Immunology

In this podcast, Maddi & I talk about innate immunity, MHC proteins, the role of T & B lymphocytes along with hypersensitivity reactions.

IMMUNOLOGY

Outline the components involved in innate immunity

Innate immunity is the first line of defence of the body. It is non-specific and consists of life-long immune mechanisms that do not require prior exposure to antigens and are not modified by repeated exposure to a pathogen. The innate immune system consists of physiochemical barriers, soluble proteins and cellular defence mechanisms.

Physiochemical barriers:

• Physical barriers include
  • Skin: the epidermis provides a layer of physical defence and is acidic. This layer also sheds periodically which removes microbes. 
  • Mucus membranes
  • Hair within nostrils: filters microbes, dust and pollutants and can expel them via sneezing
  • Cilia lining the upper respiratory tract can trap foreign particles and remove them through mucociliary clearance and coughing
  • High flow rates of urine, saliva, tears and biliary secretions also remove foreign material
• Chemical barriers
  • Sebum provides a protective layer on the skin and is bactericidal
  • Lysozymes in tears, sweat and saliva breaks bonds between components of the bacterial cell wall resulting in cell lysis
  • Gastric juice is highly acidic and destroys bacteria
  • Saliva facilitates the clearance of micro-organisms within the oral cavity and helps maintain the normal microbiota in the mouth. 
  • Normal bacterial flora: colonises various parts of the body and competes with infective micro-organisms

Soluble proteins:

• Complement
  • This is an enzyme system consisting of more than 30 glycoproteins. They can be activated by the classical pathway which is triggered by immune complexes, the alternative which is triggered by various viruses, bacteria, fungi and tumour cells, or the lectin pathway which is activated when lectin binds mannose groups in bacteria. Activation of these proteins lead to proteolytic cascades which destroy invading organisms by opsonisation, chemotaxis, and cell lysis via the insertion of perforins into cell membranes. Complement also plays a central role in the inflammatory process, removes immune complexes and serves as bridge to the adaptive immune response by activating B cells and regulating T cell activity.
• Acute phase proteins such as CRP and alpha-1 antitrypsin are mainly synthesised by the liver. They are involved in opsonisation and regulation of inflammatory mediators during the acute phase response and facilitate cellular defence and repair
• Cytokines: are proteins that mediate many of the cellular responses involved in innate immunity. They are produced in response to an antigen and function as chemical messengers to activate and regulate the immune response

Cellular defence mechanisms: consist of leukocytes, mast cells and natural killer cells.

• Leukocytes: are formed in bone marrow and lymphoid tissue and transported in the blood to areas of inflammation. Neutrophils, eosinophils, basophils and monocytes protect the body via release of cytokines and inflammatory mediators and by phagocytosis.
  • Neutrophils: are the first cell line of defense in the innate immune response and circulate in the bloodstream. They are attracted to areas of inflammation by chemotaxis. They exert antimicrobial action through degranulation and release of reactive oxygen species and cytotoxic components. They also phagocytose pathogens.
  • Eosinophils also phagocytose micro-organisms and release cytokines that produce inflammation and kill organisms. They are less active against bacteria than neutrophils and are increased in parasitic diseases and allergic responses.
  • Basophils: are unable to ingest foreign cells. They contain granules filled with histamine and participate in immediate type hypersensitivity reactions. They are important for protection against helminth infections.
  • Monocytes and macrophages: enter blood from the bone marrow and circulate for approximately 72 hours following which they migrate to tissues and differentiate into macrophages. They are activated by cytokines and bacterial endotoxins. Their functions include; phagocytosis, breakdown of damaged tissues of cells, release of cytokines which recruit other immune cells, and antigen presentation to helper T cells. They are especially important in the defense against intracellular pathogens, mycobacteria, parasites and fungi.
• Mast cells: are heavily granulated cells of connective tissues which contain proteoglycans, histamine and proteases. When they are activated degranulation occurs which creates an inflammatory cascade. They are also involved in enhancing angiogenesis and are especially important in the homeostasis of the commensal bacteria of the gastrointestinal tract. They are also involved in acquired immunity via expression of high-affinity IgE receptors and are involved in allergic reactions.
• Natural killer cells: are present in the blood, spleen and liver and contain granules with destructive enzymes and chemicals. They identify cells expressing low levels of major histocompatibility complex class 1 such as tumour or virus infected cells and bind to them. They can then kill these cells through release of cytokines and insertion of perforins.

What is the major histocompatibility complex?

When antigens are engulfed by human cells they transported to the surface of the cells and are attached to proteins to be presented to the bodies defence mechanisms. These proteins are called major histocompatibility complex proteins. Major histocompatibility complex is a group of genes located on chromosome 6 that code for these cell surface proteins which help the immune system distinguish foreign proteins from its own. The MHC is polygenic and polymorphic, thus making it difficult for pathogens to evade the host immune response. There are two important classes of MHC, class 1 and class 2. Class 1 proteins are expressed on all nucleated cells and present antigens to cytotoxic T lymphocytes which then kill the infected cell. Class 2 proteins are only found on B lymphocytes, macrophages and other professional antigen presenting cells and present antigens to helper T cells. Class 1 MHC proteins are especially important for the detection of intracellular pathogens such as viruses while class 2 MHC proteins are particularly important for extracellular antigens such as bacteria. There is also a class 3 MHC which encode for components of the complement system and other inflammatory molecules.

MHC is also called human leukocyte antigens and is a crucial part of organ transplantation. There are three major MHC class 1 genes known as HLA-A, B and C and three major MHC class 2 genes, as well as several minor genes. These closer the match between the donor recipient HLA complex, the lower the risk of organ rejection.

