Download CHAPTER 2 Immune Response to Infection

CHAPTER 2
Immune Response to Infection
The immune response to infection is presented as two major components, innate and
adaptive immunity. The primary effectors of both are cells which are part of the white
blood cell series derived from hematopoietic stem cells in the bone marrow. Innate
immunity includes the role of physical, cellular, and chemical systems which are in place
and respond to all aspects of foreignness. These include mucosal barriers, phagocytic
cells, and the action of circulating glycoproteins like complement. The adaptive side is
sometimes called specific immunity because it has the ability to develop new responses
which are highly specific to molecular components of infectious agents called antigens.
These encounters trigger the development of new cellular responses and production of
circulating antibody which have a component of memory if the invader returns.
Artificially creating this memory is, of course, the goal of vaccines.
Innate (Nonspecific) Immunity
1. Skin, mucosa are mechanical barriers
2. Cells engulf, digest and present antigens from microbes
I. Physical Barriers
1. Lysozyme digests bacterial walls
2. Cilia move particles away from the alveoli
3. M cells deliver intestinal pathogens to macrophages and lymphocytes
II. Immunoresponsive Cells and Organs
1. Stem cells differentiate to myeloid and lymphoid series
2. Thymus, spleen, and lymph nodes are immune organs
A. Cells Responding to Infection
a. Monocytes
1. Monocyte is a term for cells that include or will quickly differentiate into
macrophages or dendritic cells
2. Cells of the immune system which both phagocytose invaders and process them
for presentation to the adaptive immune system
3. Macrophages are in the circulation or in tissues
4. Surface receptors recognize pathogens
5. Dendritic cells are star-shaped tissue phagocytes in the skin and in the mucous
membranes.
6. After binding and phagocytosis dendritic cells migrate to lymphoid tissues
b. Granulocytes
1. Polymorphonuclear neutrophil (PMN) has a distinctive multi-lobed nucleus
2. PMNs have digestive and killing pathways
3. Cytoplasmic granules contain lytic enzymes and antimicrobial substances
including peroxidase, lysozyme, defensins, collagenase, and cathelicidins
4. Only in circulation unless migrate in inflammation
5. Eosinophils are non-phagocytic cells that participate in allergic reactions along
with basophils and mast cells. Eosinophils are also involved in the defense
against infectious parasites by releasing peptides and oxygen intermediates into
the extracellular fluid. It is felt these products damage membranes of the parasite.
6. Eosinophils damage parasites
c. Lymphocytes
1.
2.
3.
4.
Lymphocytes are the primary effector cells of the adaptive immune system.
In the bone marrow are marked to become T cells, B cells, or null cells
B cells may become plasma cells which produces antibodies
T cells secrete cytokines which are effector molecules for multiple immunocytes
and somatic cells.
5. Uncommitted null cells may become natural killer (NK) cells which kill cells
infected with viruses
B. Phagocytosis
1. The major cells involved are PMNs, macrophages, and dendritic cells.
2. Surface pathogen recognition mechanisms include complement or
antibody opsonization
3. Opsonin-independent mechanisms utilize the hydrophobic interactions
between bacteria and the phagocyte surface
4. Lectins bind carbohydrate moieties and protein-protein interactions based
on a specific peptide
5. Phagocytes have Toll-like receptors (TLRs) which bind LPS,
peptidoglycan and induce cytokines
6. Bound organisms taken inside fuse with lysosomes inside to from a
phagolysosome
7. Enzymes digest pathogens in acidic phagolysosome
8. Reactive oxygen killing is driven by respiratory burst
9. Reactive nitrogen effects enveloped viruses
C. Inflammation
1.
2.
3.
4.
Acute = hours to days
Chronic = weeks to months
PMNs migrate from capillaries
Enzymes and chemical mediators facilitate swelling
5. Chronic inflammation bridges the innate and adaptive immune responses.
a. Generally associated with slower growing pathogens like mycobacteria,
fungi, and
b. Lymphocytes and macrophages predominate
c. Granulomas indicate failure to resolve by adaptive cellular mechanisms
D. Chemical Mediators
a. The Complement System
1. Multiple components activated in cascade fashion when triggered
2. Pathways differ in initiation mechanism
3. Opsonization is serum coating of pathogens
i. Alternative Pathway
1. Activation is by pathogen surfaces
2. Membrane attack complex inserts and provides phagocyte receptors
3. Factor H binding accelerates C3b degradation on capsules
ii. Lectin Pathway
1. Lectins bind to mannose on pathogens
2. This binding opsonizes the pathogen and enhances phagocytosis
iii. Classical Pathway
1. Antigen antibody reaction exposes complement binding sites
2. Specific sites on the Fc portion bind and activate the C1 component of
complement
3. C3b has receptors for phagocytes
b. Cytokines
1. Cytokine is a general term for molecules released from one cell population
destined to have an effect on another cell population.
2. Chemokines are cytokines chemotactic for inflammatory cell migration
3. Interleukins (IL-1, 2, 3, etc.) regulate growth and differentiation between
monocytes and lymphocytes
4. Tumor necrosis factor (TNF) can induce apoptosis (programmed cell death) in
phagocytes
5. Interferons (INF-) are central to activation of T cells and macrophages
The Adaptive (Specific) Immune System
I. Antigens and Epitopes
1. An antigen is any substance (usually foreign) able to stimulate an immune
response
2. Epitopes fit to the combining site of T-cell receptors and antibodies
3. Haptens are small molecules which may stimulate an immune response may if
bound to a protein.
