Immune System

Immune system

Dr. Bassam Ismael
تسلسل 3 المرحلة الثالثة باطنية نظري العدد9 20\3\2018


The immune system consists of an intricately linked network of cells, proteins and lymphoid organs that are strategically placed to ensure maximal protection against infection. Immune defences are normally categorised into: The innate immune response, which provides immediate protection against an invading pathogen. Adaptive or acquired immune response, which takes more time to develop but confers exquisite specificity and long-lasting protection

The innate immune system

Anatomical barriers Phagocytic cells Soluble molecules, such as complement and acute phase proteins Natural killer cells

Constitutive barriers to infection

Skin: by renewal & replacemnt, low PH & low O2 tension, sebaceous glands (secrete hydrophobic oils that further repel water and microorganisms). Sweat also contains lysozymes, amonia & antimicrobial peptides like defensins. Mucous membranes of the respiratory, gastrointestinal and genitourinary tract provide a constitutive barrier to infection. Mucous is physical barrier & contain lysozyme, lactoferrin & IgA


IgA prevents bacteria and viruses attaching to and penetrating epithelial cells. As in the skin, lysozyme and antimicrobial peptides within mucosal membranes can directly kill invading pathogens, and additionally lactoferrin acts to starve invading bacteria of iron.



Cilia, sneezing & coughing In the gastrointestinal tract, hydrochloric acid and salivary amylase chemically destroy bacteria Normal peristalsis and induced vomiting or diarrhoea assist clearance of invading organisms Endogenous commensal bacteria compete with pathogenic microorganisms for space and nutrients, and produce fatty acids and bactericidins that inhibit the growth of many pathogens

Phagocytes

Phagocytes (‘eating cells’) are specialised cells whichingest and kill microorganisms, scavenge cellular and infectious debris, and produce inflammatory molecules which regulate other components of the immune system.

Phagocytes (‘eating cells’) Include neutrophils, monocytes and macrophages, and are particularly important for defence against bacteriaIand fungal infections


Phagocytes express a wide range of surface receptors that allow them to identify microorganisms. These pattern recognition receptors include the Toll-like receptors, NOD (nucleotide-oligomerisation domain protein)-like receptors and mannose receptors. They recognise generic molecular motifs not present on mammalian cells, including bacterial cell wall components, bacterial DNA and viral double-stranded RNA.


Engulfment of microorganisms is greatly enhanced by opsonisation Opsonins include acute phase proteins such as C-reactive protein (CRP), antibodies and complement. They bind both to the pathogen and to phagocyte receptors, acting as a bridge between the two to facilitate phagocytosis

Infection increase PMNs (polymorphonuclear) The neutrophils are recruited to the site by chemotactic agents and by activation of local endothelium The process of phagocytosis depletes neutrophil glycogen reserves and is followed by neutrophil cell death. As the cells die, their contents are released and lysosomal enzymes degrade collagen and other components of the interstitium, causing liquefaction of closely adjacent tissue. The accumulation of dead and dying neutrophils results in the formation of pus which, if extensive, may result in abscess formation.

Monocytes and macrophages

Monocytes: produced in the bone marrow and exported to the circulation, where they constitute about 5% of leucocytes they migrate to peripheral tissues where they differentiate into tissue macrophages Macrophages, function: Initiation and amplification of the inflammatory response Killing of microorganisms Resolution and repair of inflammation Link between innate and adaptive immune system

Dendritic cells

Dendritic cells are specialised antigen-presenting cells which are prevalent in tissues in contact with the external environment, such as the skin and mucosa. Once activated, carry microbial antigens to regional lymph nodes, where they interact with T cells and B cells to initiate and shape the adaptive immune response.

Cytokines

Cytokines are small soluble proteins that act as multipurpose chemical messengersTheir clinical importance is demonstrated by the efficacy of ‘biological’ therapies (often abbreviated to ‘biologics’) that target specific cytokines

Complement

The complement system is a group of more than 20 tightly regulated, functionally linked proteins that act to promote inflammation and eliminate invading pathogens. They are produced in the liver and are present in the circulation as inactive molecules When triggered, they enzymatically activate other proteins in a rapidly amplified biological cascade analogous to the coagulation cascade

There are three mechanisms by which the complementcascade may be triggered

The alternative pathway is triggered directly by binding of C3 to bacterial cell wall components, such as lipopolysaccharide of Gram-negative bacteria and teichoic acid of Gram-positive bacteria. The classical pathway is initiated when two or more IgM or IgG antibody molecules bind to antigen, forming immune complexes. These bind to C1 & trigger the cascade.


