Monday, December 23, 2013

The Link Between Autoimmunity and Infectious Disease

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

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