Basis Exam 3

what is the immune system and what is its primary goal/function

Collection of organs and vessels used to produces and delivers cells and molecules that protect us from disease

all BLANK have evolved a fully functional immune system

vertabrae

primary function of the immune system

recognize threat

eliminate threat

distingush between self and non self

mechanisms of an immune response

recognize activation deployment discrimination (self vs non-self) regulation (once all non-self are gone, stop the response)

wha are the four cardinal sign of acute inflimation

redness swelling heat pain

response of our bodies to infection or antigen (general)

Proteins, fluids, and cells from the blood all rush to the site Cytokines help attract immune cells Innate and adaptive immunity are active during a response

antigen

substance that produces immune response

antibody

protien produced by the body in response to pathogen (antigen), specific pathogen

slef-tolerance

The ability of immune cells to recognize "self" to prevent releasing its destructive components onto self tissues

failure of self tolerance

when the immune system sees "self" as an antigen and leads to the development of autoimmune diseases

what are the two interconnected system in immunity

innate immunity and adaptive immunity

innate immunity characteristics

Built-in molecular and cellular mechanisms

Encoded in the germline of the cells (body can make cell)

Evolutionary more primitive Includes physical barriers (skin, pH, mucous membranes) includes serum proteins: complement

Reaction time: minutes to hours (very quick)

no memory, not long lasting protection antigen nonspecific

adaptive immunity chracteristics

Capable of adapting to subtle molecular differences in pathogens Involves B and T lymphocytes Reaction time: Days (slower) Infinitely specific Evolves in real-time very powerful, very specifice induces memorys, respond rapidly and vigorusoly to second antigen exposure

Successful immune response to a pathogen requires

a choreographed interaction of a diverse group of cells

what type of immunce cells mount the first line of defense

innate immune cells

Phagocytes engulf.... (regarding innate immunity)

engulf pathogen and process an antigen to present

Antigen presenting cells (APCs) communicate the infection with...(regarding innate immunity)

lympohid cells (Tcells and Bcells)

Lymphoid cells coordinate the....

adaptive immune response and generate memory cells which prevent future infections

immunological componets of innate immunity

naturals barriers to infection: skin, mucous membranes cells: phagocytes, NK cells, innate lympohid cells mediators: complement, defensins, cytokines, sensors (TLR, NOD-like receptors, RAG-1)

immunolgic componets of adaptive immunity

t-lympochytes-cell mediated, B lymphocytes-antibody mediated, APCs) secreted molecules (cytokines chemokines, complement)

innate immune system physical defense

skin gastrointestinal tract respiartory tract

innate immunity mechanical defenses

normal urine flow tears salivia normal flora

innate immune system cells (leuokocytes)

Monocytes/macrophages

Mast Cell

Granulocytes

a. Neutrophils

b. Eosinophils

c. Basophils

5 compents of innate immune system

phsycial defense

mechanical defenses

cells (leukocytes)

complements system

other soulble mediators

Barrier Functions of Innate Immunity

Few microorganisms penetrate intact surfaces and tissues Epithelial cell layer mucous (respiratory tract) GI tract: stomach acid

epithelial cell layer in innate immunity

Skin, airways, GI tract and genitourinary tract Produces powerful antimicrobial peptides • Lysozyme • Defensin

mucous (repiratory tract) in innate immunity

Mixture of mucins, proteins, proteases, protease inhibitors Inhibits bacteria ability to adhere to epithelial cells Bacteria become entrapped by mucus and are removed by ciliary clearance

