BLG10B ­ Immune System1. Innate system (nonspecific) - prepared, responds within minutes. 2nd line of defense

gets called when 1st line has been penetrated, and it relies on internal defenses (antimicrobial proteins, phagocytes & other cells)

2. Adaptive (specific) defense system - attacks particular foreign substances (3rd line)

Innate Defenses

• Mechanical barriers that cover body surfaces & cells/chemicals

• Reduce workload of adaptive system by preventing entry/spread of MO

Surface Barriers - Skin & Mucosae

• First line of defense - highly effective

• Skin & mucous membranes produce a variety of protective chemicals

• Respiratory tract mucosa have structural modifications (tiny mucus coated hairs, cilia)

Internal Innate Defenses: Cells & Chemicals

Phagocytes

• Neutrophils become phagocytic on encountering infectious material in tissues

• Macrophages derive from monocytes

• Free macrophages wander throughout tissues searching for foreign invaders

• Fixed macrophages (stellate macrophages in liver) are permanent residents of their organ

Phagocytosis

• Engulfs particulate matter

• Cytoplasmic extensions bind to particle & pull it inside, enclosing it in a vesicle

• Resting phagosome then fuses with a lysosome to form a phagolysosome

• In order for a phagocyte to ingest pathogen, it must adhere to pathogen

• Many bacteria have external capsules that cover this coat & our immune system bypasses this issue by coating pathogens with opsonins

• Opsonins = proteins/Ab+ that make handles that phagocyte receptors bind (opsonization)

• Neutrophils & macrophages can acidify the phagolysosome, digesting its contents but some pathogens (Tb) can multiply within the phagolysosome

• In this case, T helper cells release chemicals that stimulate the macrophage, activating additional enzymes producing a respiratory burst

o Liberates highly destructive free radicals

o Produces oxidizing chemicals

o Increases phagolysosome's pH & osmolarity (activates other enzymes)

• Neutrophils also pierce pathogen's membrane using defensins - antimicrobial proteins

• When phagocytes can't ingest, they can release toxic chemicals into extracellular fluid

Natural Killer (NK) Cells

• Can lyse & kill cancer cells/virus infected cells before adaptive immune system

• Nonspecific & less picky

• Can eliminate a variety of infected/cancerous cells by detecting general abnormalities such as the lack of 'self' cell-surface proteins (MHC)

• Not phagocyte - kill directly by contact, inducing apoptosis

• Secrete potent chemicals that enhance inflammatory response

Inflammation - Tissue Response to Injury

• Triggered when tissues are injured

• Beneficial effects

o Prevents spread of damaging agents

o Disposes cell debris & pathogens

o Alerts adaptive immune system

o Sets stage for repair

Inflammatory Chemical Release

• Begins with flood of inflammatory chemicals released into extracellular fluid

• Released by injured/stressed tissue & immune cells

• Can also be formed proteins circulating in the blood (Ex. Mast cells release histamine)

• Macrophages have membrane receptors allowing them to recognize invaders

• These surface membrane receptors (TLRs) trigger immune responses

• Once activated, a TLR triggers release of cytokines

• Other inflammatory chemicals include kinins, prostaglandins & complement

• All dilate local arterioles & make local capillaries leakier & attract WBCs to injured area

Vasodilation & Increased Vascular Permeability

• Redness & heat due to hyperemia (congestion with blood) occurs with dilation

• Inflammatory chemicals also increase permeability of local capillaries

• Exudate - fluid with clotting factors & Ab+ - seeps from blood --> tissues, causing edema, which presses on nerve endings (pain)

• Surge of protein rich fluids into tissue sweets foreign material into lymphatic vessels for processing in lymph nodes

• Also delivers important proteins (complement & clotting factors) to interstitial fluid

• Clotting factors form a clot that acts as a scaffold for permanent repair & it isolates the injured area and prevents bacteria/harmful agents from spreading

Phagocyte Mobilization

• After inflammation, phagocytes flood damaged areas (neutrophils then macrophages)

• If pathogens provoked the inflammation, complement is activated & elements of adaptive immunity also arrive at the injured site

o Leukocytosis - leukocytosis induced factors are released by injured cells, neutrophils enter from red bone marrow. (Increase in WBCs)

o Margination - inflamed endothelial cells sprout CAMs that signal "this is the place" so when neutrophils encounter CAMs, they steop & attach to it

o Diapedesis - continued chemical signalling prompts neutrophils to flatten & squeeze between endothelial cells of capillary walls

o Chemotaxis - WBCs migrate up gradient of chemotactine agents to the site of injury (positive) & within the hour, much foreign material at the site is devoured

