Specific Immune System

The specific immune system is important as there are many instances where the innate immune system needs help in recognising and responding to pathogens. Many pathogens have developed ways of avoiding detection by the innate immune system. This is where the specific immune system is required to provide greater detection of pathogens. The specific immune system contributes to fighting a pathogen by producing antibodies and producing cytotoxic T cells, both of which are specific to the antigens on the invading pathogen. Both the creation of antibodies and cytotoxic T cells rely on T helper cells.

Lymphocytes are continuously being recirculated through the blood, lymphatic vessels, lymph nodes, spleen and MALT. They circulate through the body several times a day, spending the majority of their time in the lymph nodes and spleen. The purpose of this extensive recirculation is to maximise their chances of coming across an antigen that matches their T cell receptor (for T cells) or antibodies (for B cells).

It can take 3-5 days before there is a specific immune response to a pathogen that is invading for the first time. For this reason, once the pathogen is cleared, memory B cells and T cells continue to circulate that are specific for that antigen so that a much faster response can be made on a subsequent exposure. This is called immune memory, and is the principle behind why we give vaccinations.

Antigens

Antigens are the basis of the specific immune system. They are molecules found in any organism that can be recognised by antibodies and T cell receptors and stimulate an immune response.

They can originate from pathogens (e.g. bacteria or viruses), other organisms (e.g. in pig or human transplants) or from part of the person’s own body (e.g. in autoimmune disease).

There are millions of possible antigens, all of which the immune system has to account for.

T-cell Receptors

• T cells recognise antigens using a specific type of receptor called the T-cell Receptor (TcR)
• The base of the TcR is connected to the surface membrane of the T cell
• The end of the TcR have a “variable domain“
• This variable domain is randomly generated for each T cell during their development, and has the potential to have millions of different shapes
• All of the TcR on each T cell are identical in shape
• The different shapes of the variable domain on different T cells have the potential to perfectly match antigens
• Therefore, millions of different T cells exist that have the potential to match millions of different antigens
• T cells can’t recognise free floating antigens, they require the antigen to be presented to them by major histocompatibility complex molecules on the surface of other cells.

Major Histocompatibility Complex

This is a molecule that sits on the surface of cells that the cell can use to present antigens to T cells.

Specifically in humans, this molecule can be called Human Leukocyte Antigen (HLA). You will come across this in diseases where specific variants of HLA are higher risk of certain conditions, such as HLA B27 and ankylosing spondylitis.

The reason the words “histocompatibility” and “antigen” are used to describe this molecule, is that there are many shapes that this molecule can take. Each human has their own specific shape of MHC coded for by over 100 genes, and this forms the main reason why you will reject organs transplanted from another person or species. The closer the recipients MHC type is to the donor, the less likely the organ will be rejected.

There are two types of MHC molecules:

Class I MHC molecules:

• Found on almost all cells with a nucleus
• Present antigens that come from within the cells (i.e. from a virus that had infected and is replicating within the cell)
• Recognised exclusively by CD8 cells
• This allows CD8 cells to recognise almost any cell that has been infected with an organism and destroy it

Class II MHC molecules:

• Found mostly on dendritic cells, macrophages, monocytes and B cells
• Present antigens that come from outside the cell
• The cells pick up material from outside the cell, digest it and present the antigens on the Class II MHC molecules.
• Recognised exclusively by CD4 cells
• This allows the relevant immune cells that have come in to contact with pathogenic material to transport it and present it to CD4 cells that can then respond as T helper cells
• You wouldn’t want CD8 cells to recognise this, as it would lead to destruction of non infected cells

Activating CD4 Cells

• Activation of CD4 cells is the first step in activating the specific immune system.
• Dendritic cells are specialists at recognising pathogenic material, absorbing it and presenting it on their Class II MHC molecules
• Once activated, dendritic cells leave the tissues, enter the blood and travel to the lymphatic tissue
• They enter the paracortex in lymph nodes or the PALS in the spleen and search for the relevant CD4 cells that matches the antigen they are displaying
• Dendritic cells also wait in these areas for free floating antigens that they can pick up and display for CD4 cells

CD4 and T Helper Cells

• Once CD4 cells are activated, they proliferate like mad. This stage lasts a few days.
• They then differentiate into T helper cells.
• There are two types of T helper cells, called T helper 1 (Th1) and T helper 2 (Th2) cells. They release different cytokines that play different roles in the immune system.
• Both types of T helper cells are responsible for stimulating B cells displaying the antigen on their MHC class II molecules to proliferate and differentiate by releasing cytokines. The antibody class they differentiate into depends on the type of T helper cell.
• T helper 1 cells are responsible for:
  • Simulate B cells to produce IgG
  • They secrete IL-2, which stimulates the proliferation and differentiation of other CD4 and CD8 cells
  • They play an important role in CD8 cells recognising antigen, proliferating and differentiating into cytotoxic T cells
  • They travel to the site of infection and release cytokines that stimulate the recruitment and differentiation of monocytes into macrophages, and the activation of macrophages. This is called the “delayed type hypersensitivity reaction“.
  • Are responsible for delayed-type (Type IV) hypersensitivity reactions
• T helper 2 cells are responsible for:
  • Stimulate B cells to produce all antibodies, but notably more IgE.
  • Travel to the site of infection and release cytokines that stimulate the recruitment and activation of mast cells and eosinophils.
  • T helper 2 cells are important in parasitic infections and in type 1 hypersensitivity reactions (allergy) and asthma

