Lecture #17 Bio3124 Immunology Part I: Innate Host Resistance.

Lecture #17Lecture #17Bio3124Bio3124

ImmunologyImmunologyPart I:Part I: Innate Host Resistance Innate Host Resistance

Immunity and immunologyImmunity and immunology

immunity ability of host to resist a particular disease or

infection

immune system composed of widely distributed immune cells,

tissues, and organs

recognizes foreign substances or microbes and acts to neutralize or destroy them

Antigens: considered foreign to the host Microorganisms:Microorganisms: Bacteria, viruses, fungi, etc.

Cells and Tissues:Cells and Tissues: Cancer, blood products, organ transplants

Operates through immune cells

Cells of the Immune SystemCells of the Immune System

Leukocytes (WBC) Function in innate

and adaptive branches of immunity

Hematopoietic stem cells Myeloid

Mast PMN Monoblast

Lymphoid B and T cells NK cells

Relative numbers of WBCRelative numbers of WBC

Total and differential WBC counts changes in disease conditionsTotal and differential WBC counts changes in disease conditions

Monocytes and macrophagesMonocytes and macrophages

phagocytic cells

make up monocyte-macrophage system

monocytes

mononuclear phagocytic leukocytes

~8 hours, mature into macrophages

macrophages

reside in specific tissues

variety of surface receptors

named according to tissue they reside

in

Plymorphonuclear leukocytes (PMNs)Plymorphonuclear leukocytes (PMNs)

Basophils: 2-3 lobbed nucleus, stain bluish-black with basic dyes nonphagocytic release histamine, prostaglandins, serotonin, and leukotrienes play important role in development of allergies and hypersensitivities

Eosinophils: 2-lobbed nucleus, stain red with acidic dyes defend against protozoan and helminth parasites release cationic proteins and reactive oxygen metabolites may play a role in allergic reactions

Neutrophils 3-5 lobbed nucleus, stain at neutral pH highly phagocytic circulate in blood then migrate to sites of tissue damage kill ingested microbes with lytic enzymes and reactive oxygen

metabolites contained in primary and secondary granules

Dendritic and Mast CellsDendritic and Mast Cells

Dendritic cells: present in small numbers in blood, skin,

and mucous membranes of nose, lungs, and intestines contact, phagocytose and process

antigens display foreign antigens on their surfaces (antigen presentation)

Mast cells: differentiate in blood and connective

tissue contain granules containing histamine

and other pharmacologically active chemicals

play important role in development of allergies and hypersensitivities

DCDC

LymphocytesLymphocytes

B cells (B lymphocytes) mature in bone marrow circulate in blood settle in lymphoid organs mature ->plasma cells -> produce antibodies

T cells (T lymphocytes) mature in thymus can remain in thymus, circulate in blood, or reside in

lymphoid tissue like B cells, require antigen binding to surface receptors

for activation and continuation of replication cytokines, chemicals that have effects on other cells, are

produced and secreted by activated T cells Cell mediated immunity (CMI)

Natural Killer (NK) CellsNatural Killer (NK) Cells

small population of large non-phagocytic granular lymphocytes kill malignant cells and cells infected with pathogens (viruses)

two ways of recognizing target cells bind to antibodies coating infected cells (antibody-dependent cell-

mediated cytotoxicity (ADCC) recognizes cells that have lost their class I major histocompatibility

(MHC-1) antigen due to presence of virus or cancer

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Primary and secondary Lymphoid OrgansPrimary and secondary Lymphoid Organs

Primary: immune cell production and maturation; move to secondary sites thymus

site of T cell maturation bone marrow

site of B cell maturation in mammals

Secondary: places lymphocytes may encounter and bind antigens; Proliferate, differentiation to effector cells; eg.

Spleen filter blood, phagocytes and dendritic cells capture microbes, present antigens to T and B cells

Lymph nodes: filter lymph, microbes sampled by phagocytes, B cells differentiate to plasma cells and memory cells

Secondary Lymphoid TissueSecondary Lymphoid Tissue

lymphoid tissues

throughout the body

interface btw innate and adaptive host immunity

areas of antigen sampling and processing

associated with specific tissues

skin-associated lymphoid tissue (SALT)

mucous-associated lymphoid tissue (MALT)

gut-associated lymphoid tissue (GALT)

Types of immune responsesTypes of immune responses

nonspecific immune response (innate)nonspecific immune response (innate)

also called nonspecific resistance, innate immunity, and natural immunity

acts as a first line of defense offers resistance to any microbe or foreign material lacks immunological memorymemory

specific immune response (adaptive)specific immune response (adaptive)

also called acquired immunity, adaptive immunity and specific immunity

resistance to a particular foreign agent has “memory”

effectiveness increases on repeated exposure to agent

the two types of responses usually work together

Innate Immune ResponseInnate Immune Response

Innate immune response is the first line of host defense

4 innate barriers Anatomical (physical) barriers

Skin mucous membranes

Physiologic barriers pH Temperature Chemical barriers

– Chemical mediators: gastric juice, lysosyme, antimicrobial peptides

– complement

Phagocytic barrier Macrophage/neutrophil mediated phagocytosis

Inflammatory barrier

SkinSkin

strong mechanical barrier to microbial invasion

keratin produced by keratinocytes in outer layer

inhospitable environment for microbes

organisms removed by shedding of outer skin cells

pH is slightly acidic (pH5-6)

high NaCl concentration

subject to periodic drying

Skin commensal microbial flora out competes pathogens

Skin: epidermisSkin: epidermis

microbes enter epidermis Encounter specialized skin-

associated lymphoid tissue (SALT) Langerhans cell

phagocytic cells that can internalize antigens

differentiates to dendritic cell– move to lymph nodes-presents antigen to and activates T cells

intraepidermal lymphocyte function as T cells Have limited antigen

receptors-specialized for common skin pathogens

Mucous membranesMucous membranes

protective covering in intestine, lungs, eye etc., resists penetration and traps microbes

antimicrobial secretions

Lysozyme: hydrolyzes bond connecting sugars in peptidoglycan

Lactoferrin: secreted by activated macrophages and PMNs sequesters iron

Lactoperoxidase: produces superoxide radicals

contain mucosal-associated lymphoid tissue (MALT)

