Some pathogens, such as highly pathogenic H5N1 virus and human coronaviruses, can disrupt the balance between pro-inflammatory cytokines and anti-inflammatory cytokines and trigger life-threatening immune responses. This is achieved by a cytokine storm which is basically an excessive release of pro-inflammatory cytokines. The balance of pro and anti-inflammatory responses is important to maintain homeostasis in the immune system. If one or more of these mechanisms is suppressed or overactivated may lead to a cytokine storm. Using pathogenic human coronavirus (hCoV) infections, especially SARS-Cove, as an example, I will briefly discuss the cause and consequences of cytokine storm. hCoVs are RNA viruses which can cause infections in the respiratory and intestinal tract. Respiratory epithelial cells are its primary target. After successful virus invasion, virus replication will be initiated. Pathogenic hCoV such as SARA-CoV replicate in a very high speed early after infection compares with other viruses and leads to production of high levels of pro-inflammatory cytokines (e.g. IFN-γ and IL-1β) and chemokines (e.g. IL-8 and IP-10). In comparison, only a moderate increase in anti-inflammatory cytokine IL-10 production. The inflammatory immune response is unbalanced. This result in over induction of excessive amount of inflammatory cells, macrophages and neutrophil, infiltrated into the lungs. This leads to epithelial and endothelial cell apoptosis. Uncontrolled apoptosis of these cells will lead to severe damage in lungs and cause vascular leakage and alveolar collapse. Furthermore, the excess inflammatory cytokines and chemokines can enter the circulation and cause systemic cytokine storms. This may induce multiorgan dysfunction. Studies shown that several pro-inflammatory cytokines contribute to ARDS which is a major cause of death during SARS infection.
High pathogenic influenza H5N1 avian also generate cytokine storm but their mechanism to induce pathology is slightly different. They not only upregulated the level of pro-inflammatory cytokines but also upregulate the production of anti-inflammatory cytokines by innate and adaptive immune effector cells. Studies have found lung injury during H5N1 infection is immune-mediated. Zou and colleague's study in 2014 found that CD8+Foxp3+ Treg cells are significantly upregulated by IL-10 during H5N1 infection. While Treg cells suppressed CD8+ T cells, an enhanced viral load is observed in the lung. This suggests that CD8+ Treg cells promote H5N1 replication. Which results in multi-organ dysfunction and vascular leakage. As a result, mortality of the model animal increased.
Anti-inflammatory cytokines have an important role in regulating inflammatory responses. As discussed in the previous section, if not enough anti-inflammatory cytokines have been produced, the host will lose control of inflammatory responses and have systemic tissue damage. Studies have shown that upregulating of some anti-inflammatory cytokines by viruses can also cause severe damage to the host. Transforming growth factor beta (TGF-β) is a family of proteins secreted in a latent inactive form. TGF-β is a protein with complex functions, it can function as anti-inflammatory cytokines or pro-inflammatory cytokines based on many factors. For example, it can act as an anti-inflammatory cytokine in the presence of IL-10. Schultz-Cherry and Hinshaw’s study in 1996 showed that viral neuraminidase(NA) of influenza virus can directly interact with lantent TGF-β and activate it. The level of activation is positively correlated with the enzymatic activity of NA. TGF-β activated by the virus has the ability to induce apoptosis in non-infected cells and lymphocytes. When TGF-β is in high concentration, it induces the generation and maintenance of regulatory T cells differentiated form antigen-specific T cells and leads to immunosuppression before viral clearance. TGF-β has profibrotic effects and overproduction of it can lead to pulmonary fibrosis.
Upregulating anti-inflammatory cytokines will contribute to the persistence of viral infection. This is another complex process. In the acute phase of inflammation, inflammatory responses are rapid and only last a short period of time. If the infection is not resolved during that short duration, the inflammation becomes chronic. T cell exhaustion has been observed in various viral infections including Hepatitis B virus (HBV), human immunodeficiency virus (HIV) and LCMV, most of them cause chronic infection. This suggests that immune responses during high-grade chronic infection may induce T cell exhaustion which is a progressive loss of T cell functions and unable to induce the normal effector activities. Exhaustion can happen to both CD8+ T cells and CD4+ T cells. Several chronic infections are associated with increased level of immunosuppressive cytokine production. Some pathogens like EBV even encoded the IL-10 gene to negatively regulate the immune response. During persistent viral infection, IL-10 production starts early and the increased IL-10 production enhanced T cell inactivation. During chronic SIV infection study, partially exhausted virus-specific CD8+ T cells, which lose the ability to produce TNF-α and IL-2, contribute to its virulence.
The adaptive immune response is thought to be highly specific. However, in some special circumstances, heterologous immunity takes place.
Heterologous immunity described an altered immune response to one pathogen after the host has had exposure to another pathogen. These two pathogens may be closely related species, unrelated species or even from different groups of pathogens. For example, between bacteria and viruses. Mathurin and colleagues' study shows that in a mouse model, BCG immunization followed by antibiotic treatment will lead to partial resistance to infection with vaccinia virus. Heterologous immunity has the potential to be protective or pathogenic depends on the feature of individual pathogens. All most all types of immune cells are involved in the process. This process can be mediated by specifically cross-reactive T cells or antibodies. Why memory T cells, which should be specific to one pathogen, can recognise another unrelated pathogen? This is due to the fact that T cells recognise a very small fraction of the MHC-presented peptides and many pathogens may contain the same peptide sequence. These pathogens have the potential to be recognised by the T cell. These polyspecific T cells may alter the host's primary immune response. The new pathogen will activate mature antigen presenting cells and these cells will stimulate T cells with that similar epitope on the new pathogen in an efficient way (Fig 1B).
Many studies have shown heterologous immunity can enhance the clearance of a second unrelated virus at an early stage and the infections are normally subclinical. These studies suggested an overall benefit of heterologous immunity. However, there are also examples showing heterologous immunity cause severe tissue damage in the host body. Dengue viruses are one of them. Dengues viruses have four serotypes, and all four of them have cross-reactive T cell epitopes. When a host, who is immune to one strain of dengue virus, become infected with another strain, this may lead to severe symptoms such as dengue hemorrhagic fever and shock syndrome. What happened is cross-reactive T cells expand before the specific naïve T cells can take the response to the infection (adaptive immunity needs time to develop). The cross-reactive CD8+ T cells, however, have low affinity to the second strain of dengue virus and cannot effectively bind and kill the virus. Viral clearance slows down. Meanwhile, dengue serotypes are different enough to induce the of non-neutralizing antibody response. cross-reactive non-neutralizing antibodies binding to the viruses enhanced the infection of cells containing Fc receptors. This subsequently enhanced the viral load. With more viral RNA circulating in the blood, a stronger immune response will be triggered. This may result in a rapid increase in cytokine level in the blood and induce vascular lesion. The outcome of heterologous immunity varies and depends on the features of individual pathogens. Heterologous immunity may not be able to clear the second infection and lead to virus persistence even thought the T cell response is vigorous.
Tissue damage in the host body is normally tightly regulated by numerous cytokines and chemokines. Dysregulation of these factors can cost huge and result in severe tissue damage which may be life threatening. The immune response can be under-reactive or over-reactive and both of them are not good for the host's health in some circumstances. The dysfunction can happen in both acute immune response and chronic immune response. Immune response to a new pathogen can be altered by the adaptive immune response in heterologous immunity and has potential to cause harm.