Introduction to the Immune system: Lectures 1 and 2Hugh Bradyh.brady@imperial.ac.ukRecommended textbook: Janeways Immunobiology (7th Ed) 2008, Garland Science

Why study immunology?Several reasons, most important in terms of numbers:Infectious diseases are a major burden worldwide

Major challenges are HIV/AIDS, TB and malaria42 million people living with HIV and AIDS worldwide Malaria causes more than 300 million acute illnesses and at least one million deaths annuallyAn estimated two million deaths resulted from tuberculosis in 2002

We need new strategies or vaccines to prevent or treat infectious disease

Do pathogens want to kill us? Does theimmune system (usually) win the ght with pathogens, enabling survival of the host?

Or does the pathogen evolve to adapt to the host, including the host immune response, enabling it to more effectively persist?

Virulence and evolutionary fitness

Multiple theories:Virulence (damage to host) is detrimental to pathogen: a dead host is less effective at transmissionHighly virulent pathogens are recently emerged and will evolve towards lower pathogenicityVirulence factors confer increased fitness to pathogenVirulence may increase as pathogens evolve. Are both true? Perhaps virulence increases to a limit, after which it iscounterproductive to the pathogenMust also consider that immune response is often responsible for host damage

The role of the immune systemTo protect us from infection:

Viruses; 20-400nm (obligate intracellular)Bacteria; 1-5 mmFungi; 2-20 mmProtozoan parasites; 1- 50mmMetazoan parasites (worms) 3mm 7m

Apart from infectious diseases, why else study immunology?Autoimmune disease eg multiple sclerosis, rheumatoid arthritis

Allergy Allergy and asthma prevalence increasing300 million people suffer from asthma and >180 000 die annuallyAsthma deaths are predicted to increase by almost 20% in the next 10 years

Unwanted responses transplantation.

The immune systemPhysical barriersCellsSoluble effector proteins complement, antibodiesCytokines communication

Cells of the immune system

Lymphocytes are mostly small and inactive cells

An infection and the response to it can be divided into a series ofstages

Innate immunityMany barriers prevent pathogens from crossing epithelia and colonizing tissues

Time frame for different stages of immune response

The innate immune responseMediated (initiated) by phagocytes, NK cells and soluble proteinsPhagocytesCells specialized in the process of phagocytosisMacrophagesReside in tissues and recruit neutrophilsNeutrophilsEnter infected tissues in large numbersRecognize common molecules of bacterial cell surface using a few surface receptorsPhagocytosisCapture, engulfment and breakdown of bacterial pathogen

The largest cells in the bloodMonocytes are the precursors to macrophages in the tissueCan be tissue resident or recruited to sites of inflammationEngulf and kill viruses and bacteriaImportant for antigen presentation to T cellsMonocyte / macrophage

Macrophages are activated by pathogens and both engulf them and initiate inflammatory responses

Pattern recognition in innate immunityMicrorganisms have repeating patterns of molecular structure on their surfacein cell walls of Gram-positive and Gram-negative bacteriaPeptidoglycan molecules

Other microbial elements with repetitive structureBacterial DNA with unmethylated CpG dinucleotide repeats

The repetitive structures are known as pathogen-associated molecular patterns (PAMPs) and the receptors that recognise them as pattern recognition receptors (PRRs)

PhagocytesMost common leukocyte (white blood cell) in blood (up to 80%)Distinctive lobed nucleus and intracellular granulesHighly motile, they respond rapidly to inflammatory stimuli by migrating out of the blood and into tissues in large numbers.Recognise, engulf and kill viruses and bacteriaShort life span about 24hrsDead neutrophils are a major constituent of pus!Neutrophils

The innate immune responseInflammatory response enhances phagocytosis through acute phase proteinsMannose-binding lectin (MBL)Binds to bacterial surface with particular spatial arrangement of mannose or fucoseC-reactive protein (CRP)Binds to phosphorylcholine on bacterial surfaceComplementSet of proteins which bind to bacterial surface

Inflammatory responseAccumulation of fluid and cells at infection site (swelling, redness, heat and pain)

Complement system

Complement systemPre-formed protein cascade: Punches holes in pathogen membranes Alerts and recruits other components of immune system to danger Coats pathogens for uptake by phagocytes: opsonisation

Innate immunityFirst line of defence against infectionPre-existing or very rapid response (hrs)Recognition of pathogens is based upon pattern recognition (PAMPs) using germline encoded receptors (PRRs) or proteins.Non-adaptive No memoryEvolutionarily early

Acquired / adaptive immunitySpecific to a particular antigen detected by specific receptors on T and B cells

