Transcript General Pathology: Acute Inflammation

General Pathology:
Normal Immune Function
Lorne Holland, M.D.
[email protected]
Normal Immune Function
• Immunity is a multilayered process
– Non-specific defenses impede invasion of
the body by many organisms
– Innate immunity allows for rapid defense
against invading bacteria
– Specific immunity allows for a robust,
targeted defense against invading
organisms
Non-specific Defenses
• Mechanical barriers such as skin and
mucous membranes
• Environmental factors such as stomach pH,
sebacous secretions by skin, commenselate
organisms
Innate Immunity
• Molecules and receptors which recognize
common patterns on typical bacterial
pathogens
– Toll-like receptors
– Phagocytosis
– Complement
Macrophages
• Toll-like receptors to recognize common
molecules on the surface of pathogens
• Scavenger receptors can do the same, but
also recognize altered self molecules
(oxidized LDL, glycated proteins, amyloid,
apoptotic cells)
Complement System
Complement System
• C3a & C5achemotactic for
neutrophils and
anaphylactoids
• C56789- “membrane
attack complex”
• C3b- opsonizaton
• http://www.youtube.com/watch?v=tJJAyP
WQ3fk
Specific (Adaptive) Immunity
• The interaction between multiple cells to
produce a response to a particular
pathogen
• Most robust and adaptable type of
immunity
• Has to “learn” from exposure to pathogens
before it can respond
• “Remembers” what it has seen before
Antigens
• Molecules which stimulate a specific
immune response
• If large enough, it may have multiple
regions (epitopes) which can elicit an
immune response
• If small enough, it may not be able to
stimulate an immune response alone, but
may do so when attached to a larger
molecule (hapten)
Epitope
Epitope
Epitope
Epitope
Hapten
Albumin
Hapten
White Blood Cell Maturation
Lymphocytes
• T-cells travel from bone marrow to thymus
to be “educated”
– Negative selection
• Cells which do not respond to usual immune
stimulation undergo apoptosis
• Cells which respond too strongly to usual
immune stimulation undergo apoptosis
– Positive selection
• Cells which respond “just right’ to usual immune
stimulation mature, enter circulation and often
settle in lymphoid tissues
T Lymphocytes
• “helper cells”
– Once activated, activates complementary Bcells (humoral immunity)
– CD4 positive cells
– Settle in lymphoid tissue with B-cells
• “cytotoxic cell”
– Once activated, attacks cells bearing
recognized antigen (cell-mediated immunity)
– CD8 positive cells
– In lymphoid tissues, but also in circulation and
other tissues
Lymphocytes
• B-cells stay in marrow until mature then
into circulation and often settle into
lymphoid tissue
• When B-cells are stimulated they can
mature into plasma cells
• Plasma cells secrete antibodies
Natural Killer Cells
• Do not respond to specific immune stimulus
• More generalized in response like
macrophages
• Directly kill cells which it senses are “not
right” (virally infected, cancer, etc.)
• Inhibited by the presence of normal MHC I
molecules
Antigen Presenting Cells
• Multiple names depending on tissue where
located
– Monocytes which have left the circulation and
matured into macrophages (Kupffer cells,
microglia, histiocytes)
– Dendridic cells (Langerhans cells) from myeloid
line and/or differentiation of local connective
cells tissue cells (fibroblasts) and/or ????
• http://video.google.com/googleplayer.swf?d
ocid=-1998725615426724660
Major Histocompatibility Complex
• Molecules used to display peptide fragments
• Class I
– Found on nearly all nucleated cells
– Displays mostly (altered) self peptides
– Binds with help of CD8
– Three subclasses: A, B, C
• Class II
– Found mostly on specialized antigen presenting
cells and other immune cells
– Displays mostly exogenous, ingested peptides
– Binds with help of CD4
– Three subclasses: DP, DQ, DR
Antigen Presentation
• APCs phagocytose and digest suspicious
substance
• Fragments are attached to MHC II then
presented on cell surface
• Lymphocytes that have receptors which
recognize the fragment bind and receive a
costimulatory “handshake”
• Without costimulation, the lymphocyte will
not respond and become anergic
APC – T cell interaction
aka B7 CD80
CD 86
MHC II
APC
CD28
CTLA-4
TCR
CD4
T-cell
Humoral Immunity
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•
•
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B-cell receptors pick up antigen
Present peptides to T “helper” cell by MHC II
Costimulation, as with APCs
B-cells become activated and produce more
membrane-bound antibody
• Stimulation via bound antibody causes
differentiation into plasma cells and secretion of
antibodies
• In some rare cases, T-cell independent antigens
are recognized by B-cells
T cell – B cell interaction
BCR
CD8
B-cell
Antibody Structure
Antigen recognition sites
Light Chains
(Kappa or Lambda)
Heavy Chains
(G, A, M, E, or D)
FC (fraction crystalizable) region
Antibodies/Immunoglobulins
• IgM, the first type of antibody produced,
circulates as a pentamer
• IgG, normally the most abundant antibody in
circulation, monomer
• IgA, largest quantities found in secretions, some
also found in blood, usually a dimer
• IgE, normally small amounts in blood, bind to
surface of mast cells and play a role in allergic
responses
• IgD, normally not found in blood, expressed on
the surface of some B-cells
Antibodies/Immunoglobulins
Isotype Switching
• IgM is the primary, initial antibody
produced
• Further stimulation of CD40 on B-cell by
CD40 ligand on activated T-cells can
cause a shift in heavy chain production
to G, A, or E
Cell-mediated Immunity
• Activated T “cytotoxic” cells recognize
peptides expressed on cells by MHC I
molecules
• Induce apoptosis of presenting cell
• Also secrete a number of cytokines which
potentiate other parts of immune
response
Cell-mediated immunity
• Antibody dependent cytotoxicity
– NK cells, monocytes and neutrophils
– Recognize Fc portion of antibody attached
to cell
– Poorly understood mechanisms, but likely
involves release of perforins, granzyme, et
al.
• Phagocytosis
– Monocytes and neutrophils can also bind Fc
then engulf the cell
After Resolution
• Most responding cells undergo apoptosis
when no longer needed
• A small number of “memory” cells are
retained in lymphoid tissues
• These cells allow for rapid response to
antigens when re-exposed and can secrete
small amounts of antibody for years
• Vaccinations induce formation of
“memory” cells
Questions?