Autoimmunity
occurs when the immune system begins to wrongly attack self-antigens or various
parts of the body it’s responsible for protecting. There are mechanisms in
place to prevent this kind of problem, while still allowing B and T-cells the
variability needed to combat a wide array of pathogens (disease causing
agents). Mechanisms are in place during the production of B and T-cells that
check them for auto reactivity, such as central and peripheral tolerance. The
breakdown of these tolerance mechanisms causes autoimmunity. When central tolerance
mechanisms breakdown, auto reactive B-cells escape negative selection, in the
form of apoptosis (cell death), and are released into the lymphatic system. It
is when these auto reactive B-cells become aberrantly activated through things
like B and T-cell discordance or T-cell bypass that an attack on host tissues
begins.
Some autoimmune diseases are caused
by the production of autoantibodies against self-molecules, which are produced
when auto reactive B and T-cells escape tolerance mechanisms. The production of
autoantibodies against key components in the immune system, like inflammatory
cytokines (signaling molecules) can negatively affect the ability of the immune
system to effectively clear pathogens and prevent disease. In other words,
autoimmunity can predispose people to infection by various pathogens, which
they would normally be able to eradicate if their immune system was
uncompromised.
One of the most vital aspects of the
immune system is the ability of the various immune cells to effectively
communicate with one another and influence the environment around them. This is
done through the use of signaling molecules known as cytokines. They are a
diverse group of soluble proteins, peptides or glycoproteins that are secreted
by specific immune cells in order to elicit a specific response. Therefore many
times when an infection is detected inflammatory cytokines such as TNF-α are released, which induces things like
vasodilation. Thus, by increasing the amount of immune cells flowing to the
site of infection the environment around the pathogen is effectively skewed to
favor the immune system. Cytokines can also act as effector molecules to
polarize T-cell responses in order to rid the body of the pathogen in the
safest and most effective way possible. For instance, if an extracellular
pathogen like Streptococcus (the
bacteria that causes strep throat) began to infect your nasal system you would
want a Th2 (antibody mediated) response to be deployed as opposed to a Th1 (CTL
mediated) response. A Th2 response is much safer and more effective against
extracellular pathogens because, unlike a Th1 response, a Th2 antibody-mediated
response doesn’t involve the release of cytotoxic granules or pro-inflammatory
molecules, which could really damage these sensitive tissues. In order for a
T-cell response to be skewed towards a Th2 response the cytokine IL-4 must be
present and continue to remain in the environment. So, if a person suffered
from an autoimmune disease, which produced autoantibodies against IL-4 they
would be unable to effectively combat extracellular pathogens like Streptococcus,
and in a sense they would be
classified as immune compromised.
Several reports have
demonstrated this previously unknown link between autoimmune disease and
increased susceptibility to infectious diseases. In a study it was found that
neutralizing autoantibodies to IFN-y lead to increased risk of mycobacterial
infections. Autoantibodies were found to have neutralized IFN-y in whole blood
culture and thus prevented production of inflammatory cytokines, TNF-α and IL-12 along with
impeding MHC class I upregulation. These things are necessary components of a
successful Th1 response to mycobacteria; therefore it was shown that
autoantibodies against IFN-y affected the immune system’s ability to prevent
mycobacteria infection. A few studies on anti-IL-6 autoantibodies indicated
that patients with this form of autoantibody lead to increased susceptibility
to staphylococcal infection. In one patient it was found that when IL-6 was
inhibited, C-reactive protein (CRP) induction was also inhibited, which is a
key response factor to staphylococcal infection. It was also found that IL-6
deficient mice were also more susceptible to pyogenic (bacteria) infections.
Neutralizing autoantibodies against Th17 cytokines such as IL-22 and IL-17A
have been connected to an increase in fungal infections like candidiasis. One
of the most significant findings was in the connection between patients
diagnosed with pulmonary alveolar proteinosis (PAP) that had neutralizing
antibodies against GM-CSF present, and death due to infection. PAP is a rare
lung disease in which surfactant interferes with gas exchange and causes
coughing and shortness of breath. GM-CSF (granulocyte/macrophage
colony-stimulating factor) is vital to the antimicrobial activity of
neutrophils and macrophages. It helps the recruit neutrophils to the site of
infection by increasing the expression of an adhesion molecule (CD11b), which
helps them stick to endothelial cells. It also enhances the phagocytosis
(engulfment) of microbes by neutrophils and macrophages. PAP patients have high
levels of GM-CSF autoantibodies, which are especially abundant in the lungs.
These autoantibodies block GM-CSF from binding to its receptor and thus further
inhibit the antimicrobial activities of neutrophils and macrophages. The
relationship between PAP, autoantibodies and GM-CSF function was found when PAP
was reproduced in primates that had been given GM-CSF patient-derived
autoantibodies. Also individuals with mutations in their GM-CSF receptor were
found to have PAP.
Most of the time autoantibodies to cytokines do not neutralize
to a significant effect and cause the severe susceptibility to infection as
described above. Severe infections occur when neutralizing autoantibodies are
created against specific cytokines that are vital antimicrobial agents. It was
also noted in the report that autoantibodies that target pathogen-recognizing components,
like TLRs (toll-like receptors) or costimulatory molecules could also
potentially predispose people to infectious diseases. There have been some
puzzling results that make this area of study inconclusive. Some studies suggest
autoantibodies are produced merely as a consequence of infections. It is also unclear
as to what extent vaccines play in autoimmunity and this predisposition to
infectious diseases. In the future it will become increasingly important to
understand the underlying genetic and environmental causes of autoimmunity, and
it is believed that this understanding will allow us to gain insight into these
unanswered questions.
Primary Source:
Maddur
MS, Vani J, Lacroix-Desmazes S, Kaveri S, Bayry J (2010) Autoimmunity as a
Predisposition for Infectious Diseases. PLoS Pathog 6(11): e1001077.
doi:10.1371/journal.ppat.1001077
Other Sources:
http://www.healthtechzone.com/topics/healthcare/articles/2013/10/01/355057-frost-sullivan-raising-public-awareness-promotes-global-uptake.htm
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