GI tract: Stomach acid in innate immunity

Acid and proteolytic enzymes hostile to many bacteria

tissues and organs of the immune system: primary lympohid organs

bone marrow thymus

bone marrow

Pluripotent stem cells become immune system cells (CD4+, CD8+, CD34+ cells)

thymus

T cell maturation and differentiation T cells are groomed and "taught" to recognize and not attack self tissues T cells which attack self tissues are deleted

tissues and organs of the immune system: secondary lympohid organs

spleen lymph nodes

spleen

80% Red matter / 20% White matter Red matter: primary site of removal and destruction of old or damaged red blood cells White matter: mostly B & T lymphocytes and macrophages

lymph nodes

You have hundreds Encapsulated lymphatic tissue Immune system superhighway connected by lymph vessels Located at points of lymphatic drainage Primary function is to filter antigens from the lymphatics

red and white matter is

blood

pluripotent stem cell examples

CD4+ CD8+ CD34+

embryonic stem cell

"Baby" stem cell Pluripotent stem cell - can become ANY cell in the body

Hematopoietic Stem Cells (HSCs)

CD34+ "Adult" stem cell ability to "self-renew" differentiate into a diverse group of blood cells can't just become any cell like pluripotent stem cells

pluripotent stell cell

can become ANY cell in the body

cells of the innate immunce system

Eosinophil Neutrophil Macrophage/Monocyte Mast cell/Basophil Dendritic cell Natural Killer cell

Immune System Dysfunction

Hypersensitivity (including allergies) Autoimmune Diseases Immune Deficiency

Hypersensitivity

allergies

Exaggerated response to benign but foreign antigens asthama, pollen, food, animal dander anaphlyaxis

anaphylaxis

extreme, rapid, and sometimes lethal over-reaction of the immune response caused by IgE antibodies binding to the antigen

IgE-antigen complex triggers the releases of

inflammatory mediators and the recruitment of immune cells and fluid at the site

Common symptoms of IgE antibodies binding to antigen/hypersensitivity

sneezing, wheezing, difficulty breathing, skin eruptions (hives), up to sever bronchoconstriction

Autoimmunity

Targeting of self proteins or tissues (e.g. breakdown of self-tolerance) Chronic attack of self tissues can lead to organ/tissue destruction Genetic and environmental factors likely involved

4 types of autoimmune response

Multiple sclerosis Crohn's disease Type 1 diabetes Rheumatoid arthritis

multiple sclerosis(autoimmunity)

protien on nerve sheaths in the CNS are attacked

crohn's disease (auto immunity)

attack on intestinal tissues leads to gut destruction

type 1 diabetes(autoimmuninty)

attack an permant desitruction of the beta cells in the pancrea

rheumatoid arthritis (autoimmunity)

attack of the joints of the hands, feet, arems and legs

Immune Deficiency

Absence or defect in either innate or adaptive immunity Insufficiency of immune response to protect against infectious agents Poor immune response results in pathogens having competitive advantage can be primary or secondary Severity depends on number and type of immune response components affected

primary immunodeficency

results from genetic factors

Secondary immunodeficiency

results from immune system damage by chemical, chemotherapy, physical or biological agents

Immunoglobulin A deficiency (immune deficeny)

increased infections (may go unnoticed)

Severe combined immunodeficiency (immune deficeny)

T and B cells affected (wipes out adaptive immunity and results in early death)

HIV (immune deficency)

reduces T helper cells blunting the adaptive immune response, when T helper cell number reach zero = collapse of adaptive immunity

• Myeloid lineage

cells that arise from a common myeloid progenitor (CMP) cell Erythrocytes and platelets (not immunologically active) Granulocytes • Neutrophils • Basophils • Eosinophils

Lymphoid lineage

come from common lymphoid progenitor (CLP) B lympocytes T lympohcytes

Granulocytes

Neutrophils Basophils Eosinophils As a class, they are the first responders of the immune response All granulocytes are leukocytes (white blood cells) Multi-lobed nuclei make sets them apart from lymphocytes Contain granules that get released upon contact with pathogens Granules can have a variety of functions (based on cell type)

general functions of granules

Damage pathogen directly Direct traffic for other white blood cells Tissue remodeling at site of infection

mast cells

technically a granulocyte but is not in the blood....stays in tissues and is kind of ignored when discussing granulocytes

