Mycobacterium tuberculosis and Immune Evasion

Many of you have likely heard of tuberculosis (TB), a potentially lethal, infectious disease caused by intracellular bacterium called Mycobacterium tuberculosis. Although this bacterium usually attacks the lungs, it can also affect other parts of the body including the brain, the spine, or the kidneys. Tuberculosis germs are spread through the air, particularly when an infected person coughs, sneezes, or vocalizes. Symptoms of tuberculosis include weakness, a chronic cough, night sweats, fever, and weight loss. Tuberculosis is one of the world’s deadliest diseases. In 2012, there were 1.3 million tuberculosis related deaths worldwide (World Health Organization 2013). In fact, one-third of the world’s population is infected (Centers for Disease Control and Prevention 2013).

It is important to distinguish between two tuberculosis conditions: latent TB and active TB (also known as TB disease). Latent TB is defined by the presence of a TB infection, but the bacteria remain in the body remain inactive and do not cause symptoms. This is because the immune system acts to “wall off” the bacteria using a cellular structure called a granuloma which forms around the invaders. Active TB occurs when the immune system cannot prevent the TB bacteria from multiplying in the body. A person with active TB will be contagious and exhibit symptoms. People most susceptible to developing active TB disease are those who have been recently infected by TB bacteria or those with medical conditions that weaken the immune system such as HIV infection, tobacco use, or diabetes mellitus. Specifically, 90% of infected patients will have latent TB, while only 10% will progress to disease (World Health Organization 2013). TB is generally curable with antimicrobial drugs, but in many underdeveloped nations, access to such health care is unattainable. If untreated, 50% of active TB disease cases are fatal (World Health Organization 2013). Additionally, resistance to the medicines is increasing. This is evidenced by the emergence of multi-drug resistant TB, which is the result of bacteria that do not respond to standard anti-TB drugs (Centers for Disease Control and Prevention 2013).

Clearly, TB is a relevant concern in today’s world. An October 2013 study by Heuer et al. (http://www.biomedcentral.com/1471-2172/14/48) examined the effects of two Mycobacterium tuberculosis antigens on human dendritic cell maturation and how this affects immune response. This study was investigating the viability of these antigens as vaccine candidates, while also examining how these antigens may be involved in immune reaction or immune evasion. Antigens are entities (in this case, an element of the Mycobacterium tuberculosis) that can bind to the antigen receptor of a T or B cell (leukocytes that mediate adaptive immunity). Dendritic cells are phagocytic leukocytes that process antigen material and function as antigen presenting cells. Specifically, infection of these dendritic cells by Mycobacterium tuberculosis leads to the downregulation of the expression of MHC class I and II and CD1 (cell surface proteins which present antigens to T cells). Therefore, if there are less of these antigen presentation molecules, antigens will not be effectively presented to T cells and NKT cells so effective immune responses won’t be promoted. This suboptimal immune response is considered to be a cause of susceptibility to Mycobacterium tuberculosis.

New EAE Models More Accurately Reflect MS

Multiple Sclerosis (MS) affects about 400,000 people in the United States. In MS, the myelin sheath that coats our neuronal axons is degraded, as are the cells that produce myelin (also known as oligodendrocytes). MS is considered an autoimmune disease because the attack is facilitated by our body’s own immune system. This degradation of the myelin sheath affects the ability of our neurons to transmit electrical signals to each other. This manifests itself in the symptoms often associated with MS: numbness in limbs, paralysis and vision impairment.

In order to study MS, researchers often employ the use of animal models. Specifically, Experimental Autoimmune Encephalomyelitis (EAE) is a well recognized mice model that mimics the progression of MS. EAE is considered a Th1 focused disease with T cells secreting primarily IFNϒ. T cells are immune cells in the body that participate in cell-mediated killing of foreign pathogens (1). In MS, they recognize our myelin as a foreign substance and proceed to destroy it. One way they do this is by secreting cytotoxic cytokines, such as the aforementioned IFNϒ. When inducing EAE in mice, this Th1 response is ensured by injecting a myelin peptide(to mount an immune response against) along with complete Freunds adjuvant (CFA), which contains a bacterium called M. Tuberculosis (CFA).