• After a while, monocytes arrive & become macrophages with large lysosomes, they replace neutrophils on the battle field

Antimicrobial Proteins

• Enhance innate defenses of attacking MO directly/hindering their ability to reproduce

Interferons

• Interferons help protect cells that haven't yet been infected

• IFNs diffuse to nearby cells, which they stimulate to synthesize proteins that 'interfere' with viral replication in still-healthy cells by blocking protein synthesis & degrading viral RNA

• Because IFN isn't virus-specific, IFNs produced against a particular virus protect against other viruses too

• Family of immune modulating proteins produced by a variety of cells

o Alpha & beta - antiviral effect ^

o Gamma - secreted by lymphocytes & has widespread immune mobilizing effects, such as activating macrophages

Complement

• Group of~20 plasma proteins that normally circulate in the blood inactively

• C1-C9, factors B, D & P

Fever

• Abnormally high body temp - systemic response

Adaptive Defenses

• Body's built in specific defense system that eliminates almost any pathogen

• Amplifies inflammatory response & is responsible for most complement activation

• Unlike innate system, it must 'meet' or be primed by an intial exposure to a specific foreign substance (antigen) -- then it can protect the body

o Specific - recognizes & targets particular pathogens/foreign substances

o Systemic - immunity not restricted to initial infection site

o Has memory - recognizes & mounts even stronger attacks on previously encountered pathogens

• Humoral immunity (Ab+ mediated) - provided by Ab present in the body's fluids

• When lymphocytes defend the body, the immunity is cell-mediated immunity

o Has cellular targets

o Lymphocytes act against such targets either directly or indirectly

Antigens

• Substances that mobilize adaptive defenses & provoke immune response

• Most are large & complex molecules

Complete Antigens & Haptens

• Complete antigens have

o Immunogenicity - ability to stimulate specific lymphocytes to proliferate

o Reactivity - ability to react with the activated lymphocytes & Ab+ released by immunogenic reactions

• Proteins are the strongest antigens

• Small molecules are not immunogenic, but if they link up with the body's own proteins, the adaptive immune system may recognize the combination as foreign and mount an attack that is harmful rather than protective

• The small molecule is an incomplete antigen

Antigenic Determinants

• Only certain parts of the antigen (antigenic determinants) are immunogenic

• Free Ab/lymphocyte receptors bind to these ADs

• Different lymphocytes 'recognize' different ADs, so a single antigen may mobilize several lymphocyte populations & stimulate formation of many kinds of antibodies

• Large proteins have hundreds of chemically different antigenic determinants, which accounts for their high immunogenicity & reactivity

Self-Antigens: MHC Proteins

• Self-antigens aren't foreign or antigenic to you, but are antigen to other people

• Among the cell surface proteins that identify a cell as 'self' is a group of glycoproteins called MHC proteins

• Genes of MHC code for these proteins

• Each MHC protein has deep groove that holds a peptide (self-antigen or a foreign antigen)

• T-lymphocytes can only bind antigens that are presented on MHC proteins

Cells of the Adaptive Immune System: An Overview

• B lymphocytes - humoral immunity

• T lymphocytes - non-Ab+ producing lymphocytes that constitute the cellular arm of adaptive immunity

• APCs don't respond to specific antigens as lymphocytes do. Play essential auxiliary roles

Lymphocytes

Lymphocyte Development, Maturation & Activation

• Originate in red bone marrow from hematopoietic stem cells

• Educated:

o Immunocompetence - must be able to recognize its one specific antigen by binding to it. When B/T cells become immunocompetent, they display a unique type of receptor on their surface which enables the lymphocyte to recognize & bind a specific antigen. They are committed to react to one distinct AD. Receptors on B cells are membrane-bound antibodies.

o Self-Tolerance - Unresponsive to self-antigens

• Primary lymphoid organs (thymus & bone marrow)

• T cell education consists of positive & negative selection

• Seeding secondary lymphoid organs & circulation

• Antigen encounter & activation

• Proliferation& Differentiation

Generation of Antigen Receptor Diversity in Lymphocytes

• Our genes, not antigens we encounter, determine which specific foreign substances our immune system will be able to recognize & resist

• Antigen simply determines which existing T or B cells will proliferate & mount attack

• Our lymphocytes make up to a billion types of antigen receptors -- specified by genes

• Somatic recombination

Antigen-Presenting Cells (APCs)

• Engulf antigens & then present fragments of them on their own surfaces where T cells can recognize them

• T cells can only be activated by antigens presented to them on MHC proteins by APCs