Mucosal-Associated Lymphoid Tissue (MALT) Mucosal-Associated Lymphoid Tissue (MALT)

specialized immune barrier gut-associated lymphoid tissue (GALT) bronchial-associated lymphoid tissue (BALT) urogenital system

MALT: M cells pass antigen to a pocket under the cell-macrophages, other immune cells eliminate Ag

Physiologic barriersPhysiologic barriers

1. pH: eg. gastric juice, skin, urine etc., inhibitory effect on bacterial growth

2. Fever: oral temperature (37°C) rectal temperature (37.5°C)

most common cause of fever is viral or bacterial infection or bacterial toxins

endogenous pyrogen, a cytokine produced in response to pathogen, triggers fever e.g., interleukins IL-1, IL-6, tissue necrosis factor TNF

produced by macrophages in response to pathogenic microbes

after release, pyrogens hypothalamus and induce production of prostaglandins which reset hypothalamus to a higher temperature

Fever and the Host DefenseFever and the Host Defense

Augmentation of host immune defenses:

stimulation of leukocytes to destroy pathogen

enhances specific immune system activity

promote microbiostasis (growth inhibition) by decreasing available iron to microbes- hypoferremia is the redistribution of iron by fever making it less available to bacteria

In contrast hyperferremia – increased iron availability- during menstruation enhances virulence of N.gonorrhea

Physiologic BarriersPhysiologic Barriers

3. Chemical barriers

Defensins: cationic peptides, highly conserved, damage bacterial plasma membranes

rich in arginine and cystein found in neutrophils, intestinal

Paneth cells and intestinal and respiratory epithelial cells

Specific for bacterial membranes Alter cross membrane voltage, make

pores and leak ions

The Complement SystemThe Complement System

composed of >30 serum proteins produced in liver

Activated as a cascade

augments (or “complements”) the antibacterial activity of adaptive system

major roles:

defending against bacterial infections

bridging innate and adaptive immunity

Role in innate response

results in lysis of bacteria

mediates inflammation

Opsonization: attracts and activates phagocytic cells

Complement: alternative pathwayComplement: alternative pathway

Series of proteins Activate each other via

proteolytic cleavage C3 normally made and degraded

quickly Stabilized by Gramˉ LPS Inserts into bacterial outer

membrane Reacts with other components

Factor B, Factor D, Properdin Cleaves C5 to C5b

Complement C5b protein binds C6, C7 Forms pre-pore complex in target

cell membrane C8, C9 proteins attach Forms membrane attack complex

Lyses target membrane

Phagocytic barrierPhagocytic barrier

Phagocytosis: non-specific mechanism

monocytes, tissue macrophages, dendritic cells and neutrophils recognize; ingest and kill microbes

pathogen recognition involves two mechanisms:

Opsonic recognition mechanism Opsonins: complement factors or antibodies

Non-opsonic mechanism common pathogen components are non-

specifically recognized & activate phagocytes

OpsonizationOpsonization

process in which microbes

are coated by serum

components in preparation

for recognition/ingestion by

phagocytic cells

molecules that carry out

above are called

opsonins

some complement proteins

are opsonins

bind to microbial cells,

coating them for

phagocyte recognition

Opsonin-Independent phagosytosisOpsonin-Independent phagosytosis

involves nonspecific and specific

receptors on phagocytic cells

four main forms:

recognition by lectin-

carbohydrate interactions

recognition by protein-protein

interactions (eg. RGD motif and

receptor)

recognition by hydrophobic

interactions

detection of pathogen-associated

molecular patterns (PAMPs) by

pattern recognition receptors

(PRRs, e.g., toll-like receptors)

Back to Phagocytosis…Back to Phagocytosis… microbes or components internalized as part of a phagosome

respiratory burst reactions occur toxic oxygen products kill invading microbes

Animation:Animation: phagocytosis and antigen presentationphagocytosis and antigen presentation

InflammationInflammation nonspecific innate response to tissue injury

can be caused by pathogen or physical trauma acute inflammation is the immediate response of

body to injury or cell death the release of inflammatory mediators from injured

tissues initiates a cascade of events which result in the signs

of inflammation cardinal signs

redness (rubor) warmth (calor) pain (dolor) swelling (tumor) altered function (functio laesa)

Acute Inflammatory ResponseAcute Inflammatory Response

involves chemical mediators Chemokines: released by injured cells

Selectins: cell adhesion molecules on activated capillary endothelial cells

Integrins: adhesion receptors on neutrophils

various processes occur Margination, diapedesis, extravasion

More About Acute Inflammation…More About Acute Inflammation…

events which result in elimination of invading

pathogens

capillary dilation and increased blood flow bring more

antimicrobial factors and leukocytes that kill pathogens

temperature rise stimulates inflammatory response

fibrin clot may restrict pathogen movement

phagocytes accumulate in inflamed area and destroy

pathogens

bone marrow is stimulated by various chemicals to release

neutrophils and increase rate of granulocyte production

Animation: Acute inflammationAnimation: Acute inflammation