Table of Contents
The Immune Response
Immune responses are classified into innate and adaptive immunity. Innate immune system is nonspecific to infectious agents and consists of mechanisms and molecules which have a rapid response to infection.
Whenever there is potential microbial or viral infection, innate immunity acts as the first line of defence. Innate immunity is inherent to an individual and does not have any memory to respond to the infection. Earlier exposure to any particular antigen does not alter the response.
Innate immunity is made up of physical, chemical and biological barriers in the form of specialized cells and soluble molecules. Physical barriers include skin and mucous membranes.
These collectively identify the potential threat i.e. the microbial or viral infection and consequently, the innate immune system cells and complement system are activated for effective elimination of invading pathogen and its products.
The main effector cells, which include neutrophils, macrophages, dendritic cells and natural killer (NK) cells, rapidly reach the site of infection or tissue damage and cause resolution of infection and tissue repair. However, the innate immune system does not confer long lasting protection.
PRR: Pattern Recognition Receptors
PRRs are receptors of innate immune system that are on a lookout for pathogenic infections. PRRs are protein molecules encoded in the human genome that cannot be changed throughout the lifespan of any individual and are mainly present on important immune cells like macrophages and dendritic cells.
PAMPs are pathogen associated molecular patterns while DAMP stands for damage associated molecular patterns. Both are highly conserved motifs derived either from pathogens (PAMPs) or self-molecules (DAMPs) respectively.
PAMPs lead to cytokine and chemokine production in response to a pathogenic infection. Through an assortment of proteins and by recognition of PAMPs, PRRs can activate inflammation, clotting and complement pathways, opsonisation and apoptosis induction.
On the other hand, in case of certain autoimmune diseases, acute myocardial infarction, atherosclerosis and cancer, sterile inflammation is induced by the release of DAMPs. These are endogenous molecules which are released following tissue injury or tissue stress.
PRR are divided into 3 categories: cellular (e.g. CD14, MARCO), intracellular (e.g. NODs, PKR) and soluble forms (e.g. C-reactive protein, mannan-binding lectin). Cellular receptor is able to respond to all bacteria having common components in their cell walls and not to any protein specific to any single micro-organism.
There are many receptor families (PAMPs), and diverse receptors in every family strengthen the innate immune response and decrease chances of pathogen evasion. These receptors are capable of bringing about a synchronized reaction to pathogenic infection due to extensive communication among different signalling pathways.
Toll-like receptors (TLRs), C-type lectin receptors (CLRs), cytosolic NOD like receptors (NLRs), RIG-I-like receptors (RLRs), AIM2-like receptors (ALRs) make up the multiple families of PRRs.
Pro-inflammatory cytokines, chemokines and antiviral molecules are expressed as a result of triggering of the intracellular signal transduction cascades due to recognition of ligands by PRRs.
In contrast, multiprotein inflammasome complexes are formed due to activation of some ALRs and NLRs, which in turn provide a platform for cleavage and activation of caspase-1. A rigid regulation of PRR signalling is necessary for elimination of pathogens and simultaneous prevention of excessive PRR activation as it can cause autoimmune and inflammatory disorders to develop.
Innate Immune Signalling Overview
Activation and signalling of PRR is a multifactorial intricate process resulting in comparable outcomes. Due to activation of PRR, proteins undergo conformational changes and intracellular signalling pathways are activated leading to amplification of signals and initiation of innate immune response. Signalling complex assembly is dependent on the specific adapter proteins which further engage various signalling components. Activation of PAMPs by PRRs takes place.
Endogenous ligand molecules like ATP and heat shock proteins are known as damage associated molecular patterns (DAMPs). PRRs use specific adaptors and different adaptor proteins result in the activation of different signalling pathways. e.g: family transcription factors NFκB (Nuclear Factor kappa B) and IRF (interferon regulatory factor) upregulation; mitogen-activated protein kinases (MAPK) i.e. stress kinase pathways stimulation; and caspase-1 activation.
Eventually, the pro-inflammatory cytokines, chemokines and anti-viral proteins are upregulated.
An inflammasome is basically a high molecular weight complex which leads to activation of inflammatory caspases and cytokines of the interleukin-1 family. Inflammasomes act as immune guardians of the cytosol, which in turn acts as a watch guard by identification of intracellular pathogens with the help of PAMPs. Multiprotein inflammasome complexes are formed due to activation of some ALRs and NLRs which provide a platform for cleavage and activation of caspase-1.
