Exam 3: Regulation of the Immune System Flashcards
what needs to happen to self antigens generated by B and T cells
must be destroyed or turned off
how is adaptive immune response regulated
recognize and eliminate foreign invaders
kill target cells (infected/tumor cells)
autoimmunity
immunodeficiency/immunosuppression
what happens when excessive adaptive immune response
allergies
autoimmunity
amyloidosis
lymphoid tumors
what happens when there is a defective adaptive immune response
increased infections
increased cancers
tolerance
there is not an immune response to a specific antigen (self antigen)
when do lymphocytes become tolerant
immature lymphocytes become tolerant to an antigen if they first met in fetal life
where was tolerance observed
chimeric calves
central tolerance
immature self reacting lymphocytes within thymus, bursa, or bone marrow die or alter their receptor specificity
immature T and B cells in primary lymphoid organs
peripheral tolerance
mature lymphocytes that encounter self antigens are turned off, or suppressed by T regulatory cells
mature T and B cells in secondary lymphoid organs
what results in development of calf chimeras
fusion of the placentas of dizygotic twin calves
why is each chimera tolerant to it’s twin’s cells
will each chimera accept a skin graft from its twin despite the genetic differences
Hematopoietic stem cells from each animal colonize the bone marrow of the other
yes, they will accept a skin graft
recognize each others antigens as “self” because they were in contact during fetal development
duration of tolerance in T and B cells
T cells much more easily rendered tolerant than B cells
Once tolerant, T cells remain tolerant for much longer
why is it easier to induce tolerance in T cells
T cells only use gene conversion
B cells use gene conversion, somatic mutation, and gene recombination
central T cell tolerance
no functional T cells with receptors that can bind to self antigens
in central T cell tolerance how many gene arrangements will be out of frame
2/3 of possible gene arrangements will be out of frame
these will recognize self antigens
what happens to cells with non functional TCRs
apoptosis –> negative selection
how can T cells in thymus recognize self antigens located elsewhere
negative selection
thymic epithelial cells produce a transcription factor - AIRE
AIRE helps to express different proteins from different tissues
if a T cell binds to a thymic epithelial cell and recognizes self antigens –> die
AIRE – autoimmune regulator
positive selection in regards to central T cell tolerance
positive selection ensures that cells that recognize self-MHC molecules survive
how does thymus induce T cell tolerance
negative selection
Central T cell tolerance - positive vs negative selection
negative selection - makes sure T cells don’t react with self antigens
positive selection - makes sure T cells respond to foreign antigens and react with MHC
peripheral T cell tolerance
clonal anergy
T cells require multiple signals in order to respond to antigen
if these signals are insufficient or inappropriate the T cell responses to antigen will be suppressed
in secondary lymphoid organs
what produces activation of peripheral T cell tolerance
blocked CD28 - CD80 interaction
what is clonal anergy
the prolonged antigen specific suppression of T cell function
different doses of antigen induce peripheral tolerance differently
very high and very low doses of antigen - induce tolerance
high doses of antigen can induce a form of clonal anergy called immune paralysis
moderate doses of antigen - induces immune response and antibody production
immune paralysis
can be induced by high doses of antigen
the high dose of the antigen probably bypasses APCs and reach the Th cell receptors directly and in absence of co-stimulation they trigger anergy
Central B cell tolerance
primary lymphoid organs
VDJ rearrangement, gene conversion, somatic mutation
immature B cells can recognize self antigens (55-75%)
B cell suppression at early stages in animal’s development
Peripheral B cell tolerance
food allergies
absence of co-stimulation
repeated exhaustive antigen stimulation = short lived plasma cells, no memory cells = tolerance
oral proteins in high doses induces clonal deletions and anergy
oral proteins in low doses induces development of T regulatory cells – why most people don’t develop immune responses to most foods (why most people aren’t allergic to most foods)
central B cell tolerance mechanism
in primary lymphoid organs
immature B cell –> low dose of antigen –> clonal abortion
peripheral B cell tolerance mechanism
in secondary lymphoid organs
mature B cell –> exhaustive antigen challenge –> clonal exhaustion
mature B cell –> absence of co-stimulation –> functional deletion
mature B cell –> excessive suppressor cell activity –> functional deletion
mature B cell –> excessive T-independent antigen –> functional deletion and receptor blockade
what is the main characteristic of immune response induced by T-independent antigens
produce only 1 type of antibody –> IgM (produced by plasma cells)
no participation of T helper cells
no memory cells
what does an inadequately low immune response lead to
immunodeficiency and increased susceptibility to infection
what does an excessive immune response lead to
allergies or autoimmunity
increased antigen leads to
