lecture #17 bio3124 immunology part i: innate host resistance
TRANSCRIPT
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