Briefly describe the functions of T and B cells

Both T and B cells are lymphocytes that are derived from multipotent haematopoietic stem cells in the bone marrow and are a vital component of the acquired immune system.

T progenitor cells migrate from the bone marrow to the thymus where they mature. They cannot bind to antigens directly but need to have broken down peptides of the antigen presented to them by antigen presenting cells. T cells are involved in cell mediated immunity. There are four main types of T cells; helper, cytotoxic and regulatory

• Helper T cells
  • Make up approximately 2/3 of the T cells and express CD4 receptors. They produce cytokines, activate macrophages and stimulate B lymphocytes to form plasma cells and antibodies. Helper T cells bind to MHC class 2 molecules.
• Cytotoxic T cells
  • Express CD8 receptors. They are responsible for removing pathogens and infected host cells. 
• Regulatory T cells
  • Express CD4 and CD25 receptors. They help to modulate the immune response, prevent autoimmune disease and prevent cytotoxic cells from causing an excessive immune reaction
• Memory T cells
  • Following an infection, antigen-specific memory T cells are formed. These are important because they can quickly expand their colony upon re-exposure to an antigen, thus providing a quick and effective immune response.

B cells are involved in the humoral immune response.

B cells can be activated directly by an antigen, unlike T cells. They can also be activated by T cells. When a B cell encounters its matching antigen, it engulfs it and displays fragments on MHC class 2 molecules. This attracts helper T cells which secrete cytokines and helps the B cell clone proliferate producing plasma cells. Plasma cells secrete antibodies to specific antigens which directly attack antigens and also activate the complement system. Some B cells also differentiate into memory B cells which become activated if there is a reinfection by the same antigen. This helps to launch a rapid response against the pathogen in the future.

What are immunoglobulins

Immunoglobulins, also known as antibodies, are large Y shaped proteins produced by plasma cells and are a vital part of the immune system. They can directly attack invaders by agglutination and lysis or can indirectly attackvia activation of the complement system. Immunoglobulins consist of two heavy chains and two light chains joined to form a Y shaped protein. Both the heavy and the light chains have constant and variable regions. The constant regions determine some of the biological properties of the antibody and they are divided into five major classes, IgG, IgM, IgA, IgD and IgE depending on the constant region of the heavy chain.

The variable region contains the antigen binding site and mediates antigen recognition. It gives the antibody its specificity for an antigen and provides diversity, allowing the immune system to recognise a wide variety of antigens. Immunoglobulins occur in two main forms, soluble antibodies which are in the blood and membrane bound antibodies which are attached to the surface of B cells and otherwise known as B cell receptors. The membrane bound immunoglobulins detect antigens and facilitates the activation of B cells and subsequent differentiation into plasma or memory B cells.

• IgG: is the predominant immunoglobulin class present in human serum, comprising about 70%. It is the only class that can cross the placenta and thus can provide passive immunity to the fetus. It is the primary immunoglobulin involved in the secondary immune response. IgG activates the complement system opsonises bacteria and neutralises toxins and viruses. 
• IgA: comprises about 15% of total immunoglobulins and is abundant in mucosal secretions such as saliva, tears and breast milk. It inhibits bacterial and viral adhesion to epithelial cells and directly neutralises some toxins. It is a very weak complement activating antibody.
• IgM: comprises about 10% of total immunoglobulins. It is the major immunoglobulin produced during the primary antibody response, on first exposure to an antigen. Therefore, the presence of IgM generally indicates a current or recent infection. It is a potent activator of the complement system and a powerful agglutinating antibody, thus is efficient in neutralization of antigens.
• IgD: secreted n small amounts, seem to function mainly as cell surface receptors for antigens
• IgE: primarily defends against parasitic infections and is also involved in immediate hypersensitivity reactions and atopy. They bind to mast cells and basophil surface receptors with high affinity. Antigen binding to IgE then triggers release of inflammatory substances from these cells such as histamine, resulting in some of the clinical manifestations of an allergic reaction.

Classify the hypersensitivity reactions. Briefly describe the pathophysiological processes underlying each reaction and give an example of each.

Hypersensitivity is an exaggerated or inappropriate immune response that results in tissue damage. There are four types of hypersensitivity reactions; type 1 immediate, type 2 cytotoxic, type 3 immune complex and type 4 delayed.

Type 1: Immediate or ‘classic’:

• IgE is synthesised by B cells on first exposure to an antigen and binds to mast cells via the high-affinity Fc receptors. On repeated introduction, the antigen binds IgE on these sensitised mast cells which causes degranulation. This results in the release of vasoactive substances including histamine, heparin and platelet activating factor which cause vasodilatation, smooth muscle constriction and increased vascular permeability. It may result in systemic or local effects. Examples include food or insect allergies.

Type 2: cytotoxic

• Antibody mediated cytotoxic reaction involving IgG or IgM antibodies binding to a cell surface. This results in complement activation causing mast cell activation, neutrophil recruitment and cell lysis via complement membrane attack complex and phagocytosis. Examples include transfusion reactions, haemolytic disease of the new born and myasthenia gravis.

Type 3: immune complex

• Immune-complex mediated reaction resulting in deposition of antigen-antibody complexes in host tissue. This also activates complement and neutrophils resulting tissue damage. The immune complexes can also be deposited in the walls of arterioles resulting in vasculitis. Examples include rheumatoid arthritis, SLE, polyarteritis nodosa and post-streptococcal GN.

Type 4: delayed

• This is cell mediated without complement activation and without formation of antibodies.
• Antigen presentation to T cells which then become sensitised and proliferate.
• The T cells release cytokines which attract macrophages and lead to local inflammation. This response can take hours to days. After prolonged antigenic stimulation the macrophages can fuse to form giant cells.
• Examples include contact dermatitis, tuberculosis