The actions of inflammasomes have been implicated in an immediate inflammatory response, both physiological and pathological. The cells of the innate immune system secrete mature forms of caspase-1 and interleukin-1β (IL-1β) which is characteristic of the activation of the inflammasome.
Sensor proteins containing various inflammasomes have been described, those being NLRP1 (NALP1), NLRP3 (NALP3), IPAF (NLRC4), NLRP6 (NALP6), NLRP12 (NALP12), RIG-I and AIM-2 (absent in melanoma 2). Asc (apoptosis-associated speck-like protein), an adapter protein is necessary in most of the inflammasomes for the purpose of recruitment of caspase-1 to inflammasome complex.
There is cleavage and activation of caspase-1 when there is binding to the inflammasome. Thus, its different targets are cleaved which leads to maturation and secretion of pro-inflammatory IL-1β.
Activation of inflammasomes can take place due to several different signals like bacteria and microbial toxins, xeno-compounds, cytoplasmic pathogen-associated molecular patterns (PAMPs) and/or endogenous danger signals (DAMPs).
Beneficial or harmful inflammatory responses are associated with the inflammasome activity. Maintenance of homeostatic tissue function gives rise to beneficial responses while sterile inflammation due to host-derived particles like monosodium urate (MSU) crystals (involved in the pathogenesis of gout) and environmental particles like asbestos, silica as well as metallic nanoparticles (involved in lung inflammation) lead to harmful inflammatory responses.
Activity of inflammasomes is also concerned with several erstwhile diseases like cancer and metabolic diseases (such as type 2 diabetes, atherosclerosis), certain neurodegenerative diseases (such as Parkinson, Alzheimer, Prion), autoimmune diseases (like multiple sclerosis) along with inflammatory bowel diseases.
Acute Phase Inflammatory Response
Inflammare in Latin means to set on fire and it is usually self-limiting and controlled. Acute phase inflammation is an immediate, short duration inflammatory response of a tissue to injury that involves host cells, blood vessels as well as proteins.
Acute inflammation can be considered as the first line of defence against injury. Changes in the microcirculation, which include fluid exudation and leukocyte emigration from the blood vessels to the area of injury, are the hallmark of acute inflammation. Acute inflammation takes place prior to establishment of the immune response and it is mainly intended at removal of the injurious agent.
Acute inflammation leads to elimination of early causes of cell injury and removes necrotic cells as well as necrotic tissues. It also causes the initiation of repair, which may be potentially harmful.
Inflammatory components that cause the destruction of pathogenic microorganisms can also destroy the normal bystander tissue. White blood cells as well as plasma proteins are the components of inflammatory process. These are carried to the site of infection or tissue damage. Production of chemical mediators like cytokines leads to induction of inflammation.
Various stimuli of acute inflammation are:
- Bacterial, viral, fungal, parasitic infections
- Microbial toxins
- Tissue necrosis due to ischemia, trauma, physical or chemical injury like thermal injury, irradiation or certain environmental chemicals
- Foreign bodies like splinters, dirt, sutures
- Immune reactions or hypersensitivity reactions
Cardinal signs of acute inflammation
Clinically, there are five cardinal signs that are the hallmark of acute inflammation:
- Rubor (redness)
- Calor (increased heat)
- Tumor (swelling)
- Dolor (pain)
- Functio laesa (loss of function).
The first four signs were described by Celsus while the fifth one was added later by Virchow.
Consequences of acute inflammation
In case of an acute inflammatory response, various natural anti-inflamatory factors are released. These include cytokines, protease inhibitors, antioxidant enzymes, lipoxins, glucocorticoids, kinases, phosphatises and transcriptional factors.
By and large, the cytokines are pro- or anti-inflammatory factors. Equilibrium between these factors decides the result of an inflammatory response. Pro-inflammatory cytokines, such as IL-1β, IL-8 and IFN-γ are implicated in early inflammatory response as well as amplification of inflammatory reactions whereas IL-4, IL-10 and IL-13 are anti-inflammatory cytokines that lead to limitation of inflammatory responses.
