Overview of the Immune System

Innate vs Adaptive Immunity

At the broadest level, the immune system is divided into innate immunity and adaptive immunity. The cells and components involved in each are shown below:

During an infection, the innate immune system is the first to be engaged. The innate response is:

• Fast – includes physical (skin) and chemical (stomach acid) barriers, tissue-resident immune cells, the complement system and signalling molecules, which activate immediately upon detection of an infection
• Non-specific – uses ‘pattern recognition receptors’ (PRRs) to recognise the generic pathogen-associated molecular patterns (PAMPs) of pathogens instead of responding to specific pathogens

Adaptive immunity is slower to develop but recognises specific antigens associated with pathogens. The adaptive response:

• Generates millions of B and T cells – each with a unique receptor that recognises one specific antigen
• Recognises specific antigens – leading to activation, proliferation and differentiation of the corresponding specific B or T cell into effector cells that can eliminate the pathogen
• Generates an immunological memory – resulting in faster, stronger and more specific responses upon re-exposure to the same pathogen

The Innate Response

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Fig 1
Overview of Innate Immunity

Innate barriers

Before the immune system proper is even engaged, several innate barriers prevent pathogens from entering and establishing an infection:

• Physical barriers – skin, mucous membranes, bronchial cilia, nasal hair (traps inhaled particles)
• Chemical barriers – low pH of the stomach, vagina, and skin, secretory IgA, lysozyme, and defensins in secretions
• Biological barriers – resident microbiota that competitively exclude potential pathogens
• Physiological responses – coughing, sneezing, vomiting and diarrhoea physically expel pathogens

The innate barriers are covered in more detail here.

Acute inflammation

When a pathogen breaches the innate barriers, tissue-resident immune cells recognise PAMPs via PRRs and initiate acute inflammation. Key processes in acute inflammation include:

• Phagocytosis – directly destroys pathogens, via oxygen-dependent and oxygen-independent mechanisms.
• Opsonisation – opsonins coat the pathogen and enhance its recognition by phagocytes essentially tagging it for destruction.
• Recruitment of immune cells – neutrophils and monocytes are recruited to the site of infection by squeezing through endothelial cells of blood vessels (‘diapedesis’) and entering the tissue space (‘extravasation’).
• Chemotaxis – chemicals called chemokines are secreted at the site of infection attracting neutrophils and monocytes.
• Acute phase response – a systemic response including fever, increased hepatic production of acute phase proteins, and mobilisation of neutrophils from the bone marrow into the blood.

More detail on acute inflammation can be found here.

Complement system

Infection causes sequential activation of circulating proteins labelled C1-C9. These activated proteins ‘complement’ (enhance) the innate response by:

• acting as opsonins (C3b)
• recruiting immune cells (C3a, C5a)
• directly lysing pathogens (C5b-9)

More detail on the complement system can be found here.

Cytokines

Cytokines are immune signalling molecules that regulate the immune system. TNF, IL-1 and IL-6 are the classical ‘trio’ of pro-inflammatory cytokines secreted by tissue-resident immune cells and are the main cytokines driving the immune response.

The MHC and antigen presentation

The major histocompatibility complex (MHC, also known as human leukocyte antigen or HLA in humans) is a large gene locus encoding molecules that present antigens to T cells. It comprises the major genetic factors that determine histo- (tissue) compatibility during transplantation, which gives it its name.

The immune system may need to respond to intracellular (e.g. viruses) or extracellular (e.g. bacteria) pathogens. Intracellular microbes are hidden inside host cells and the appropriate response would be to kill the infected cell. Extracellular microbes are exposed and can be directly targeted.

To accommodate these two different approaches, the MHC is divided into MHC class I and MHC class II.

You can read more about MHC classes I and II here.

The Adaptive Response

B and T cells

B cells and T cells comprise the adaptive immune response. Adaptive immunity is highly antigen-specific, arising from the generation of millions of B and T cells with unique receptors. This is achieved during their development through a process called V(D)J recombination, where gene segments are randomly rearranged and inaccurately joined.

During an infection, the adaptive immune response is engaged when a B or T cell recognises its specific antigen. This results in the activation, proliferation and differentiation of the cell into effector B or T cells.

After activation, B cells undergo a process called affinity maturation, where they increase their antigen-binding affinity by deliberately introducing mutations into their antigen-binding genes and selecting for the highest affinity variants.

Mature B cells then differentiate into plasma cells which secrete a soluble form of their antigen-binding receptor called an antibody.

Antibodies are highly specific for their target antigen and can:

• bind to extracellular microbes and neutralise them
• opsonise microbes for phagocytosis
• activate the complement system

T cells differentiate into either CD8+ cytotoxic T cells or CD4+ helper T cells (of which many subtypes exist).

Immunological Memory

The defining feature of adaptive immunity is the generation of immunological memory.

After an infection, a population of long-lived memory B and T cells is retained. Upon re-exposure to the same pathogen, these memory cells proliferate and differentiate into effector cells faster than during the primary response. B cells also undergo further affinity maturation to produce a more specific antibody response.

This is the basis of vaccination, where exposure to a harmless form of a pathogen generates memory cells that protect against future infection.

More information on the secondary immune response can be found here.