3. The lectin pathway is activated by the direct binding of mannose-binding lectin to microbial cell surface carbohydratesActivation of complement by any of these pathways results in activation of C3. This, in turn, activates the final common pathway, in which the complement proteins C5–C9 assemble to form the membrane attack complex. This can puncture target cell walls, leading to osmotic cell lysis.This step is particularly important in the defence against encapsulated bacteria, such as Neisseria spp. and Haemophilus influenzae

Mast cells and basophils

Play major role in allergy Mast cells present mainly in skin & gut Basophils present in blood. Both contain large cytoplasmic granules which contain preformed vasoactive substances such as histamine. Mast cells and basophils express IgE receptors on their cell surface These trigger an inflammatory cascade which increases local blood flow and vascular permeability, stimulates smooth muscle contraction, and increases secretion at mucosal surfaces.

The adaptive immune system

This has three key characteristics:• It has exquisite specificity and is able to discriminate between very small differences in molecular structure.• It is highly adaptive and can respond to an unlimited number of molecules.• It possesses immunological memory, such that subsequent encounters with a particular antigen produce a more effective immune response than the first encounter.


There are two major arms of the adaptive immune response: humoral immunity involves antibodies produced by B lymphocytes; cellular immunity is mediated by T lymphocytes, which release cytokines and kill immune targets.

Lymphoid organs

The primary lymphoid organs are involved in lymphocyte development: Bone marrow Thymus Secondary lymphoid organs: After maturation, lymphocytes migrate to the secondary lymphoid organs. These include the spleen, lymph nodes and mucosa-associated lymphoid tissue.

Humoral immunity

B- lymphocytes: These specialised cells arise in the bone marrow. Mature B lymphocytes (also known as B cells) are found in bone marrow, lymphoid tissue, spleen and, to a lesser extent, the blood stream. These cells differentiate into either longlived memory cells, which reside in the lymph nodes, or plasma cells, which produce antibody.

Immunoglobulins

Immunoglobulins (Ig) are soluble proteins made up of two heavy and two light chains The heavy chain determines the antibody class or isotype, i.e. IgG, IgA, IgM, IgE or IgD. The antigen is recognised by the antigen-binding regions (Fab) of both heavy and light chains, while the consequences of antibody-binding are determined by the constant region of the heavy chain (Fc)

Actions of antibodies

Facilitate phagocytosis by acting as opsonins Facilitate cell killing by cytotoxic cells Complement activation May act directly to neutralise the biological activity of toxins. E.g. IgA


The humoral immune response is characterised by immunological memory: that is, the antibody response to successive exposures to antigen is qualitatively and quantitatively different from that on first exposure.



When a previously unstimulated (naпve) B lymphocyte is activated by antigen, the first antibody to be produced is IgM, which appears in the serum after 5–10 days. Depending on additional stimuli provided by T lymphocytes, other antibody classes (IgG, IgA and IgE) are produced 1–2 weeks later.

If, some time later, a memory B cell is re-exposed to antigen, the lag time between antigen exposure and the production of antibody is decreased (to 2–3 days), the amount of antibody produced is increased, and the response is dominated by IgG antibodies of high affinity.

Cellular immunity

T lymphocytes (also known as T cells) mediate cellular immunity and are important for defence against viruses, fungi and intracellular bacteriaT lymphocytes can be segregated into two subgroups on the basis of function and recognition of HLA molecules. These are designated CD4+ and CD8+ T cells, according to the ‘cluster of differentiation’ (CD) antigen expressed on their cell surface.

CD4+ lymphocytes can be further subdivided into subsets on the basis of the cytokines they produce:• Typically, Th1(T-helper) cells produce IL-2, IFN-γ and TNF-α,and support the development of delayed type hypersensitivity responses • Th2 cells typically secrete IL-4, IL-5 and IL-10, and promote allergic responses .• A further subset of specialised CD4+ lymphocytes known as regulatory cells are important in immune regulation of other cells and the prevention of autoimmune disease.