Your Guard Against Microscopic Freeloaders.

MECHANISM OF INFLAMMATORY RESPONSE

We are born with a natural barrier that does not distinguish between different pathogens, this barrier is known as the first line of defence. It includes Physical barriers such as skin, mucous, hair and cilia, Physiological barrier which includes Fever, Gastric acid, Saliva and Tears and Phagocytic barrier which includes the action of phagocytes. The reaction of tissues to an injury or localized invasion of pathogens trigger inflammation which involves a series of vascular, cellular and molecular events

STEP-1 (PATHOGEN DETECTION)

i) MAST CELLS

These are present in the connective tissue and are earliest to respond. The Mast cells have receptors on the surface which can detect the presence of the Endotoxins released by the Pathogen. Mast cells, in response, release many signalling molecules among which histamines and Leukotrienes are the most abundant.

ii) TISSUE DAMAGE

The Endotoxins released by the pathogen damage the cell. Phospholipids present in the cell membrane of the damaged cell are utilised by an enzyme called Phospholipase A2 (PLA) which breaks down the phospholipids into Arachidonic acid. Upon enzymatic action, it converts into Inflammatory mediators bringing the inflammatory response.

STEP-2 (VASODILATION)

Inflammatory mediators bind to the receptors present on the smooth muscle cells present in the vicinity of capillaries, signalling them to relax. This allows the blood vessels to widen. This process is important, as it slows down the blood flow and allows the interaction of leukocytes with the vascular endothelium. These mediators also signal endothelium cells to contract to create spaces between them from where plasma can leak out. The accumulation of fluid in the interstitial space causes oedema or swelling and often results in pain.

STEP-3 (EXTRAVASATION)

i) ROLLING ADHESION

Inflammatory mediators stimulate the endothelial cells to start expressing P-selectins. These P-selectins interact with Mucin CAM present on the surface of any leukocyte (eg-Neutrophil). The type interaction between them is weak making it possible for them to rollover from one P-selectin to another.

ii) ACTIVATION

CXCL8 is secreted by the endothelium cells which activate the Neutrophils to express integrins

iii) TIGHT BINDING

This type of interaction relies on integrins present on leukocytes and ICAM-1/ ICAM2 present on the endothelium. This type of interaction is relatively firmer, stopping the rolling motion

iv) DIAPEDESIS

The leukocytes make their way out of the capillaries by squeezing through the walls. This further involves the interaction with PCAM's which facilitates the process.

https://www.youtube.com/watch?v=R8VzquHdwZw

v) MIGRATION

Leukocytes move along the concentration gradient of chemokines which are produced at the site of infection. This is known as positive chemotaxis. Upon pathogen detection, Macrophages secrete Interleukin-1 (IL-1) and Tumour Necrotic Factor Alpha (TNF-α). They stimulate endothelial cells to start expressing E-selectins. Allowing further movement of leukocytes towards the site of infection.

STEP-4 (FEVER)

Interleukin-1 (IL-1) and Tumour Necrotic Factor Alpha (TNF-α) migrate to the Hypothalamus, stimulating it to secrete a molecule called PGE2 which increases our body temperature.

STEP-5(PHAGOCYTOSIS)

Phagocytosis is a process in which particle-like solid substance, especially pathogens, are engulfed by phagocytes. This is the step, which involves the killing of the pathogen and is by far the most important one.

i) RECOGNIZING THE PATHOGEN

Phagocytes are equipped with Pathogen Recognition Receptors(PRR's) which play a crucial rule in recognizing a pathogen. PRR's can identify general patterns of molecules present on the surface of a pathogen called Pathogen-associated molecular pattern(PAMP's) which gives them the ability to differentiate between somatic cells of the body and pathogens. PAMP's are conserved within a group of microbes, for example, Bacterial lipopolysaccharides(LPSs) found on the cell membranes of gram-negative are considered to be the prototypical class of PAMPs. The interaction of PAMP's and PRR's trigger the phagocytes to initiate engulfing the pathogen.

ii) INGESTING THE PATHOGEN TO FORM PHAGOSOME

After the pathogen has been recognised, the phagocyte binds to the surface of the pathogen using molecules present in the blood plasma. Then, the plasma membrane of the phagocyte extends from either side until the pathogen has been completely surrounded and internalised inside a vesicle called the phagosome.

iii) FORMATION OF PHAGOLYSOSOME AND RESIDUAL BODY

One of the lysosome present inside the phagocyte, containing digestive enzymes, fuses with the phagosome to form Phagolysosome. The action of enzymes such as Proteases breaks down the pathogen, thereby killing it. The antigens still remain intact in Phagolysosome and does not get digested. The vesicle is now called the Residual body.

