The Immune System

The term immunity is derived from a Latin word “Immunis” meaning “exempted or free from burden”. In scientific terms burden refers to diseases caused by pathogens or due to dysregulation of the host itself. Thus, Immunology is study of how the body protects itself from a variety of pathogens such as bacteria, viruses, fungi, parasites and protozoa.

The human immune system is highly specialised and a complex mechanism. It has evolved with the capacity to recognise self from non-self thereby mounting a powerful response against the invading microorganisms only. It consists of two main branches: the Innate immune system and the adaptive immune system. The fine balance between the two provides adequate defence

This is our first-line rapid defence mechanism and it is present from birth. It lacks specificity and memory (cf. adaptive immunity) which leads to an identical immune response each time an infection occurs with the same pathogen. However, it plays a critical role in shaping the adaptive immune response.

Innate immunity comprises of physiological barriers, cellular and hurmoral (soluble) elements.

•Physiological barriers – such as skin and mucosal surfaces which prevent pathogen entry and flushing through continual mucociliary clearance.

This is initiated later during development and has specialised features such as high specificity and immunological memory. Adaptive response is ‘learned’ and the intensity of the response increases with repeated exposure. This forms the basis of vaccination strategy.

Adaptive immunity also consists of both cellular and humoral components and mediated by specialised cell types called the lymphocytes.

• Cellular components include: phagocytes (macrophages & neutrophils) which engulf the entire pathogen. In addition, natural killer cells, mast cells, basophils, and eosinophils also play a key role in defence against viral-infected cells, allergens and parasites respectively. Recognition of Pathogen-associated molecular patterns (PAMPs) is achieved by means of Pattern-Recognition Receptors (PRRs) expressed on the surface of innate immune cells.

• Humoral – these are soluble molecules present in secretions and blood. These include lysozyme, lactoferrin, opsonins, Complement proteins, manan-binding lectin, and C-reactive protein.

• Humoral consists of neutralizing antibodies produced by highly differentiated B lymphocytes called the plasma cells.

There are fives classes of antibodies: IgM, IgD, IgG, IgA and IgE. These have different properties and therefore provide protection at different body locations.

• Cellular response is carried out by T-lymphocytes which are further sub-divided into CD4+ (helper) and CD8+ (cytotoxic) T-cells. T-cells recognise small peptides derived from the foreign pathogen called antigens in the context of MHC class I or class II molecule.

Intracellular pathogens

Helminth infections

Extracellular pathogens

Immune suppression

TCRViral peptide

Virus

MHCClass I

FasLFas

Granules

host defence to parasitic infection and in allergic reactions. Mast cells are located at the boundaries between tissues and the external environment. They are key players in the inflammatory response as they can be activated to release a wide variety of inflammatory mediators, by many different antigens including allergens, pathogens and physiological mediators.

Dendritic CellsDendritic cells are responsible for the initiation of adaptive immune responses. They are bone marrow -derived leukocytes and are the most potent type of antigen-presenting cells. These cells are specialised to capture and process antigens, converting proteins to peptides that are presented on major histocompatibility complex (MHC) molecules recognised by T cells.

Natural Killer (NK) CellsCells of the

Immune System

Macrophages

Basophil

CD8+ T Cells

CD4+ T Cells

Mast Cells

Macrophages are specialised cells involved in the detection, phagocytosis and destruction of bacteria and other harmful organisms. In addition, they can also present antigens to T cells and initiate inflammation by releasing cytokines (such as Il-1 and IL-6) that activate other cells. They originate from blood monocytes that leave the circulation to differentiate in different tissues. Macrophages migrate to and circulate within almost every tissue, patrolling for pathogens or eliminating dead cells.

Basophils make up less than 1% of leukocytes in humans. They are highly granular mononuclear cells and their differentiation is driven by IL-3. They share many similarities with their tissue resident counterparts, the mast cell. Like mast cells, basophils become activated by antigen crosslinking of FcRI receptor-bound IgE and undergo rapid degranulation and release their cellular contents. In addition, basophils can be.

NK cells represent one of the three subsets of lymphocytes. They belong to the innate immune system and form a first line of defense. In particular they provide protection against viral and bacterial infections and they help to detect and limit the development of cancer. NK cells have the ability to kill tumour cells without any priming or prior activation. Additionally, NK cells secrete cytokines, for example INF and TNF, which constitute a second important defence mechanism during an immune reaction.

CD8+ T cells are very important for immune defence against intracellular pathogens, such as viruses, and for tumour surveillance. CD8+ T cells recognise peptides presented by MHC Class I molecules, found on all nucleated cells. When a CD8+ T cell recognises its antigen and becomes activated, it has three major mechanisms to kill infected or malignant cells. The first is secretion of

These are long lived tissue resident cells with an important role in many inflammatory Responses including

cytokines, primarily TNF-α and IFN-γ, which have anti-tumour and anti-tumour and anti-viral effects. The second major function is the production and release of cytotoxic granules, which contain perforin, and granzymes proteins which cause the apoptosis of the target cell. The third major function of CD8+ T cell destruction of infected cells is via Fas/FasL interactions.