Chronic inflammation as the name suggests is of a longer duration. It occurs when the preliminary acute inflammatory response cannot eliminate the inflammatory agent. It is necessary to measure the effects of different cytokines in order to understand the communication amongst the inflammatory cells.
This inflammatory process involves the lymphocytes, plasma cells and macrophage infiltration. These inflammatory cells lead to tissue destruction. Resolution of the inflammation takes place by fibrosis and angiogenesis.
Chronic inflammation, if unresolved, is a central component of various chronic conditions such as autoimmune diseases as well as neurodegenerative diseases. Examples include tuberculosis, silicosis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Alzheimer’s disease and cancer.
An imperative element of the innate immune system is the complement system, that confers protection particularly against the invading infectious agents like bacteria, viruses and protozoa.
Using different complement pathways, it produces biologically active products. These result in pro-inflammatory mediators which bring in the PMNs and lead to production of opsonins and lytic factors for bacteria as well as nucleated cells. Opsonins promote phagocytosis.
The three pathways of complement activation are the classical pathway, alternative pathway and lectin pathway. The complement system is made up of a complex of different proteins. 9 different proteins have been recognized, namely C1 to C9.
C1 is a heat labile component that forms the major bulk of the complement system and consists of 3 sub-proteins, C1q, C1r, C1s which are bound together by calcium. C2 is also a heat labile component whereas C3 is a heat stable component that has an ability to combine with yeast cell wall and leads to its inactivation.
C4 is a heat stable component that is inactivated by ammonia and hydrazine. C5 to C9 are the components that cause cell lysis by punching holes in the cell membrane thereby leading to impairment of function. C5 to C9 are the terminal components of classical as well as alternate pathway.
Classical pathway is dependent on 9 proteins acting in a sequence. It is activated when IgM or IgG combine with the cell membrane in the presence of complement. Alternate pathway bypasses the activation of C1, C4 and C2 and directly activates C3.
The binding of C3b to antigen-antibody complexes, antibody sensitized cells and viruses makes them adhere to cells that possess immune adherence receptors i.e. PML, macrophages, some B-lymphocytes, primate RBCs etc. C1-C5 also enhance the susceptibility to phagocytosis. Complement is also responsible for death of tumor cells.
Type I interferon response
Interferons are named so because they ‘interfere’ with viral replication. They were the first cytokines to be discovered.
The type I IFN family is made up of many IFN members, single IFN, and subtypes that are present in swine and ovine species in that order. Type I interferons induce antiviral responses by binding to a common receptor, the type I IFN/receptor (IFNAR) that is expressed on an extensive array of cell types. These are induced vary fast and perform a critical role in defense against viral infection. At every stage in the life cycle of the virus, they have a defensive role.
Type I IFNs not only induce proteins with their direct anti-viral effects but also regulate various aspects of the innate as well as adaptive immunity. Type I IFN promotes the survival and proliferation of NK cell by induction of production of IL-15. They upregulate the MHC surface expression and also that of CD80, CD86 and CD40.
Type I IFN activate naïve CD8+ T cells, and play a role in the survival of activated CD4+ as well as CD8+ cells along with the development and proliferation of B cells. In most cases, there is recognition of the viral infections by host PRRs that leads to type I IFN production.
When the viruses are recognized, various TLRs such as the TLR3, TLR4, TLR7, TLR8, and TLR9 as well as some intracellular PRRs like RIG-I and PKR produce type I IFN. There is induction of plentiful proteins on activation of PRRs that leads to triggering of complex signalling pathways.
Along with viruses, type I IFN production is also significant during bacterial infections and in the treatment of several malignant disorders such as myeloma, renal cell carcinoma, and melanoma.
NK cells activating and inhibitory response
Natural killer cells are large, non-phagocytic, granular lymphocytes that constitute 5–10% of total lymphocytes. They are not formed in response to Ag but are naturally present. Their action is non specific and they do not require Ab. They can kill a multitude of transformed and virally infected cells.
Their activity is increased by INF and interleukin-2. They cause cell lysis by release of cytolytic factors such as perforins, lymphotoxin, TNF and NKCF. NK cells are involved in an early response to infection by certain viruses and bacteria. They are essential for immune surveillance and natural defence against virus infected cells and malignant mutant cells.