Neutrophils

50-70% of circulating leukocytes Professional phagocyte (Phagocytose pathogens opsonized with complement or IgG into lysosomes) Polymorphonuclear cells (PMNs) (another name for it) First cells to respond to an area of damage or inflammation Primary defense against invading bacteria Primary function is phagocytosis ("small eater") Numbers in circulation spike in the presence of an infection Migrate to infected/inflamed tissue in response to chemotactic factors Granular contents are released into the lysosomal space which destroys pathogens essentially good at injesting and clearing pathogens

neutrophils: segmented(segs)

Most mature neutrophils Usually the majority of circulating neutrophils

neutrophils: banded (bands)

Less mature Adhere to blood vessels of peripheral blood, lungs, spleen and liver Usually less in circulating blood

neutrophils: left shift

Bands counted on left of microscope in lab; Segs counted on right Shift from more segs to more bands in circulating blood Sign of infection (usually bacterial) Mature neutrophils (segs) being used up fighting the infection Immature neutrophils (bands) are being pumped out to help

basophils

<1% of circulating leukocytes

Non-phagocytic Release inflammatory mediators in response to antigen binding IgE on its cell surface •

Histamine (very potent): Increases blood vessel permeability and smooth/dialate blood vessels to get immune cells to site of inflamation muscle activity, they contain and relase them

Leukocyte most associated with IgE mediated inflammation

eosinophils

1-3% of circulating leukocytes Motile phagocytes, freely move from blood to tissues and back Primary defense in parasites (things too big for phagocytosis) Are capable of phagocytosis (but not a professional) • Primarily antibody complexes Usually found in high numbers • Around antibody-antigen complexes • Clustered around large parasites/worms • In tissues infected with parasites Attach to parasites and exocytose their granules into the microenvironment causing cellular lyses of the parasite

monocytes(innate immunity leukocyte)

5-10% of circulating leukocytes Heterogeneous group of cell types • Bone marrow: pro-monocytes • Blood: differentiate into mature monocytes • Inflammatory monocytes: • Patrolling monocytes:

inflammatory monocytes

Enter tissues quickly in response to infection

patrolling monocytes

Crawl slowly along blood vessels and are more involved in stopping immune reaction

MONOCYTES/MACROPHAGES (innate immunity lekoucytes)

macrophages formed when monocyte migrate into various tissues in response to infection Macrophages (tissue) are more active and have more Fc and complement receptors (activate easier) • Professional APC; Professional phagocyte • Specialize in the tissues 1. Kupffer cells in the liver 2. Osteoclasts in the bone 3. Microglial cells in the CNS

kupffer cells in

liver

osteoclasts in

the bone

micorglial cells in the

CNS

Mast cells

Professional phagocyte • APC but NOT a Professional APC Release inflammatory mediators (eg histamine, heparin, serotonin) Are associated IgE-mediated inflammation • skin, lungs, nasal mucosa, and connective tissues Can phagocytize, destroy, or present bacterial antigens to T lymphocytes (so an APC but not a professional APC)

Natural Killer Cell (NK Cell)

Uniquely equipped to kill variety of infected cells and controlling early signs of cancer • Virus infected cells • Cancer stricken cells Viruses and tumors minimize MHC Class 1 expression to avoid CD8+ detection Recognizes MHC 1 on cell surfaces • MHC Class 1 recognition sends a "stand down" signal to NK Cells • Attacks cells that have lost their MHC 1 expression Kill cells via cytotoxic granules (perforin and granzymes)

Dendritic Cells

Professional Antigen presenting cell (APC) Professional phagocyte Process antigen and present to T cells The "Messenger" between innate and adaptive immune system Concentrate in tissues that contact external environment (skin, lungs, nose, stomach) Once activated, move to lymph nodes and interact with T cells and B cells (hence messenger status)

