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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:
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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)
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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
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Factor B, Factor D, Properdin
Cleaves C5 to C5b
 Complement C5b protein binds C6, C7
 Forms pre-pore complex in target
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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
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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
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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