Julie’s cancer.
The chronic inflammation caused a great deal of damage to Julie’s tissues, most notably in
her lungs. The extensive tissue damage resulted in elevated levels of circulation C-reactive protein
(CRP), which was critical in diagnosing Julie’s SLE. CRP is an acute phase protein that is secreted
by the liver in response to IL-6 secreted by macrophages. Its purpose is to bind phosphocholine of
dying cells, marking them for destruction by the complement system. The increased inflammation
also caused an increase in the release of Heat Shock Proteins (HSPs), particularly HSP-70 and HSP90. HSPs are chaperone proteins that are released in response to some sort of cellular stress such
as heat, infection of inflammation. They help the cell block the apoptosis pathway and increase the
expression of Epidermal Growth Factor Receptor. Thus, these HSPs allow the cells to both resist
death and grow at an accelerated rate, making Julie’s cancer faster growing and more difficult to
treat.
The tissue damage caused by chronic inflammation also affects the Th1/Th2 balance. M1
macrophages typically associated with phagocytosis and antigen presentation whereas M2
macrophages are associated with ECM repair and cell growth, like in wound healing. The Th1
response is the “cell-mediated response” which relies primarily on cytotoxic T-cells and has been
shown to have a better anti-cancer response. The Th2 response is the “humoral response” that
relies primarily on B-cells synthesizing antibodies and has been shown to have a poorer anticancer response. When Julie’s cells were destroyed during inflammation the cellular debris had be
removed by macrophages, specifically M2 macrophages. These M2 macrophages have been shown
to promote the Th2 response and inhibit the Th1 response, causing a polarization of here immune
system towards Th2. This polarization resulted in both a decrease in her immune systems anticancer response as well as an accelerated rate of cancer growth due to the increased secretion of
EGF by M2 macrophages.
The combination of all these factors lead to an increase in the metastatic abilities of Julie’s
cancer cells. Macrophages can create an environment that is conducive to metastasis by releasing
chemotactic factors that promote angiogenesis and the formation of ECM collagen fibers, which
help the cancer cells survive outside of the tumor microenvironment.