More pieces of the puzzle

An antigen is any material to which the immune system reacts. Antigens are usually foreign materials from invading micro-organisms, but can include foods and inorganic chemicals. Harmful immune responses to the body’s own molecules can sometimes occur. This is called autoimmunity. To prevent this, the immune system eliminates most auto-reactive cells.

Antibodies are a group of proteins made by B-cells. Each antibody recognises a specific antigen, like a lock and key. B-cells usually cannot produce antibodies without help from CD4 type-2 (Th2) helper cells. A B-cell is activated when its cell surface antigen-specific receptor recognises its specific antigen, causing production and release of specific antibodies as the B-cell proliferates.

T-cells also have specific antigen receptors on their surface. These are structurally related to antibodies. CD4 and CD8 on the surface of T-cells help the T-cell receptor bind to an antigen when it is presented to them.

At the heart of the immune system is the ability of lymphocytes to recognise and respond to substances called antigens, whether they are infectious agents or part of the body ('self' antigens).

When T-cells move from the bloodstream to the thymus, they are programmed to weakly recognise ‘self’ molecules, called major histocompatibility complex (MHC) molecules. MHC molecules are found on all cell surfaces and are an active part of the immune system.

When a virus infects a cell, an MHC molecule binds to a piece of that virus (antigen) and displays the antigen on the cell's surface. T-cells only recognise an antigen when it is bound to an MHC molecule. Cells that can display antigen with MHC are called antigen-presenting cells. There is a positive selection to ensure that the T-cell can interact with MHC molecules correctly. Secondly, there is a negative selection to eliminate those T-cells that interact too strongly with MHC molecules containing ‘self’ antigen, as they would be self-destructive.

T-cells that survive this process mature and migrate out of the thymus. MHC molecules are so genetically diverse that each individual person has their own unique selection. Lymphocytes strongly recognise non-self MHC as foreign. This is why matching for tissue type (MHC) is critical in organ transplants.

Each MHC molecule that displays an antigen is recognised by a matching or compatible T-cell receptor. For the T-cell to respond to the foreign antigen on the MHC, another molecule on the antigen-presenting cell must send a second signal to the T-cell and a corresponding molecule on the surface of the T-cell recognises the second signal.

Once the MHC and the T-cell receptor interact, and the co-stimulatory molecules interact, one of several actions can occur. The T-cell may activate a response to the antigen, it may tolerate the antigen, or it may die. The course of action is determined by which co-stimulatory molecules interact and how well they interact.

The main antigen-presenting cells are dendritic cells and, less often, macrophages. One type of MHC molecule (class I) contains a protein called beta-2 microglobulin which is released from activated or killed cells, including lymphocytes. It can be measured in blood as a marker of immune activation. It is possible that the immune system’s efficiency in dealing with antigens varies by the type of MHC molecules produced.

B-cells are best known for making antibodies. Their maturation process takes place in the bone marrow. Developing B-cells also undergo a type of culling process to eliminate self-reactive antibodies. If there is a strong reaction between the B-cell receptor (IgD or IgM on the surface of the B-cell) and a ‘self’ antigen, that particular B-cell dies. In this way, the body learns to produce antibodies only to foreign antigens. If this process misfires and B-cell receptors react to ‘self antigens’, autoimmune disease results.

As B-cells mature, they rearrange gene components and reproduce in great number. In this process, mutants develop. A natural selection takes place and the antibodies that can best counter target antigens survive.

The genetic code of lymphocyte antigen receptors in the thymus and the bone marrow is so varied that there are billions of variations in antibody and T-cell receptors. For each specific antigen, there are several T- and B-cells able to recognise it. Activated lymphocytes proliferate and live for years. These cells constitute the memory characteristic of acquired immunity.

The human MHC molecules, also known as human leukocyte (or lymphocyte) antigens (HLA), genetically determine an individual’s response, and the intensity of the response, to various antigens and are known to affect the rate of HIV disease progression. There are two main classes of HLA.

HLA class I proteins are found on almost all human cells and each person has six markers out of a possible 200 variations. The class I markers detect cells that have been infected (or impaired by cancer) and alert killer T-cells to their presence.

Class I consists of HLA A, B, and C and they present antigen to CD8 T-cells, leading to CD8 T-cell activation. When CD8 T-cells recognise antigen presented by HLA class I, they kill the cell presenting it. This is how CD8 T-cells destroy cells infected with viruses, including HIV. HLA class I contains a protein called beta-2 microglobulin that is released from activated or killed cells, including lymphocytes, and it can be measured in blood as a marker of immune activation.

HLA class II proteins are only on certain cells and each person has a distinct pattern of eight markers from a possible 230 variations. Class II consists of HLA DP, DQ, and DR. When antigen-presenting cells such as macrophages and dendritic cells present antigen-derived peptides with the HLA class II molecules to CD4 T-cells, the T-helper cell is activated. It then secretes chemical messengers called cytokines (e.g. interferons, interleukins) to stimulate an attack from B-cells, phagocytes, and other T-cells.

Chemical messengers produced by leukocytes when antigen is encountered are called cytokines. This is a generic term for several types of non-antibody proteins that act as intercellular messengers. Cytokines impact communication, interaction, and behaviour (stimulation or inhibition) among cells – regulating immune response by guiding cell growth and migration. Generally, cytokines act locally, stimulating nearby cells into action.

Types of cytokines include interleukins, lymphokines, monokines, and several related signalling molecules, such as tumour necrosis factor (TNF) and interferons.

Lymphokines are secreted by activated T-helper cells and monokines are produced by activated macrophages and monocytes. GM-CSF (granulocyte macrophage-colony stimulating factor) simulates blood cell production (haematopoiesis), as do some of the interleukins (e.g. IL-3 and IL-7).

Other interleukins activate immune cell proliferation and differentiation, e.g. IL-2, produced by activated CD4 Th1 T-cells, stimulates the growth of other CD4 and CD8 T-cells and can help B-cells. Interferons respond to viruses and intracellular parasites, as well as interfering with the synthesis of new virus. Tumour necrosis factor is another cell signalling molecule that can induce tumour cell death and produce a range of pro-inflammatory actions.

Chemokines are small protein molecules that attract certain white blood cells, causing them to move in a particular direction. This directional movement of a cell is known as chemotaxis. Chemokines include RANTES and the macrophage inflammatory proteins (MIP) 1 alpha and 1 beta. Certain chemokines are able to facilitate or block HIV entry into cells.

In HIV infection, some cytokine activity is disrupted. Cytokines have been clinically investigated as therapies for people with HIV as they can both facilitate or block HIV entry into cells.