immune response is prolonged
decreased antigne leads to
immune response stop
what do these cells present antigens to Langerhans cells follicular dendritic cells DC1 DC2
Langerhans cells –> T cell response
Follicular dendritic cells –> B cell response
DC1 –> Th1
DC2 –> Th2
what type of immune response are these cells involved in
DC1 –> Th1
DC2 –> Th2
DC1 –> Th1 —> cellular immune response
DC2 –> Th2 —> antibody mediated immune response (humoral)
how are immunoglobulins regulated
neonatal isoerythrolysis
colostrum
inhibitory B cell receptor (CD32)
what in colostrum rich in
antibodies
what does CD32 do
binds to antibodies and produces an inhibitory signal
what delays the onset of immunoglobulin synthesis in a newborn animal
presence of maternal antibody - negative feedback process
what happens when animal ingests maternal antibodies
takes more time to produce their own antibodies
they were previously protected by ingested maternal antibodies so they didn’t need to produce their own
what happens when an animal doesn’t ingest maternal antibodies
produces own antibodies much quicker
what happens in cross linking between BCR and CD32
cross linkage between BCR and CD32 by antibody and antigen can turn off a B cell by activating a phosphatase that in turn blocks signaling by tyrosine kinase
when crosslinking antigens, CD32 blocks activation of B cell and induces apoptosis in B cell
what kind of receptor is CD32
Fc receptor (antibody receptor)
antibody regulation:
what does IgG do
what does IgM do
IgG – suppress the production of IgG/IgM
IgM – suppress the production of IgM
what is main function of CD80 or CD86 binding to CD152
suppression
regulatory T cells (Treg)
Natural Treg – thymus
Induced iTreg – intestine
suppress Th cell activity
suppress CD8 T cell activity
Oral Ag — iTreg
what is the function of regulatory T cells
suppression of T cell and macrophage function
how are Treg generated
by the combined actions of IL-2 and TGF-B as well as the presence of retinoic acid
what to Treg produce
suppressive cytokines
TGF-B
IL-10
IL-35
what is CTLA4
cytotoxic T lymphocyte associated protein 4
CD152
Treg suppression of other immune responses - direct contact
- Treg cells
- direct contact of Treg with T effector
- TGF-B, proteins and granzymes, galectin 1, CTLA4, TRAIL
Treg suppression of other immune responses - suppressive molecules
- Treg
- suppressive molecules
- IL-10, TGF-B, IL-35, prostaglandin E2
Treg suppression of other immune responses - interference with antigen presentation
- Treg
- interference with antigen presentation
- Neuropilin1, IDO
where does IL-10 come from
Th cells Treg cells dendritic cells B cells M2 macrophages
what is main function of IL-10
suppression
IL-10 - Suppression of macrophages
reduced antigen presentation reduced MHC II expression reduced co-stimulation increased apoptosis reduced IL-6, TNF-a, NO
IL-10 – suppresses Th1 cells
reduced IL-2, IFN-y, TNF-a
IL-10 – suppresses Th2 cells
reduced IL-4, IL-5
IL-10 – enhances Treg cells
enhances Treg cells
IL-10 – suppresses Th17 production
reduced IL-17
IL-10 – suppresses NK cells
reduced IFN-y, TNF-a
IL-10 – suppresses DCs
reduced MHC II expression
reduced adherence molecules
reduced co-stimulation
where does TGF-B come from
T cells B cells Macrophages Platelets Neutrophils
what is the main function of TGF-B
regulation
TGF-B – regulates T cell activation
reduces T cell proliferation
antagonizes IFN-y and IL-12
TGF-B – other cells
regulates cell proliferation
regulates growth
regulates differentiation
regulates motility
TGF-B – regulates macrophages
enhances integrin expression
enhances phagocytosis
reduces respiratory tone
reduces cytotoxicity
TGF-B – regulates B cell function
reduces B cell proliferation
promotes IgA production
promotes apoptosis
Regulatory cells - Macrophages (M2)
induce tolerance
suppress inflammation
inhibit dendritic cell antigen presentation
regulatory factors – indoleamine 2, 3 dioxygenase
tryptophan degradation
regulatory cells - dendritic cells
DC1
DC2
??????
regulatory cells - natural suppressor cells
suppress B and T cell proliferation
suppress immunoglobulin production
proinflammatory cytokines
IL-1
TNF-a
IL-6
HMGB-1
how central nervous system and immune system interact 1
- central nervous system releases encephalins, endorphins, somatostatin, somatotropin
- activates immune system
- immune system releases proinflammatory cytokines
- induce fever, sleep, appetite which act on central nervous system
how central nervous system and immune system interact 2
- central nervous system releases hormones related to stress, adrenals, and steroids
- activates immune system
- immune system releases proinflammatory cytokines
- induce fever, sleep, appetite which act on central nervous system
how central nervous system and immune system interact 3
- central immune system activate sympathetic nervous system and antibody formation
- activates immune system
- immune system releases proinflammatory cytokines
- induce fever, sleep, appetite which act on central nervous system
what do these do Encephalins B Endorphin a Endorphin Somatostatin Somatotrophin
Encephalins - T cytotoxic increase
B Endorphin - T cytotoxic increase, antibody production increase
a Endorphin - antibody production decrease
Somatostatin - immune response decrease
Somatotrophin - immune response increase
