Pakistanis scientists achieve a significant breakthrough in the fight against COVID 19. DOW university’s research team has prepared intravenous immunoglobulin (IVIG) with plasma obtained from recovered patients of coronavirus through which COVID 19 victims can be treated.

We heard a lot about this achievement by Pakistan. Let’s discuss below what is immunoglobulin.

Overview

• Immunoglobulin is also known as an antibody, which is a glycoprotein in nature and secreted by plasma cells (WBCs).  
• The immunoglobulin domain is a large, Y-shaped protein that consists of four polypeptide chains with two identical heavy chains and two identical light chains and connected by a disulfide bond
• There are 2 main forms of immunoglobulin; soluble Ig ( IgA, IgE, and IGG) and membrane-bound immunoglobulin ( IgD and IgM).
• There are 5 placental mammal antibodies isotypes known as IgA,  IgD, IgE, IgG, and IgM. 
• Intravenous immunoglobulin is a blood product derived from serums of between 1000-1500 individuals by the passive immunity process. It is a choice of treatment for peoples with immunodeficiency
• The therapeutic effects of IVIG go beyond antibody replacement in those patients with antibody deficiency.

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SIGNIFICANT BREAK THROUGH BY DOW UNIVERSITY OF HEALTH SCIENCES:

DOW University’s research team has developed intravenous immunoglobulin (IVIG) with plasma collected from recovered patients of coronavirus through which they can treat COVID 19 patients. Vice-chancellor of DOW University of health sciences Prof.Dr.Saeed Quraishy said it is a very important breakthrough in the war of COVID 19.

The team was able to get a first blood sample in March 2020 and managed to separate bodies chemically, purified it, and later concentrated the antibodies using the ultrafiltration techniques that eliminate the remaining rejected materials from the final product. This is the first global report of isolation, formulation, and safety demonstration of immunoglobulin purified from recovered COVID 19 patients and can be the light of string in this time of crisis when the whole nation expects national researchers to come ahead and serve the nation.

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The laboratory testing and safety trial of the formulated product which was done in animals has been successful. The principal of DOW College of Biotechnology Dr. Shaukat Ali and his efforting team deserves an appreciation by the government and local people. Still their drive to collect further blood donations is continued and in parallel they are working on scaling-up their production process.

Already six world-renowned multinational companies have joined hand to proceed in a similar direction to produce IVIG from recovered patients; in the regard DOW university has taken lead in developing the first local IVIG against the strain causing COVID 19 diseases in Pakistan.

Immunoglobulin:

Immunoglobulin is also known as an antibody, which is a glycoprotein in nature and secreted by plasma cells (WBCs).  They act as an immune response to a foreign invasion called an antigen, like viruses and bacteria. It works by recognizing, binding and neutralizing or burst the antigen. The antibody immune response is highly complex and excessively specific.

Structure:

 The immunoglobulin domain is a large, Y-shaped protein that consists of four polypeptide chains with two identical heavy chains and two identical light chains and connected by a disulfide bond. Ig domain contains about 70110 amino acids and categorized into different classes according to their size and function. The immunoglobulin protein domain consists of 2 layer sandwich with 7-9 antiparallel B- stands, arranged in two B-sheets. The Y-shaped protein consists of 6 regions;

• Fab region: also called as fragment antigen-binding. It is “arm” like a structure that recognizes and binds with a specific region. 
• Fc region: It is the base of Y, which plays a role in modulating immune cell activity and determines the antibody class effect
• Heavy chain: There are 5 types of mammalian Ig heavy chain which defines the class of antibody. firstly it is denoted by Greek letters like α, δ, ε, γ, and μ. Now, these chains are found in IgA, IgD, IgE, IgG, and IgM and heavy chains differ in size and composition.
• The heavy chain consists of two parts; a constant part which is identical in all immunoglobulin isotypes (but differ in Ig of different isotypes), and a variable part which is different in all Ig except those Ig which is produced by same B-cells.
• light chain: There are two types of Ig light chains, which are classified as lambda (λ) and kappa (κ). it is also consist of 2 domain; constant and variable and each antibody contains 2 light chains that always identical.
• paratope( antigen-binding site): It is an amino-terminal end and responsible for binding to an antigen.
• ginge region.

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 Isotypes :

There are 2 main forms of immunoglobulin; soluble Ig ( IgA, IgE, and IGG) and membrane-bound immunoglobulin ( IgD and IgM).

There are 5 placental mammal antibodies isotypes known as IgA,  IgD, IgE, IgG, and IgM. They have the same “Ig” prefix with different biological properties, function, location, and ability to deal with different antigens. The different suffixes of the immunoglobulin isotype indicate the different heavy chains.