Aside from IFNϒ, IL-23 has emerged as a notable cytokine because mice deficient for it remained protected against EAE pathology. Furthermore, IL-23 promotes the differentiation of inflammatory Th17 cells (2). Numerous EAE models currently exist; some more representative of MS in certain clinical regards (e.g., onset, clinical progression, and remission). Therefore, it’s vital to always explore new EAE models in an effort to find one that best represents human MS. In a recent study by Smith et al. 2011, researchers replaced M. tuberculosis with C. rodentium (CRA)in the injected adjuvant. CRA is a bacteria known to induce an IL-23 dependent Th17 response (as opposed to the aforementioned M.tuberculosis-mediated Th1 response) to find out whether different EAE phenotypes would emerge.

Regulatory T Cells in Patients with Whipple's Disease

Classical Whipple’s Disease (CWD) is a rare, multisystemic infection of the duodenal mucosa. Macrophages infected with Tropheryma whipplei, a gram positive bacterium, first attack the intestinal mucosa and then disperse throughout the body to the intestinal epithelium, capillary and lymphatic endothelium, synovium, heart, lungs, liver, brains, eyes and skin. Symptomatic manifestations are most commonly reported in the intestines, and include weight loss, diarrhea, and abdominal pain (Schijf et.al 394). Additionally, T.whipplei infection can spread to the brain and heart and cause inflammation of the heart muscle. [1]

Schinnerling and colleagues argue that host immune deficiency plays a major role in the persistence and systematic spread of CWD. The authors suggest that healthy adults generally display an efficient humoral, or antibody, and cellular immunological response that effectively combats T.whipplei. However, immunological defects are believed to weaken the immune response and enable the pathogen to successfully infect the host [2]. The defects present in the peripheral blood and the duodenal mucosa of CWD patient include, but are not limited to, impairment of T cell proliferation, and diminished Th1 reactivity.

T cells are a type of white blood cell that helps recognize and eradicate invading pathogens that cause disease. Th1 cells are a brand of T cells that specialize in intracellular pathogen disposal. Specifically, Th1 cells secrete IL-2, IFN­-y, and LT, which are cytokines, or signaling chemicals, that initiate a robust inflammatory response. A Th1 response is generally avoided in mucosal tissues because inflammation is an aggressive immune response that can damage the delicate tissue of the mucosa. Consequently, a Th2 response is initiated in the mucosa to avoid cell damage and effectively combat extracellular pathogens. Th2 cells secrete cytokines, such as IL-4, IL-5, and IL-10, to suppress a Th1 response and initiate antibody production. Antibodies neutralize pathogens without damaging surrounding host cells [3].

iNKT Cells Protect Post-Stroke Patients from Infection

Stroke is the second leading cause of death in the Western world after heart disease (Donnan et al. 2008). The medical condition is characterized by the rapid death of brain cells in a localized area due to inadequate supply of oxygen. There are two types of strokes: ischemic (lack of blood flow) and hemorrhagic (leakage of blood). Increased susceptibility to infection is the major cause of death that results from stroke (Kimura et al. 2005; Langhorne et al. 2000). The main mechanism behind the increased susceptibility seen in post-stroke patients is immunosuppression. If you think about this situation from the brain’s perspective, it makes a lot of sense for the body to promote immunosuppression after an ischemic attack because this protects the post-ischemic brain from tremendous inflammation. However, there is always a catch. Although the brain is protected from inflammation, post-stroke immunosuppression leaves the body prone to infection. The mechanism behind the observed immunosuppression is not well established. However, a recent study by Wong et al. (2011) reveal the role of invariant NKT (iNKT) cells in the immunosuppression process. NKT cells are a type of T cell that shares characteristics with both T cells and natural killer cells. NKT cells express both an αβ T cell receptor and molecules associated with NK cells. iNKT cells are so called invariant because they possess the invariant T cell receptor α chain. Many iNKT cells recognize the CD1d molecule, which binds self and foreign lipid antigens. iNKT cells are also primarily located in the liver and the spleen

In the study, Wong et al. used a rodent model of stroke called midcerebral artery occlusion (MCAO) in order to mimic the condition of stroke. Normally, iNKT cells move through the hepatic blood vessels. However, when they are activated by CD1d ligands, their movement is restricted. Using intravital spinning disk confocal microscopy, a technique that allows researchers to study living blood vessels in the context of inflammation and coagulation, the authors examined the movement of the iNKT cells both before and after inducing stroke in the animals. They found that after stroke, there was a significant reduction in the movements of iNKT cells and an increase in the number of stationary iNKT cells. These results suggest that brain injury is capable of changing the movement behavior of iNKT cells.