Transcript Slide 1
Immunology
Part I: Innate Host Resistance
Lecture #17
Bio3124
Immunity 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: Bacteria, viruses, fungi, etc.
Cells and Tissues: Cancer, blood products, organ
transplants
Operates through immune cells
Cells 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 WBC
Total and differential WBC counts changes in disease conditions
Monocytes 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)
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 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
DC
Lymphocytes
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) 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-
Pore forming agents
mediated cytotoxicity (ADCC)
recognizes cells that have lost their class I major histocompatibility
(MHC-1) antigen due to presence of virus or cancer
Primary 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 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 responses
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 memory
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 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
Skin
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: 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 nodespresents antigen to and
activates T cells
intraepidermal lymphocyte
function as T cells
Have limited antigen
receptors-specialized for
common skin pathogens
Mucous 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)
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 cellmacrophages, other
immune cells eliminate Ag
Physiologic 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 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 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 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 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 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
Opsonization
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 phagosytosis
involves nonspecific and specific
receptors on phagocytic cells
four main forms:
recognition by lectincarbohydrate 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…
microbes or components internalized as part of a phagosome
respiratory burst reactions occur
toxic oxygen products kill invading microbes
Animation: phagocytosis and antigen presentation
Inflammation
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 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…
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 inflammation