Microbial Sensors of Innate Immunity

When pathogens penetrate the skin they are confronted by phagocytes with "microbial sensors" Evolutionary products called pattern recognition receptors (PRRs) that recognize molecular patterns on pathogens Critical role in initiating the innate immune response (cytokine release) Three major groups of phagocyte "microbial sensors" (PRRs) 1. Toll-like receptors (TLRs) 2. NOD-like receptors (NLRs) 3. RIG-I-like helicase

Three major groups of phagocyte "microbial sensors" (PRRs)

Toll-like receptors (TLRs) NOD-like receptors (NLRs) RIG-I-like helicase

Phagocytosis: innate immunity

Follow chemoattractant signal Use adhesion molecules to stop at site of infection Recognize, engulf, create endocytic vesicle (phagosome), kill pathogen May occur with or without antibody Most efficient when antibodies coat target (opsonization) Opsonization can occur several ways 1. IgG alone can act as opsonin 2. Antibody and antigen complex triggers complement which generates opsonin (classic pathway) 3. Alternative pathway of complement activation via build up of C3b

Antimicrobial mechanisms that eliminate pathogen in phagosome: innate immunity

Acidification in the phagosome

Toxic oxygen-derived products are generated (hydrogen peroxide)

Toxic nitrogen oxides are produced Antimicrobial peptides

Different phagocytes use different mechanisms (these are most common)

several ways of opsonization

IgG alone can act as opsonin Antibody and antigen complex triggers complement which generates opsonin (classic pathway) Alternative pathway of complement activation via build up of C3b

COMPLEMENT SYSTEM: COMPONENTS

Key component of innate immunity 30+ proteins found in the blood or on cell membranes Cascade that clears infective pathogens Complement is activated through a sequence of enzymatic reactions (complement cascade) Recruits cells of the adaptive immune system Once activated lysis of the cell wall is compromised via Membrane Attack Complex (MAC)

Complement System: Function

Major functions of complement 1. To lyse certain microorganisms and cells via MAC 2. To stimulate the chemotaxis of phagocytic cells 3. To coat (opsonize) foreign pathogens to promote phagocytosis There are two different pathways to stimulate the complement cascade 1. Classic pathway 2. Alternative pathway

Compliment System: Activation Pathways

classic, alternative pathway, and membrane attack complex (MAC)

classic pathway of compliment

antibody binds to its target antigen and activates the complement cascade IgG and IgM can activate complement

the alternative pathway of compliement

Relies on the inability of some bacteria to clear spontaneously produced C3b from their cell surface Buildup of C3b on the cell activates complement

Membrane Attack Complex (MAC)

End result of the complement cascade Cylinder shaped protein that gets inserted into the pathogens cell wall MAC causes cell lysis • allows fluid entry causing the cell to swell and eventually lyse

3 end functions of compliment

Opsonize pathogens Recruit inflammatory cells Kill pathogens with MAC

Things that differentiate the adaptive immune system:

1. Specificity 2. Memory 3. Ability to amplify the immune response via cytokines 4. Evolves with each subsequent antigen exposure

Adaptive System Major Arms

humoral arm

cell-mediated arm

humoral arm

think proteins dissolved in the blood

humor=serum

Soluble immune proteins in the blood

1. Antibodies (B cells become plasma cells and make antibodies)

2. Complement interactions with adaptive immune system

cell-mediated arm

T lymphocytes (CD4+ and CD8+)

• Thymus derived lymphocytes

• Defend against infections that are intracellular (viruses)

CD4 T cells encourage B cells to become plasma cells and make antibodes

Lymphoid progenitor cells develop into

to main lymphocyte populations

what are products of Lymphoid progenitor cells(cells of the adaptive immune system)

T cells and B cells

T cells are specific for BLANK antigens

individual

antigens are presented to the T cell receptor (TcR) by...

APCs

Antigens are presented to the T cell receptor (TcR) by APCs which initiates what and results in what

initiates T cell activation and result in clonal proliferation of T cell against that antigen

T lympohocytes develop in the BLANK from HSCs into BLANK

bone marrow into common lymphoid progenitor (CLPs) cells