4. B cells multiply, differentiate and produce antibody
5. Protein antigens must be processed first
II. Recognition of Foreignness
1.
2.
3.
4.
Distinguishing between self and nonself is essential to maintaining homeostasis.
MHC gene complex codes surface molecules of human cells
MHC class I molecules are in the membrane of almost all cells but
MHC class II are present only on certain leukocyte such as macrophages,
dendritic cells and some T and B cells
5. MHC I presents cytoplasmic peptides to CD8+ T cells
6. MHC II presents foreign peptides to CD4+ T cells
II. The T Cell Response
The major roles of T cells in the immune response are:
1. Recognition of peptide epitopes presented by MHC molecules on cell surfaces
2. Production of cytokines that act as intercellular signals and mediate the
activation and modulation of various aspects of the immune response
3. Direct killing of foreign cells, of host cells bearing foreign surface antigens
III. CD4+ Helper T Lymphocytes
1. Helper T cells (TH cells) are marked by the presence of the CD4 cell surface
antigen.
2. TH cells are stimulated by MHC II presented antigen
3. TH1 pathway is to cell-mediated reactions
4. TH2 pathway is to antibody production
5. Clonal expansion includes memory cells
IV. CD8+ Cytotoxic T Lymphocytes
1. CD8+ cytotoxic T lymphocytes (CTLs) are characterized by the CD8 cell surface
marker
2. CD8+ lymphocytes react with MHC I
3. Eliminate virally infected cells through a complement-like action
V. Superantigens
1. Superantigens bind directly to MHC proteins and Tcr Vβ region
2. Higher proportion of T cells are stimulated
VI. Cell- Mediated Immunity
1.
2.
3.
4.
Of primary importance with intracellular pathogens
Helper and cytotoxic T lymphocytes interact
Macrophages are mobilized and enhanced
In tuberculosis, IFN-γ inhibits the replication of the mycobacteria inside
macrophages
5. In viral infections CD8+ cytotoxic lymphocytes destroy their cellular habitat
VII. B Cells and Antibody Responses
1.
2.
3.
4.
5.
6.
7.
8.
B cells carry epitope recognition sites on their surface
Stimulated cells differentiate to form memory, plasma cells
Two broad types of antigen triggering, T-cell dependent and T-cell independent.
T-dependent has memory
T-cell independent responses are weaker and lack memory
T-independent matures slowly with poor response under 2 years of age
Antigen processing causes delay in antibody response
Learning system increases affinity with time or secondary challenge
A. Antibody Structure
1. Immunoglobulins have tetrameric structure combining light chains and heavy
chains
2. Isotypes are defined by type of heavy chain
3. Fab sites bind antigen
4. Fc fragment recognized by complement, phagocytes
5. Combining site is idiotype
6. Fab is antigen-binding region
7. IgM has five subunits
8. IgA is a monomer or dimer
a. Functional Properties of Immunoglobulins
i. Immunoglobulin G - IgG
1. Bivalent molecule with specific combining site and constant region
2. Constant region binds phagocytes
3. Antibodies produced during secondary response neutralize toxins and
viruses
4. Binding may block attachment receptor
ii. Immunoglobulin M - IgM
1. Effective agglutinating antibody
2. Binds complement at multiple sites
iii. Immunoglobulin A - IgA
1. sIgA is produced at mucosal surfaces
2. Secretory piece combines molecules and resists proteolysis
3. Interferes with attachment of microbes to mucosal surfaces
b. Antibody Production
1. After a lag phase, the primary response lasts for weeks and then declines
2. IgM is first followed by IgG, called the IgM/IgG switch
3. Following a subsequent exposures or boosters the secondary response or
anamnestic response ensues.
4. Secondary response involves memory and is primarily IgG
5. IgG affinity for antigen is greater
Adverse Effects of Immunologic Reactions
1. Mechanisms I-IV involve antibody and cell-mediated injury
2. Allergy, asthma, diabetes are due to hypersensitivity
3. Infection is a small part
I. Antibody-Mediated (Type II) Hypersensitivity
1. Antibody directed against microbe epitope also reacts with host cells
2. Rheumatic fever is caused by Type II molecular mimicry
II. Immune Complex (Type III) Hypersensitivity
1. Excess antigen-antibody complexes are deposited in tissues
2. Complement-mediated inflammation causes injury
3. Serum sickness is reaction to animal immunoglobulin
III. Delayed-Type (Type IV) Hypersensitivity (DTH)
1.
2.
3.
4.
DTH is a cell-mediated immune reaction
Requires time for TH1 response to develop
Inflammation causes continuing local injury.
Primary mechanism of injury in tuberculosis, fungal infections, and many
parasitic diseases.
Favorable Use of the Immune Response
I. Natural Immunity to Infection
1. Infection often confers life-long immunity
2. Clinical disease is not required
II. Passive Immunity
1. Passive immunity is the transfer of antibodies from one person to another.
2. Transplacental IgG protects the fetus
3. Can also be from a therapeutic product where specific antibodies are infused as in
rabies, botulism and tetanus.
III. Vaccines
1. Vaccines artificially stimulate immunity through exposure to an antigenic
substance
2. Live vaccines use attenuated strains which produce a mild infection
3. Components of killed microbes may still be antigenic
4. Killed vaccines may require purification of antigens