The Immune System: Inflammation and Innate Immunity

OVERVIEW OF THE IMMUNE SYSTEM

- Immune system: a collection of organs, tissues, POLYMORPHONUCLEAR LEUKOCYTES
cells, and cell products that work together to - Also called granulocytes
differentiate cell from non-self - Multibody nuclei
1. Innate Immunity - Neutrophils
§ First line of defense 1. Make up nearly all PMNs in blood
§ Non-specific 2. Engulf microbes by phagocytosis
§ Present before birth - Basophils and Eosinophils
§ Always on 1. Phagocytose less efficiently
2. Adaptive Immunity 2. Release products toxic to microbes
§ Slower response, more specific 3. Vasoactive chemical mediators à
§ Faster if immune system is important for inflammation
primed à generates memory cells
§ Must “see” antigen MAST CELLS
• Antigen: any chemical - Contain many granules rich in histamine and
compound, chemical, or heparin
foreign structure to the - Similar in structure to basophils
body that will elicit an - Reside in connective tissue and mucosa
adaptive immune response - Do not circulate in the blood
such as the production of - Role in inflammation, wound healing, and allergy
antibodies response (high affinity receptors for IgE
antibodies)
CELLS OF THE IMMUNE SYSTEM
- Blood is composed of 2 portions: liquid (plasma) MONOCYTES, MACROPHAGES, AND DENDRITIC CELLS
and solid (RBCs, WBCs, platelets) - Monocytes
- WBCs stem from precursors stem cells produced 1. Single nucleus
in bone marrow 2. Engulf foreign material
1. Can differentiate in myeloid (innate) 3. Precursors of macrophages and dendritic
and lymphoid (adaptive) stem cells or cells
erythroid stem cells (give rise to RBCs - Macrophages
and platelets) 1. Widely distributed
2. Phagocytose foreign material
2. WBCs of innate immunity:
3. Innate: kill foreign invaders directly
§ Polymorphonuclear leukocytes
4. Adaptive: present antigens on cell surface
(PMNs)
to T cells à antigen presenting cells (APCs)
§ Monocytes
- Dendritic Cells
§ Macrophages
1. Located in spleen, lymph nodes, and
§ Dendritic cells
Langerhans cells
§ Mast cells
2. Phagocytose
§ Natural Killer cells 3. APC
4. Can pick up soluble antigens from
DEVELOPMENT OF WBCs environment
5. Important in adaptive immune response

WHITE BLOOD CELL DIFFERENTIALS

- White blood cell differential: balance and total
of all WBCs in the blood
1. Elevated neutrophils à possible bacterial
infection
2. Elevated lymphocytes à possible viral
infection
3. Elevated eosinophils à possible allergy or
parasitic infection
 The Immune System: Inflammation and Innate Immunity

LYMPHOID ORGANS 3. Gut-associated lymphoid tissue (GALT)

- Lymphoid stem cells à lymphocytes and natural § Includes tonsils, adenoids, Peyer’s
killer cells patches
1. Lymphocytes are main participants in AIS § Key antigen sampling and
- Primary lymphoid organs adaptive immunity inductive sites
1. Lymphocyte maturation occurs here w/in intestinal wall
§ Bone marrow (B cells) produce § M Cells: part of Peyer’s patches
antibodies that take up microbes from
§ Thymus (T cells) à aid in intestines and store for
antibody production; effectors of macrophage phagocytosis
antigen-specific immunity
- Secondary lymphoid organs PHYSICAL BARRIERS TO INFECTION à LUNGS
1. Where lymphocytes encounter antigens - Cilia line the nasal cavity
§ Lymph nodes - Sneezing: forceful expulsion of air from lungs to
2. Spleen clear organism from respiratory tract
3. Peyer’s patches - Respiratory Mucociliary elevator
4. Tonsils, adenoids - Organisms that make it to the alveoli are not
5. Appendix easily expelled
1. Met by alveolar macrophages to
PHYSICAL BARRIERS TO INFECTION à SKIN phagocytose
- Protective shield covered w/ keratin
- Sebum for protection CHEMICAL BARRIER TO INFECTION
1. Acidic pH inhibits bacterial growth - Acidic pH of stomach
- Competition limits colonization by pathogens - Lysosomes in tears à degrade cell walls of gram-
- Constant shedding positive bacteria
- Skin-associated lymphoid tissue (SALT): - Superoxide radicals like lactoperoxidase
recognizes microbes that may slip past physical - Defensins: Small cationic peptides that kills by
barrier destroying microbial cytoplasmic membrane
1. Langerhans cells phagocytose 1. Effective against gram-positive and
gram-negative bacteria, fungi, some
PHYSICAL BARRIERS TO INFECTION à MUCOUS viruses
MEMRBANES
- Form largest interface between human host and THE INFLAMMATORY RESPONSE
environment - Phagocytic cells can enter tissues via
- Non-specific defense mechanisms extravasation (usually confined to bloodstream)
1. Barrier against invading pathogens - Signs of inflammation (HERPA)
§ Tight junctions 1. Heat @ site
§ Selectively permeable 2. Edema
2. Mucous coats surfaces and traps microbes 3. Redness
§ Lysosome: chemical barrier to 4. Pain
prevent infection; cleaves cell 5. Altered function or movement @ the
wall peptidoglycan affected site
§ Lactoperoxidase: produces toxic - Basic inflammatory response
superoxide radicals 1. Host becomes infected
- Semi-specific innate immune defense 2. Macrophages engulf pathogens and
mechanisms release cytokines
1. Microbe-associates molecular patterns 3. Vasoactive factors and cytokines deliver
(MAMPs) additional macrophages
2. Mucosa-associated lymphoid tissue (MALT) 4. Some cytokines initiate healing
§ Populated by T cells, B cells,
plasma, and macrophages
§ Target antigens that mass
through mucosal epithelium
 The Immune System: Inflammation and Innate Immunity