During TCR activation, Naïve CD4+ T cells may differentiate into one of several T helper (Th) cell lineages, including:- Th1, Th2, Th17 and Treg. The cytokine environment determines the terminal lineage commitment and the cytokine expression profiles of the Th cells. Th1 cells are involved in cell-mediated immunity. They are responsible for control of intracellular pathogens such as viruses and some bacteria. IL-12 and IFN-γ are important cytokines involved in Th1 responses.Th2 cells promote humoral responses and are important in the defence against large extracellular organisms, utilising cytokines such as IL-4, IL-5 and IL-13. Th17 are a newly identified Th cell lineage, they produce Il-17, this is a pro-inflammatory cytokine, and these cells have been broadly implicated in autoimmune diseases.

activated without IgE crosslinking. Basophils are recruited to sites of inflammation and they can be directly activated by a variety of pathogen-associated molecular patterns (PAMPs). When stimulated, basophils release their granule contents including histamine, and generate and release LTC4. In addition, activated basophils produce cytokines, most notably IL-4 and IL-13

T-Regulatory Cells As the name suggests regulatory T cells (also called Tregs) are T cells which have a role in regulating or suppressing other cells in the immune system. Tregs control the immune response to self and foreign antigens and help prevent autoimmune and inflammatory diseases. Tregs produced in the thymus are termed ‘natural’ , and those formed by differentiation of naïve T cells in the periphery are called ‘adaptive’.

B CellsB cells are central to the humoral adaptive response. Once activated, B cells differentiate into plasma cells that are capable of secreting antibody molecules into the circulation. Once bound to a target, antibody molecules can activate the classical pathway of the complement system, thereby directing it to neutralise its targets with great specificity. As with the cellular adaptive response, the humoral adaptive response can be enhanced by a helper T cell response.

Allergy

Immunodeficiency

Cancer

Autoimmunity

The Allergic Response

Immunodeficiency is a state in which the ability of the immune system to fight infectious disease is compromised or entirely absent. These diseases can be classified into two groups:- Primary and secondary (acquired). Primary immunodeficiencies are inherited and can range from very serious to very mild.  The serious forms are often noticeable at birth or shortly thereafter.  However, very mild forms may not be diagnosed until later in life, during adolescence or young adulthood.

Secondary immunodeficiencies are the result of particular external processes or diseases. Common causes for secondary immunodeficiency are malnutrition, ageing and particular medications. Many specific diseases directly or indirectly impair the immune system. This includes many types of cancer, particularly those effecting cells of the immune system (leukaemia, lymphoma and multiple myeloma), and certain chronic infections. Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV).

Allergic reactions occur to normally harmless environmental substances known as allergens; these reactions are acquired, predictable, and rapid. Allergy is classified as one of four forms of hypersensitivity, termed type I (or immediate) hypersensitivity. It is characterized by excessive activation of mast cells and basophils by IgE antibody resulting in an extreme iinflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies and reactions to the venom of insects such as wasps and bees.

Diseases of the Immune System

The immune system must be able to maintain a balance between the type of response generated. In cases of hyper-responsiveness to harmless antigens, it may lead to the development of allergy or indeed autoimmunity. In contrast, insufficient activation may result in state of immunodeficiency and overwhelming infections. In addition, defects in the regulatory mechanisms can result in tumour progression and survival.

Produced by: Kate Wetenhall & Rehana SaleemGrade A Trainee Clinical Scientists in ImmunologyRoyal Preston Hospital

Hypo-responsivenessHyper-responsiveness

Autoimmunity is defined as the loss of immunological tolerance (both central & peripheral) and a failure to distinguish between ‘self’ and ‘non-self’. Autoimmune diseases can either be organ-specific affecting one particular organ/tissue e.g. Type 1 diabetes mellitus, hashimoto’s thyroiditis, and coeliac disease or they can be non-organ specific affecting multiple bodily sites e.g. SLE, Sjogrens syndrome, and rheumatoid arthritis.

They are more common in female. The incidence has increased in the last three decades and causes significant morbidity and mortality. The immune regulatory mechanisms responsible for ensuring ‘education’ of T-cells and B-cells are defective. Hence, unable to control the development of self-reactive response. Molecular mimicry may also play a critical role in the development of such processes.

Burnet’s theory of immunosurveillance states that transformed cells capable of developing into tumours are continually arising but they are recognised and eliminated by the immune system.

However due to lack of sufficient surveillance, many of these may escape and develop into potentially life threatning cancers. This has serious implications for immunodeficient and immunosuppressed individuals. Lymphomas and leukaemias of various origin develop as a result. For example B & T-cell leukaemias, monocytic leukaemia and Multiple myeloma (plasma cell cancer).

In addition, tumour cells employ several escape mechanisms such as lack of antigenecity, active immunesuppression and killing of the host cells which allows them to survive.