• IgA:  it is the first line of defense against the antigen. It prevents the colonization of pathogens in the mucosal areas, like the gut, respiratory tract, urogenital tract. It is also found in saliva, tears, and breast milk. IgA has subclasses like IgA1, which found in serum and derived in bone marrow, and IgA2 which is a secretory form of IgA.
• IgD: It functions as a binding receptor on B cells and found in a small amount in blood serum. It activates antimicrobial effect by binding to basophils and mast cells as an immune response to pathogens.
• IgE: It plays a role in hypersensitivity reaction when it triggers histamine secret from basophils and mast cells for defense from allergens. It also provides immunity from parasitic worms.
• IgG: It is the most common type of antibody and representing about 75% of serum antibody. It is the only antibody which capable to cross the placenta to give passive immunity to the fetus. It has 4 subclasses of IgG. its main mechanism of action is compliment mediated destruction.
• IgM: It is present on the B cells and it eliminates pathogens in the early stage as primary immune response. Apparently, its basic function is to control B cell activation, as its large size gives good binding avidity.

How immunoglobulin work:

Neutralization: it is an antigen-antibody reaction in which antigen receptors is blocked by antibody and make it ineffective. This process can be reversible. 

Agglutination: It is an interaction between antigen and antibody in an equivalent proportion which results in the invisible clump, which are attractive targets for phagocytes.

Precipitation: It is a serum soluble reaction based on antigen and antibody which exist in optimal proportion and makes insoluble products like precipitation, which is also a sweet target for phagocytes. 

Complement activation or fixation: It is also called as complement cascade in which immune system enhanced or complement the antibody and phagocytes to clear pathogens and damage cell from an organism in two ways; 

1- lysis; breakdown 

2- inflammation by chemotactically.

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 Intravenous Immunoglobulin therapy:

Intravenous immunoglobulin is a blood product derived from serums of between 1000-1500 individuals by the passive immunity process. It is a choice of treatment for peoples with immunodeficiency and to treat a number of health conditions like;

• Autoimmune disorder –>dematomyositis, immune thrombocytopenia, and Kawasaki disease, Guillain–Barré syndrome.
• Secondary immunodeficiency → HIV
• Neurological disease→ multi-motor neuropathy, stiff person syndrome, myasthenia gravis.
• After acute and complication transplants.
• Acute infections like pediatric HIV

The clinical departments using a large amount of IVIg are neurology, hematology, immunology, nephrology, rheumatology and dermatology departments.

Mechanism of action:

one understandable mechanism includes the possibility that donor antibodies may bind directly with the abnormal host antibodies, stimulating their removal; the possibility that IgG stimulates the host’s complement system, leading to enhanced removal of all antibodies, including the harmful ones; and the ability of immunoglobulin to block the antibody receptors on immune cells (macrophages), leading to decreased damage by these cells, or regulation of macrophage phagocytosis. Indeed, it is becoming more clear that immunoglobulin can bind to a number of membrane receptors on T cells, B cells, and monocytes that are pertinent to autoreactivity and induction of tolerance to self.

 Some believe that immunoglobulin therapy may work via a multi-step model where they introduce immunoglobulin a type of immune complex in the patient. Once these immune complexes are formed, they can combine with Fc receptors on dendritic cells, which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state

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There are 3 routes of administration; intramuscular, intravenous, and subcutaneous. Intramuscular and subcutaneous are considered poor routes because of extreme pain and poor efficacy but subcutaneous would be secondary route choice while intravenous safe but have adverse side effects. 

Side Effects of Immunoglobulin Therapy:

Although immunoglobulin therapy is generally considered safe but can have severe side effects like;

• Localized side effects → Itching, redness, and hives around the injection site.
• Local side effects →  Increase heart rate, hyper or hypotension, diarrhea, nausea, abdominal discomfort, vomiting, myalgia, arthralgia, dizziness, severe headache, fatigue.
• Serious side effects → MI, tachycardia hyponatremia, hemolysis hemolytic anemia, thrombosis, hepatitis, anaphylaxis, meningitis, transfusion-related acute lung injury, etc.

Immunoglobulin therapy can also interfere with the natural ability of the body to produce a normal immune response, that can result in falsely elevated blood glucose level and interfere with IgG-based assays.

Uses of IV immunoglobulin

The therapeutic effects of IVIG go beyond antibody replacement in those patients with antibody deficiency.

Other users;

•  autoimmune, 
• infectious, and
•  idiopathic diseases. 

IVIG is an approved treatment for;

• multifocal motor neuropathy 
• chronic lymphocytic lymphoma
• chronic inflammatory demyelinating polyneuropathy
•  Kawasaki disease and ITP. 

How it is prepared?

Through this method immunoglobulin is prepared after separation of antibodies found in the blood of recovered patients from the corona. 

Steps of IV immunoglobulin;

• antibody proteins extracted from healthy blood donors
• Prepared immunoglobulin
• Infuse in in your veins by needle

This process only can be done in hospitals.

Outline 

Pakistan has lead the efforts against the novel coronavirus COVID 19 by first isolating the SARS-COV-2 virus by genome sequencing, then discovering human genes resisting the virus, and now has isolated and purified the antibodies composed of immunoglobulin’s fraction of the plasma of the recovered patients.