In case, the pathogen is resistant to digestive enzymes the phagocyte forms free radicals that are more effective in causing cause more damage to the pathogen. However, it may also cause damage to the phagocyte as these free radicals are not specific. So, in a way, the phagocyte sacrifices itself to kill the pathogen. This process is called an Oxidative burst.

v) ANTIGEN PRESENTATION BY MACROPHAGE

In case the phagocyte is a macrophage which is one of the antigen-presenting cells, it can present the antigens on its surface. It does so by building the MHC class II ( Major histocompatibility complex) complex my manipulating chromosome number 6 to rearrange itself and form a protein complementary to the antigen. Now, on the MHC class II formed, it presents the foreign antigen.

v) EXOCYTOSIS

In case the phagocyte is not a Macrophage, the membrane of Residual body fuses with the plasma membrane of Phagocyte to open a passage for antigens to exit back into the interstitial space. From the interstitial fluid, these antigens enter the lymphatic system.

ACQUIRED IMMUNITY

Is a slower, but long-lasting response. It is activated to support our innate immune system. It is specific and involves the production of immunological memory. The major cells involved are T cells which are involved in cell-mediated immunity, and B cells which are primarily responsible for humoral immunity. Both their actions are triggered by the presence of antigens. B-Lymphocytes also known as B-cells are produced in the bone marrow and then travel to the spleen where they get matured. T- Lymphocytes also known as T-cells are also produced in the bone marrow, but travel to Thymus gland for maturation.

i) HUMORAL IMMUNITY

In this type of immunity which involves antibodies and is mediated by macromolecules such as antigens.

STEP-1( B-CELL ACTIVATION)

When a naive B lymphocyte comes in contact with the antigens flowing in the interstitial fluid of lymphatic vessels, it gets loosely bound to the receptors present on the surface of B cells. By, receptor-mediated endocytosis, this receptor- antigen complex will enter the cell. The antigen is processed and presented on the B cell's surface by MHC-II proteins.

STEP-2( B-CELL PROLIFERATION)

B cell will bind to the helper T cell making them active. The active helper T cell releases cytokines such as (Interleukin-4 and Interleukin-5) which stimulate B cells to divide and proliferate into two types of cell.

1- Memory cells

Which remain inactive, and can survive for decades. In case, the same pathogen attacks again they provide a robust antibody-mediated immune response.

2-Plasma cells

Which produce antibodies and release them into the circulatory system. These antibodies when encounter antigens on the surface of the pathogen, bind to every single one of the antigens and prevent them from attaching to any host cell (Neutralize). Antibodies also attract Macrophages to phagocytose the pathogen.

ii) CELL MEDIATED IMMUNITY

This immunological response occurs in three phases and involves T- lymphocytes which are of 3 kinds-

A) Helper T cells- not only activate B-cells but also the B) Cytotoxic T cells, which mainly target Tumour cells or cells infected with the virus. C) Regulatory T cells- Deactivate the Cytotoxic T cells after they have performed their task.

PHASE-1 (ACTIVATION PHASE)

The MHC-II receptor presents the antigen on the surface of the macrophage which binds to T-cell receptor (TCR) of T- helper cell. This interaction causes macrophage to release IL-12 which causes T helper cell to make IL-2 receptor and also release IL-2 which acts on other T helper cells activating them along with itself. As a result of this interaction, the T helper Lymphocyte releases to important chemokines-

i) TNF-γ which confirms the binding with macrophage,

11) IL-1 which activates Cytotoxic T cells and induces its proliferation.

PHASE-2( EFFECTOR PHASE)

On the infected cell, MHC-I proteins present the antigens of the virus. The cytotoxic cell identifies the antigens presented on the cell and binds to it, releasing chemical perforin which perforates the membrane of the infected cell causing it to burst.

PHASE-3( REGULATORY PHASE)

Regulatory T cell deactivates the cytotoxic T cell after the viral infection has been brought under control.