- Acute inflammatory response KILLING MECHANISMS OF PHAGOCYTOSIS

1. Traumatic introduction of microbes - Phagosome formation
2. Macrophages engulf microbes, release - Phagosome-lysosome fusion (phagolysosome)
cytokines and chemokines permits:
3. Cytokines cause capillary vasodilation 1. Oxygen-independent mechanisms
and loosening of endothelial tight § Lysozyme à destroys cell walls
junctions § Lactoferrin à bind iron and keep
4. Cytokines initiate synthesis of selectins it away from bacteria
on endothelial cells § Defensins
§ Bind to carbohydrates on 2. Oxygen-dependent mechanisms
neutrophils à expression of ICAM-1 § Kill by making various highly
and ICAM-2 reactive oxygen radicals that
5. Neutrophils squeeze through more bind and damage lipid, proteins,
permeable endothelium DNA, and RNA
6. Bradykinin activates mast cells to 3. Macrophages, mast cells, and neutrophils
degranulate and stimulates generate reactive nitrogen intermediates
prostaglandin production to register pain that serve as potent cytotoxic agents
- Chronic inflammation
1. Results from persistent presence of a SURVIVING PHAGOCYTOSIS
foreign body causing persistent tissue - Live within a phagosome à Coxiella
damage - Escape from the phagosome
2. Causes of chronic inflammation 1. Gain access to cytoplasm
§ Infection 2. Shigella and Listeria
• Body may form a - Prevent phagosome-lysosome fusion
granuloma à aggregation 1. Secrete proteins
of mononuclear 2. Salmonella
inflammatory cells - Trigger apoptosis
surrounded by 1. Shigella
lymphocytes
§ Nonliving, irritant material NATURAL KILLER CELLS
• Wood splinters, asbestos, - Effector lymphocytes of innate immune systems
surgical implants that control several types of tumors and
microbial infections by limiting spread and tissue
PHAGOCYTOSIS damage
- Phagocytotic WBCs have protective measures to - Don’t kill microbial cells directly à seek out and
not accidently phagocytose host/self-cells destroy affected host cells
- Human cells contain glycoprotein CD47, bacterial - Recognize target cells in one of 2 ways:
cells do not 1. Major Histocompatibility Complex (MHC)
- Some bacteria like Streptococcus pnemoniae are class 1 molecules
not easily phagocytized § Found on all host cells
1. Need to undergo opsonization à joining § If no MHC class 1 molecules, cell is
of innate and adaptive immune forces destroyed
- Opsonization: coating of pathogens with 2. Antibody Fc Receptors
antibodies in order to increase their § Antibody-dependent cell-mediated
susceptibility to ingestion by phagocytes cytotoxicity (ADCC)
1. Adaptive immunity produces antibodies § When Fc receptors on NK cells
which bind to antigens link to an antibody-coated host
2. Antibodies bind to bacterial cell cell
3. Fc region (antibody tail) points outward
allowing phagocyte to bind and engulf
 The Immune System: Inflammation and Innate Immunity

NATURAL KILLER CELL ACTION - 3 complement activating pathways

1. Natural killer cells recognize cells w/o MHC class 1. Classical à depends on antibody/adaptive
1 molecules. NK cells release cytotoxic molecules immune system
2. Perforin forms a pore & destroys target § Does not immediately provide host
membrane integrity w/ protection
3. NK cells release cytotoxic proteins 2. Alternative à does not require antibody
or adaptive immunity
TOLL-LIKE AND NOD-LIKE RECEPTORS § Can attack microbes before
- Toll-like receptors (TLRs) on host cells enable specific immune response
innate immune system’s rapid response 3. Lectin à requires the synthesis of
1. Recognize MAMPs mannose-binding lection in response to
2. Send signal to interior of cell to start cytokine released from macrophage
production of interferon and pro- § Lectin coats microbes, tagging
inflammatory cytokines them for destruction
3. Restricted to membranes of host cells - Goal of complement cascade: insert pores into
- NOD-like receptors are proteins that are microbial membranes to destroy membrane
important intracellular sensors of MAMPs integrity and destroy the cell

FEVER AS AN IMMUNE RESPONSE

- Normal body temp is 38-38°C (97-100 F)
- Fever is anything above 100.4 F (38 C)
- Thermoregulation
1. Heat sensors
§ Skin, large organs, spinal cord
2. Hypothalamus
§ Controls vasoconstriction and
vasodilation
3. Pyrogens
§ Substances that cause fever
§ External à bacterial toxins
§ Internal à interferons, cytokines
- Advantages of fever: pathogens out of “comfort
zone”; enhance immune response
- Disadvantages of fever: patient discomfort; very
high fever (above 107.6 F) damages brain

COMPLEMENT
- Rapidly acting part of the innate immune
response
- Composed of numerous soluble protein factors
constantly present in the blood
1. Series of 20 proteins in the blood
2. Help prevent blood infections
3. Cascading event
4. Triggering complement cascade can have
a # of outcomes:
§ Membrane attack complexes
(MACs)
§ Attracts WBCs
§ Facilitate phagocytosis and
opsonization