Module 1 - Back to Basics immunity

cytokine

general term for any soluble protein secreted by immune cells that affects the behavior of cells bearing appropriate receptors

biological activity of cytokines

• pleiotropic activity

• redundant activity

• synergist activity

• antagonist effect

• cascade induction

pleiotropic activity

different biological effects depending on the nature of the target cell

redundant activity

two or more cytokines can mediate similar functions

synergist activity

combines effects of two cytokines on cellular activity is greater than the additive effects of individual cytokines

antagonist effect

the effect of one cytokine inhibits the effects of another

cascade induction

the action of one cytokine on one target cell induces that cell to produce one or more additional cytokines

chemokines

small cytokines that bind to cell surface receptors and induce cell movement towards the chemokine source. Low molecular wight and structurally homologous, with highly conserved disulphide bonds

roles of chemokines

roles in inflammation, development of lymphoid organs, regulation of lymphocyte trafficking in LN, migration of DCs from site of infection into draining lymph nodes

Chemokines and chemotaxis of inflammatory cells

• increase adhesion of leukocytes to endothelium

• induce migration of leukocytes toward site of infection of tissue damage

• chemokine gradients strongly bias the actin assembly to the cell’s leading edge and in the direction of cell movement

Functions of the immune system

• immunological response

• immune effector functions

• immune regulation

• immunological memory

myeloid lineage

red blood cells, megakaryocytes, granulocytes, monocytes, macrophages and dendritic cells

lymphoid lineage

B lymphocytes, T lymphocytes, innate lymphoid cells, and natural killer cells

defensins

Disrupt bacteria, fungi, and membrane envelopes of some viruses

cathelicidins

secreted constitutively by epithelial cells, and in addition to antimicrobial activities, also modulate the immune response

histatins

potent antifungal

complement system

several plasma proteins that work together to opsonise microbes, promote phagocyte recruitment, and directly kill microbes

acute phase proteins

biologically active molecules, secreted mainly by hepatocytes, that assist the host in eliminating bacteria

C-reactive protein and Mannose-binding protein

activate complement and act as opsonins; CRP recognises altered self and non-self molecules

serum amyloid proteins

induce production of proteins tha degrade the extracellular matrix; recruit immune cells to inflammatory sites

phagocytes

internalise opsonised microbes into phagosomes where they are digested

NK cells

kill targets, without killing themselves, by releasing lytic granules perforin and granzymes

humoral immunity

B lymphocytes secrete antibodies that eliminate extracellular microbes

Cell mediated immunity

T lymphocytes either activate macrophages to destroy phagocytosed microbes or kill infected cells directly.

Functional significance of specificity

ensures that immune responses are precisely targeted to microbial pathogens

Functional significance of diversity

enables immune system to respond to a large variety of antigens

Functional significance of memory

leads to enhanced responses to repeated exposures to the same antigens

Functional significance of clonal expansion

increases number of antigen-specific lymphocytes from a small number of naive lymphocytes

Functional significance of specialization

generates responses that are optimal for defence against different types of microbes

Functional significance of Contraction and homeostasis

allows immune system to respond to newly encountered antigens

Functional significance of nonreactively to self

prevents injury to the host during responses to foreign antigens

Antibody function

• recognises epitopes on surface of antigens

• antigens may be recognise by more than one antibody when more than one epitope exists

• the antigen-binidng site can accommodate soluble macromolecles in their native state

neutralisation

• neutralises diptheria toxin by blocking attachment to target cells

• blocks locally acting toxins or extracellular matrix-degrading enzymes

• bind to flagellum and interfere with motility

• prevent bacteria binding to epithelial cells

haematopoietic stem cells

gives rise to all red and white blood cells

macrophage

phagocytosis and activation of bactericidal mechanisms, antigen presentation and cytokine producation

neutrophil

phagocytosis and activation of bactericidal mechanisms. Degranulation and release of neutrophil extracellular traps (NETs)

• most abundant population of circulating white blood cell and acute inflammatory reactions

• cytoplasmic granules have lysozyme, collagenase, elastase, defensins and cathelicidins

basophil

promotion of allergic response and augmentation of anti-parasitic immunity

dendritic cell

antigen uptake in peripheral sites, antigen presentation and cytokine production

• sample antigen from throughout the body and migrate to lymph nodes to present antigens to T cells

Types of DCs

• classical dendritic cells

• plasmacytoid dendritic cells

• monocyte-derived DCs

• langerhans cells

eosinophil

• killing of antibody-coated parasites

• IL-5 has central role in eosinophil development, activation and survival

• bind to worm larvae through antibody and complement receptors and release intracellular granules

mast cells

• release of granules containing histamine and active agents

• long-lived, tissue-resident cells found in mucosal and epithelial tissues throughout the body

professional antigen presenting cells

• secrete proteins that attract and activate other immune cells

• internalise pathogens via phagocytosis, digest into peptides, and present them on membrane surfaces via MHCII

• upregulate co-stimulatory molecules required for the optimal activation of helper T cells

NETs

large, extracellular, web-like structures composed of cytosolic and granule proteins assembled on a scaffold of decondensed chromatin.