CD8 and Cytotoxic T Cells

• Dendritic cells pick up antigenic material, display it on MHC class I molecules (as well as class II) and travel to lymphatic tissue
• Dendritic cells are unique in that they are able to display antigens on class I molecules without being infected with the pathogen
• This is recognised by CD8 cells that have TcRs specific to that antigen
• These cells then undergo dramatic proliferation and differentiation into cytotoxic T cells specific to that antigen
• T helper cells play a important (often essential) role in the process

Cytotoxic T cells are essential for the destruction of cells that have been invaded by pathogens (e.g. viruses). This is because once inside a cell, pathogens are essentially hidden from antibodies and other cells, which is why cytotoxic cells are so important. The infected cell will process antigen from the invader and present it on Class I MHC molecules on it’s cell surface so that the cytotoxic T cell knows it has been invaded and can destroy it. They destroy infected cells by two mechanisms:

1. “Granule exocytosis”, where they spray the infected cell with enzymes that destroy the membrane and cause cell lysis and death.
2. By activating the Fas molecule. The Fas molecule is like a self destruct switch, that once activated causes the cell to undergo apoptosis.

Antibodies

Antibodies are also known as immunoglobulins.

They are complex molecules made up of two heavy chains and two light chains arranged in a Y shape.

The bottom of the Y contains the “Fc portion”, and this remains the same amongst all antibodies. This portion is used for binding to cells of the immune system. It binds on the cells Fc receptor (FcR).

The top of the Y contains the “variable region”. This section has millions of possible configurations, with the intention of being able to match a specific antigen. This is very similar to the variability on the TcR.

Antibodies come in 5 different classes:

• IgA
  • This is heavily secreted in mucous to protect mucous membranes from infection, such as in saliva, respiratory secretions and breast milk.
  • In blood it has the simple Y structure.
  • In secretions it the Ys attach at the Fc portion in pairs.
• IgD
  • IgD is found on B cell membranes, and is unstable and doesn’t last long when secreted into the blood.
• IgE
  • IgE is found in only low levels in the blood.
  • In the blood it has a simple Y structure.
  • It is important in asthma and allergy, and measuring specific IgE to allergens (e.g. peanuts) can give an indication about a person’s allergy status.
• IgG
  • This is the most common antibody in the blood.
  • Measuring IgG is useful to detect a patients immunity to a condition (e.g. response to a vaccine or having previously had a condition such as chickenpox).
  • In the blood it has a simple Y structure.
• IgM
  • This is the first antibody produced in an acute infection.
  • Measuring IgM gives a good indication of an acute infection, as it tends to disappear once the infection is going (unlike IgG).
  • In the blood it has a snowflake appearance, with 5 molecules combined at their Fc portion.

B Cells

• B Cells use antibodies on their surface membranes to recognise antigens from pathogens.
• These surface antibodies are either IgM (most often) or IgD.
• Each B cell has only antibodies specific to one antigen. For example, if you chose one B cell at random from within a lymph node, it may have antibodies that are only useful to a specific antigen that is found on a specific bacteria that only exists in some remote part of the world, or may never exist. That specific B cell will never encounter than antigen, and so it is never able to contribute to the immune response. Alternatively, you may choose a B cell that has the antibody for and antigen on a virus that causes a common cold, and when the person picks up that specific virus, that B cell multiplies furiously and becomes essential to the immune response for fighting off the immediate infection and protecting against that virus in the future.
• B cells sit in lymph nodes, spleen or MALT and pick up antigens that are specific to their antibodies. They then process that antigen and present it on their MHC class II molecules. T helper cells that are specific to that antigen can then recognise them and will be stimulated to produce cytokines that activate the B cell.
• Once activated by antigen and T helper cells, they undergo differentiation and become either plasma cells or memory B cells. This happens in germinal centre of lymph nodes, the spleen and MALT.
• Differentiation into plasma cells involves changes within the cell that
  • Make the antibody even more specific to the antigen it has encountered. This is called “affinity maturation“.
  • Chooses whether to produce IgA, IgE, IgG, IgM or IgD and from then on can only secrete one of these. This is called “antibody class switch“.
  • Starts to produce vast amounts of antibodies

• Memory B cells also undergo affinity maturation and antibody class switch,. They don’t produce as much antibody but live a very long time. Their role is to stick around after the acute infection, so that in the event of an infection with the same organism again they can respond much faster.

The Function of Antibodies

Antibodies help the immune system fight off an infection in a variety of different ways:

1. Antibody-antigen complexes activate the classical pathway of the complement system.
2. Antibodies can attach themselves to enemy toxins (which are themselves antigens) and neutralise their toxic effects.
3. Antibodies can attach themselves to the receptors of viruses and bacteria preventing certain functions of that pathogen. For example, it can stop viruses from recognising cells it may want to invade, therefore preventing viral invasion. It can bind to receptors in the bacterial cell wall that are important for allowing the bacteria to take in essential nutrients, therefore starving the bacteria and reducing its pathogenicity.
4. Antibodies can attach themselves to pathogens, then clump together to slow the spread of the pathogen down. This is called agglutination.
5. Antibodies can act as opsonins, attaching themselves to pathogens and making it easier for phagocytes to recognise and destroy pathogens that may have otherwise escaped recognition by the primitive measures of macrophages or neutrophils.
6. “Antibody-dependent cell-mediated cytotoxicity“. Antibodies can attach themselves to pathogens or abnormal cells and are then recognised by natural killer cells, neutrophils, macrophages or eosinophils that then kill the pathogen.