Have you ever wondered about your army? No, I am not talking about the army which is protecting our nation. I am talking about our body’s army. That is, Antibodies(Ab).
Why not read this article? After going through it, you will have fare idea about:
- Antibodies structure
- How are they produced?
- How do they mature?
- What are their types?
- How do they function?
Let’s move on.
First let us go through its structure briefly.
- There are 2 Heavy (H) chains and 2 Light (L) chains.
- H chains are coded by V (variable), D (diversity), J (joining) gene segments where as L chains are coded by V and J gene segments.
- There is a C (constant) portion that is involved with both chains.
- There are many disulfide linkages between both L-L and L-H chains.
- Fab region (ab- Antigen binding) – consisting Variable (V) and Constant(C) regions on both L and H chains.
- It has NH2 terminal.
- Fc region (c-crystallisable) – consists only Constant region.
- It does not contributed by L chain.
- It has COOH terminal.
- It has complement and macrophage binding site.
- In between both Fc and Fab region, there is hinge region which has 2 disulfide bonds between 2 H chains.
Before going ahead, we shall know about role of Fc portion by learning about Staphylococcus aureus (A#1).
A#1. S aureus: Beta haemolytic and gram, catalase and coagulase positive spherical shaped bacteria.
- Can cause pneumonia, endocarditis (inflammation of heart walls) and osteomyelitis (inflammation of bone that can later lead to avascular osteonecrosis i.e. bone tissue death without blood supply when infection spreads).
- S aureus has Protein A as an essential virulence factor which is found in its peptidoglycan cell wall.
- Mechanism of its infection is such. The protein A binds to Fc portion of IgG. This is the portion where macrophages and phagocytes bind, leading to phagocytosis (engulfing of the particles that are larger than 0.5 micrometer).
- Therefore, if the Fc portion is binding to Protein A, its unable to bind the macrophages and also to activate complement. This is how, S aureus infects as our immune system is unable to beat S aureus.
Q#1: Which is found more in human body, B-cells or genes?
A: The total numbers of B-cells are way more than the total number of genes (22300 to be exact, discovered in Human Genome project). On the other side, B-cells are said to be about 10 billion of different types.
So, how is that possible? Easy, by lying about the data!
The simple reason is that there is recombination during the Ab production. Let me elaborate:
- 1st there are more than 50 V (Variable) gene segments, more than 25 D (Diversity) gene segments and 6 J (Joining) gene segments. Now, just think if recombination occurs between these, just how many combinations there can be.
- Even more if the recombination is occurring randomly between H and L chains.
- Even even more if there is a DNA polymerase called TdT (terminal deoxynucleotidyl transferase) that randomly inserts nucleotides to V(D)J gene segments during recombination (A#2).
A#2. During V(D)J recombination: V, D and J genes are found on chromosome 14.
- First, any of the D and J genes are going to join together.
- Then, V gene will link with these.
- While doing this, unused genes will be spliced off.
- Therefore, at the end of mRNA of B-cells (remember Abs are produced by B-cells known as plasma cells), there will be only one gene of each of V, D and J genes.
- TdT polymerase adds nucleotides to gene segment during V(D)J recombination without template dependent manner unlike typical polymerases.
- This recombination provides them their vast diversity.
Now, do you think it is hard to have their number more than the genome itself? Definitely no.
So now, let us count the actual number of the recombination. No, no! We will not do that. It’s already enough.
Now, you may ask- ‘But Abs also show specificity towards the antigens.’ Yes, they do. And we are just going to discuss this now.
Their specificity is developed by isotype switching i.e. formation of different Ig and somatic hypermutation.
- In the arrangement of genes after J genes, there are C genes present that form the constant portion of the H chain. Such as there is first C-mu and then C-delta that produces IgM and IgD respectively.
- This is the reason that IgM and IgD are the first antibodies produced during immune response.
- During class switching, these genes are spliced off after which the genes that remains are for IgG i.e. C-gamma, IgA i.e. C-alpha and IgE i.e. C-epsilon.
- It is a mechanism that occurs after class switching (as we talked, activated B cells matures and proliferates into IgG, IgA and IgE.)
- In this, as the B cells continue to multiply, the mutations occur between the segments of V, D, J as they have highly mutated portions.
- This mutation causes some of the proliferated cells to have more affinity and some of them less. Cells with more affinity proliferate more, making that Ab more and stronger the affinity towards antigen. This is called Affinity maturation.