• Major types are dendritic cells, macrophages & B lymphocytes

Dendritic Cells

• Found at body's frontiers

• Efficient antigen catchers

Macrophages

• Widely distrusted throughout lymphoid organs & connective tissues

• Often present antigens to T cells to be activated themselves

• Certain effector T cells release chemicals that prod macrophages to become activated & true 'killers' that are insatiable phagocytes and secrete bactericidal chemicals

B-Lymphocytes

• B cells don't activate naïve T cells

• They present antigens to T helper cells to obtain 'help' in their own activation

Humoral Immune Response

Activation & Differentiation of B Cells

• Immunocompetent but naïve B lymphocyte activated when matching antigens bind to it

• Antigen binding followed by receptor-mediated endocytosis of the cross-linked antigen receptor complexes (clonal selection). Followed by proliferation & differentiation

• Most cells dominate into plasma cells (Ab+ secreting effector cells of humoral response)

• Plasma cells secrete antibodies

• Secreted Ab+ each with the same antigen-binding properties as the parent B cell, circulate in blood/lymph

• Clone cells that don't become plasma cells become memory cells

Immunological Memory

• Cellular proliferation & differentiation = primary immune response

o Lag period of 3-6 days (time needed for B cells to proliferate)

• Secondary immune response

o Faster, prolonged & more effect

o Memory cells provide immunological memory

• Within 2-3 days Ab+ concentration in the plasma rises steeply to reach higher levels than in the primary response

• Secondary response Ab+ bind with greater affinity & blood levels remain high for weeks to months

• Same events occur in cellular immune response

Antibodies

• Aka immunoglobulins constitute the gamma globulin part of blood proteins

• Ab+ are proteins secreted in response to an antigen by effector B cells called plasma cells, and the antibodies bind specifically with that antigen

• Grouped in 5 classes

Ab+ Targets & Functions

• Can't destroy antigens, but can inactivate them & tag them for destruction

• Common event is the formation of antigen-antibody complexes

• Neutralization

• Agglutination

• Precipitation

• Complement Fixation & Activation

Cellular Immune Response

• T cells are best suited for cell-cell interactions

• When antigens are presented to a T lymphocytes, they provoke a cellular response

• 2 major populations of T cells based on which of the 2 structually related cell differentiated glycoproteins -- CD4 or CD8 -- a mature T cell displays

• CD4 & CD8 are surface receptors

• When activated they differentiate into 3 kinds of effector cells of cellular immunity

o CD4 cells become T helper cells that help activate B cells, other T cells & macrophages, and direct the adaptive immune response

o CD8 cells become cytotoxic T cells that destroy any cells in the body that harbor anything foreign

o Some become T regulatory cells which moderate the immune response

• Activated CD4 & CD8 cells can also become memory T cells

MHC Proteins & Antigen Presentation

• T cells can recognize & respond to only processed fragments of protein antigens displayed on surfaces of body cells

• Antigen presentation is necessary for activation of T cells & normal functioning

• Surface proteins on which antigens are presented to T cells are MHC proteins

• Two classes of MHC proteins

Class I MHC Proteins

• Found on the surface of all body cells except RBCs

• Antigens displayed are endogenous -- fragments of proteins synthesized inside the cell

• In an infected cell, endogenous antigens may also include fragments of foreign antigens that are synthesized with the infected cell but 'belong to' the pathogen

• As proteases degrade cytoplasmic proteins, a random sample of the resulting protein fragments is transported into the endoplasmic reticular

• Inside the ER, these peptides bind to newly made class I MHC proteins

• Transport vesicles export the 'loaded' class I MHC proteins to the cell surface

• Class I MHC proteins are crucial for activating naïve CD8 cells & 'informing' cytotoxic T cells that infectiious microorganisms are hiding in body cells

• When Class I MHC proteins display fragments of our own proteins, cytotoxic T cells passing by get a signal to ignore them

• But when they display foreign antigens, they signal invasion

• Class 1 MHC proteins

o act as antigen holders

o form the self part of the self-nonself complexes that Tc cells must recognize

Class II MHC Proteins

• Less wiespread

• Typically found only on the surfaces of cells that present antigens to CD4 cells: dendritic cells, macrophages & B cells

• Peptides they bind are longer & come from exogenous antigens -- antigens from outside the cell that have been engulfed by the cell that displays them

• Engulfed exogenous antigens are broken down by proteases inside a phagolysosome

• Vesicles from the ER containing Class II MHC proteins fuse with the phagolysosome & antigen fragments bind to MHC protein

• Vesicle is exported to cell surface where class II MHC proteins displays its prize for CD4 cells to recognize