Response improves with time

Results in MEMORY =Protection against re-infection with the same pathogen

Evolutionarily late only present in vertebrates

Involves T and B lymphocytes

B cellsProduce antibodiesSometimes called humoral immunity

T cellsT cell receptor (TCR)

only recognises foreign antigen as a peptide on an MHC molecule presented by an antigen presenting cell (APC)

Pathogen Recognition: T and B cell receptorsT and B cells have receptors specific for only one antigen

Genes for the antigen receptors are re-arranged in each cell every cell is different

Gene rearrangement results in receptors that can recognise a huge variety of antigens (108 different specificities in a human at one time)

T and B cell responses are initiated in secondary lymphoid organs - lymph nodes and spleenHaematopoiesisB cellsNeutrophils etcT cell development

Primary and secondary immune responses

Smallpox - an immunology success storyEvolution of smallpox lesions on proximal upper extremity on days 3, 5, and 7 of lesions

1796 Exposure to cowpox protects against smallpox

Jenner

SmallpoxVaccinationwell known in16th centuryChina

Smallpox is the only major human disease to have been eradicated.

The Adaptive Immune responseCreates millions of different B and T cells for specific antibody-mediated and cell-mediated immunityAntibody-Mediated Immunity (AMI)Involves B lymphocytes, plasma cells and antibodiesHumoral immunityName derives from antibodies found in body fluids (humors - old medical term)Cell-Mediated Immunity (CMI)Involves T lymphocytes, antigen-presenting cells and MHC (major histocompatibility complex) moleculesCellular immunity

Antibody-mediated (humoral) immunityDirected against extracellular microorganisms and toxinsB-lymphocytes (B cells)Differentiate into plasma cells which produce antibodiesFunction as antigen-presenting cells (APCs)Classification of Antibodies (Immunoglobulins)Immunoglobulin M (IgM)Immunoglobulin G (IgG)Immunoglobulin A (IgA)Immunoglobulin D (IgD)Immunoglobulin E (IgE)

Cell-mediated immunityDirected against intracellular microorganisms Phagocytic cells and nonphagocytic cellsT-lymphocytes (T cells)Differentiate into effector cells following antigen presentation by antigen presenting cells (APCs)Activate B lymphocytesFunctional types of T cellsHelper (CD4 T cells)TH1 and TH2 cellsCytotoxic (CD8 T cells)Regulatory (Suppressor)CD4 Tregs CD8 Tregs

The nature of antigensHistorically named as antibody generatorsMolecule which stimulates production of and binds specifically to an antibodyContemporary view distinguishes betweenAntigenMolecule which can bind to specific antibody but cannot elicit adaptive immune responseImmunogenMolecule which can stimulate adaptive immune responseBest immunogens are proteins with MW > 10,000

The nature of antigensCarbohydrates, nucleic acids and lipids are also potential antigens / immunogensHaptenSmall (low MW) molecule unable to elicit immune responseCombines with larger carrier molecule which together function as immunogenAntibody may react independently with hapten following hapten/carrier adaptive immune responseExamplePenicillin G (MW of 372)Albumin (MW of 66,000)

Antigens are the moleculesrecognized by the immuneresponse

Epitopes are sites withinantigens to which antigenreceptors bind

An antibody binds an antigen directly whereas a T-cell receptor bindsa complex of antigen fragment and self molecule

The nature of antibodiesAntibodies are glycoproteinsExist as monomers, dimers or pentamers of basic structureBasic antibody structure has 4 polypeptide chains2 identical light chains2 identical heavy chainsRegions of heavy and light chainsVariableConstant

The nature of antibodiesAlso referred to asImmune globulins / Immunoglobulins (IG)Immune serum globulins (ISG)Gamma globulinsContemporary immunologyAntibodySecreted form of IG made by plasma cellsImmunoglobulinAntigen binding molecules of B cells (B cell antigen receptors)

Classification of Antibodies (Immunoglobulins)Five (5) classes (isotypes)IgAIgGIgMIgDIgEBased on structural differences in constant regions of heavy chainsClasses have specialized effector functions

High affinity IgG and IgA antibodies neutralize bacterial toxins and can inhibit infectivity of viruses

IgE has specialized role activating Mast Cells

B cells and antibody-mediated immunityB lymphocytes originate from stem cells in bone marrowMaturation takes place in bone marrow followed by migration to secondary lymphoid tissueAntigen exposure in secondary lymphoid tissueFollowing exposure to antigen, B lymphocytes differentiate into plasma cells and memory cellsPlasma cells produce antibodies of all IG class