- Hence, making them more and more specific.
So, now we have understood how Ab’s types are formed. But what are those types? This brings us to the next question.
What are the types and functions of Ab?
First, let us go through their function in general manner. They don’t have any complex function. They basically perform 3 functions. These are-
- Neutralization- Ab after binding to pathogen like bacteria, prevents their entry into the host cells.
- Complement activation- They activate complement system that enhances opsonisation.
- Opsonisation- Ab operating as markers, binds to pathogen and calls out other immune defenses. After binding, they are then recognised by phagocytes hence promoting phagocytosis.
These were some general functions about Ab. Now about their types! As we talked, there is class switching.
1st Ab that are expressed are IgM and IgD on naïve mature B cells (A#3). Then as B cells differentiate into plasma cells (found in germinal centres of lymph nodes, a 2o lymphoid organ), they start forming IgG, IgA and IgE.
A#3. B cells: These are produced and mature in Bone marrow -> travel to spleen for final maturation into naïve mature B cells. Spleen, a 2o lymphoid organ is the site for antigen-antibody contact where Abs actually perform their activities.
- It is produced during the 1o i.e. immediate response to antigen while providing the time to humoral response (antibody-mediated response) to strengthen.
- It is a pentavalent Ab. Actually, it is present as monomer on B cell, which are joined as a single pentamer structure by a component know as J chain (a polypeptide) released by glandular and mucosal cells.
- Have excellent avidity (A#4) as it has 10 antigen binding sites.
- But low affinity (A#4).
A#4. Avidity: All antigen-antibody binding interactions.
Affinity: Individual antigen-antibody binding strength.
To understand clearly, imagine 2 persons. Person A with only 1 arm and Person B with both the arms. A is stronger relatively. So, A will have low avidity but more affinity and B will have more avidity but low affinity.
- IgD- Its actual function is yet not fully discovered but it is said to active B cells. To know more click here.
- IgG-It is the most common Ab found in the blood.
- It provides a strong 2o response against pathogens and neutralizes toxin.
- It is the only Ab that can cross placenta and provides passive immunity (readymade antibodies) to fetus.
- Also it has longest life, so after baby’s birth the Ig can still be seen for a few weeks.
- In other words, you can think about it as a Ig for fetus, where fetus requires Ig that can cross placenta and provides strong protection even after birth.
- It is a monomer when in circulation and dimer when secreted.
- It also contains J chain when crosses through mucosal epithelial cells.
- Its function is to protect the mucous membranes from bacteria or viruses as it coats the pathogen which later is washed away with mucosal secretions like tear, saliva or mucus.
- It is also found in breast milk/colustrum (mother’s first milk).
Q#2. You know that Ab are proteinaceous structure themselves. So how come, IgA are not digested by intestinal enzymes?
A. Because, it has a secretory component (A#5) from intestinal epithelial cells that protects it from proteases and acid.
A#5. Secretory component: When IgA gets into intestine. It enters into its epithelial cell via receptor, which enters into the cell itself along with the IgA. This is knows as by transcytosis i.e. various macromolecules are moved across the cell in vesicle. This receptor-IgA complex while being secreted to the luminal side of epithelial cell in intestine, gets cleaved i.e. proteolysed within the receptor molecule. Meaning, a part of receptor remains inside the epithelial and other part is still attached with the IgA, which is known as secretory portion. This component wraps around IgA dimer preventing its degradation.
- It binds to basophils and mast cells.
- When there is allergen exposure, it cross links and triggers cell activation causing them to release substances like histamine (an inflammatory mediator) producing allergic symptoms.
- Mediates Type I hypersensitivity reactions. For ex.- Anaphylaxis, a life-threatening allergic reaction that can lead to fainting and shallow breathing.
- Also mediates immunity to parasites by activating eosinophils (type of WBC).
So, this was all about Ab for now.
Before leaving out, let us go recap what we have learned.
- How many light and heavy chains and Variable, diversity and joining gene segments constitute the antibody structure?
- Name a gram positive, catalase positive, beta haemolytic bacteria that is the number one cause of osteomyelitis.
- Which antibodies are formed at first and provide non-specific protection against the microbes?
- Can pentameric antibody cross placenta to provide immunity to fetus?
- What is secretory component and its role?
Sometimes, in the near future I will be talking about more of Hypersensitivity reaction, complementary system. If you are interested, comment below. I will try to write about it as soon as possible seeing your support.