Process occurs primarily through neutrophil death.

Innate Lymphoid Cells (ILCs)

• arise from the same common lymphoid precursore as T and B cells — lack clonally distributed diverse receptors

• ILCs are stimulated by the same types of stress signals that alert neutrophils, macrophages and dendritic cells

• ILC1, 2, and 3

Natural killer cells

• Kill infected and unhealthy/tumour cells using perforin and granzymes

• traditionally defined as CD3-CD56+ lymphocytes; secrete cytokines (IFN-gamma, TNF-alpha)

Primary lymphoid organs

Lymphocytes arise from stem cells in the bone marrow and differentiate in central lymphoid organs

• B cells in Bone Marrow and T cells in Thymus

Lymph nodes

Encapsulated secondary lymphoid organs with anatomic features that favour the initiation of adaptive immune responses to antigens carried from tissues by lymphatics

Spleen

• trapping and responding to blood-borne antigens

• antigens and lymphocytes are carried into the spleen via the splenic artery

inflammation

protective, tightly regulated immune response to harmful stimuli like pathogens, dead cells, tissue damage and irritants.

• macrophages and neutrophils release prostoglandins, leukotrienes and platelet-activation factor

pattern recognitions receptors (PRR)

recognises unique microbial macromolecules by the presence of repetitive structural proteins

toll-like receptors

• found on cell surface and on intracellular membranes — can recognise microbes on in different cellular locations

IL-1B

• activates vascular endothelium, activates lymphocytes, local tissue destruction, increases access of effector cells

TNF-a

• activates vascular endothelium and icnreases vascular permeability, which leads to increase entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes

IL-6

lymphocyte activation, increased antibogy production

CXCL8

chemotactic factor recruits neutrophils, basophils and T cells to site of infection

IL-12

activates NK cells, induces the differentiation of CD4 T cells into Th1 cells

Complement system

• collection of more than 50 soluble proteins present in blood and other body fluids

• circulate in an inactive form (zymogen), that can be activated by specific trigger

functions of complement system

• initiators and mediators of complement cascases

• opsonisation

• inflammatory mediators

• lysis of pathogens

• signal specific cell functions

• regulation and degradation of complement components

major pathways of complement activation

• classical pathway

• lectin pathway

• alternative pathway

C3a, C5a

peptide mediators of inflammation, phagocyte recruitment

C3b

binds to complement receptors on phagocytes → opsonization of pathogens, removal of immune complexes

lectins and ficolins

proteins that recognise carbohydrate components as its specific receptor molecules

Major Histocompatibility comples

collection of genes encoding proteins that enable the host to distinguish self and non-self

• includes more than 200 genes and have many possible variations

• human MHC is called HLA — human leukocyte antigen, its a codominant gene

where does allelic variation occurs in MHC molecules?

• predominantly within the peptide-binding region

• most differences are localised to exposed surfaces of the extracellular domain farthest from the membrane, and to the peptide-binidng groove

Structure of MHC molecules

• broad specificity — many different peptides can bind to the same MHC molecule

• each MHC can only display on peptide at one time and bind only peptides

• stable surface expression of MHC molecule requires bound peptide

• slow off rate

Class I MHC

• idnetify all nucleated cells of the body as “self”

• bind to normal (self) peptides and antigens extracted from intracellular pathogens — signalling to the immune system that is it an infected host cell

• small binding pockey (8-11 amino acids)

• endogenous antigen processing

Class II MHC molecules

• expressed by professional antigen presenting cells

• bind to antigens degraded as a consequence of phagocytosis or receptor mediated endocytosis

• larger deeper pockets (13-30 amino acids)

• exogenous antigen processing

phagocytosis

• actin-dependent process of specifically internalising particulate targets

• ability to engage in phagocytosis is restricted to specialised cells

intracellular processing of protein antigens

• Class I MHC pathway — protein antigens int he cytosol are tagged for degradation by ubiquitylation for entry into the ubiquitin-proteosome system

• MHC II — mostly relies on lysosomal proteolysis to convert proteins into peptides suitable for presentation

B cell receptor complex

• membrane bound immunoglobulin (IgM/IgM) with a unique specificity

• two heavy chains and two light chains, each one with variable and constant region

• associated with invariant Igα and Igβ molecules which ITAMs in their cytoplasmic tails
  

T cell receptor complex

• there are two types of TCR: αβ TCRs and γδ TCRs

• heterodimer consisting of two transmembrane polypeptide chains, designated TCR α and β convalently linked to each other by a disulfide bride between extracellular cysteine residues

V(D)J recombination

• genes that encode diverse antigen receptors of individual B and T cells are generated by the recombination of different variable (V) region gene segmetnns with diversity (D) and joining (J) gene segments

postive selection

• In T cells, ensures the maturation of T cells whose receptors recognise self MHC

• In B cells, positive selection preserves receptor-expressing cells and is coupled to the generation of different B cell subsets