• Class II MHC proteins loaded with foreign antigens signal CD4 cells that help is required

MHC Restrictions

• Different requirements for the class of MHC protein that presents antigens to them

• CD4 cells (become Th) restricted to binding antigens only on class II MHC proteins, which are typically displayed on APC surfaces

• CD8 cells (Tc) are activated by antigen fragments on Class I MHC proteins, also found on the surface of APCs. Once activated, Tc cells look for this same antigen presented on class I MHC proteins located on any cell in the body

Activation & Differentiation of T cells

Antigen Binding

• T cell antigen receptors (TCRs) bind to an antigen-MHC complex on the surface of APC

• TCR has variable & constant regions, but has 2 polypeptide chains

• TCRs must perform double recognition (self-antigen & foreign antigen)

• The TCR that recognizes the nonself-self complex triggers multiple intracellular signaling pathways that lead to T cell activation

Co-Stimulation

• Once antigen binding has occurred, T cell is stimulating but still 'idling'

• Before a T cell can proliferate, it must bind to one or more co-stimulatory signals which appear on the surfaces of APCs in tissues that are damaged or invaded by pathogens

Proliferation & Differentiation

• Cytokines released by APCs or T cells promote this process

• A period of apoptosis occurs where activated T cells die off - critical because activated T cells are hazards

• Produce huge amounts of inflammatory cytokines

Cytokines

• Chemical messengers involved in cellular immunity

• Include interferons & interleukins

• Include hormone like or paracrine like glycoproteins

• Some cytokines promote T cell proliferation

• All activated T cells secrete 1+ other cytokines that help amplify & regulate a variety of adaptive and innate immune responses

Roles of Specific Effector T Cells

Helper T Cells

• Help activate B & T cells, and help both to proliferate

• Interact directly with B cells displaying antigen fragments bound to class II MHC

o Releases cytokines that prod B cells into dividing more rapidly

o signals for Ab+ formation to begin

• Activate CD8 cells - Th cells cause dendritic cells to express on their surfaces the co-stimulatory molecules required to activate CD8 cells

• Amplification of Innate Defenses

• Subsets of Th cells - depends on type of antigen & the site at which its encountered

o Th1 - stimulate inflammation, activate macrophages & promote differentiation of cytotoxic T cells

o Th2 - defend against parasitic worms

o Th17 - release IL-17 which promotes inflammatory responses against extracellular microbes

Cytotoxic T Cells

• Directly attack & kill other cells

• Roam body, circulating in/out of blood & lymph – immune surveillance

• Main targets are virus-infected cells. Can also attack tissue, cancer & foreign cells

• Must 'dock' on the target cell by binding to a self-nonself complex

• All body cells display class I MHC antigens so Tc cells can destroy all infected or abnormal body cells

• Use perforins & granzymes

Regulatory T Cells

• Dampen immune response either by direct contact or by releasing inhibitory cytokines

• Important in preventing autoimmune reactions because they suppress self-reactive lymphocytes in the periphery -- outside lymphoid organs

Homeostatic Imbalances of Immunity

Immunodeficiencies

• Congenital/acquired conditions that impairs production or function of immune cells

• Most devastating are severe combined immunodeficiency syndromes which result from various genetic defects that produced a marked deficit of B & T cells

HIV & AIDS

• Interferes with activity of helper T cells

• Severe weight loss, night sweats, swollen lymph nodes

• Biology of HIV

o Aids caused by human immunodeficiency virus (transmitted in body secretions)

o HIV destroys Th cells depressing cellular immunity

o Virus multiples in lymph nodes throughout asymptomatic period (10 years)

o HIV targets CD4 cells via their CD4 surface proteins

o HIV envelope glycoprotein complex that fits into CD4 receptor

o Once connected, virus fuses with the target cell

o Uses viral enzyme Reverse Transcriptase to produce DNA from RNA

o DNA copy (provirus) inserts itself into target cell's DNA

• Treatment & Prevention

o Fusion inhibitors prevent virus from entering cell

o Integrate inhibitors block virus from integrating its genetic info into host

o Reverse transcriptase inhibitors & protease inhibitors inhibit important viral enzymes needed for viral replications

Autoimmune Diseases

• Loses ability to distinguish self from foreign

o Rheumatoid arthritis, myasthenia gravis, MS, grave's disease, type 1 diabetes, systemic lupus erythematosus, glomerulonephritis

• Treatment

o Most widely used treatments suppress the entire immune system

o Blocking actions of various cytokines using Ab against them or receptors

o Blocking co-stimulatory mol required to activate effector cells