Immune tolerance/regulation of lymphocytes

 immune regulation is required to;

o avoid access lymphocyte activation and tissue damage during normal protection
responses against infection
o prevent inappropriate reactions against self antigens
 lymphocyte responses
o the 3 signal model
 antigen recognition These 3 signals licence the cell to
 co-simulation respond
 cytokine release

o self-limiting response
 the principal mechanism
 immune response eliminates antigen that initiated response
 manifestation
 decline of immune responses
 the end of the response
 resolution
o no tissue damage
o returns to normal
o phagocytosis of debris by macrophages
 repair
o fibroblasts and collagen synthesis
o healing with scar tissue regeneration
 chronic inflammation
o active inflammation
o ongoing attempts at damage repair
o failures of control mechanisms is the underlying cause of immune-mediated
inflammatory diseases
 immune-mediated inflammatory diseases
 systemic or organ-specific
  caused by failure of tolerance regulation
 may be caused by
o T cells
o Antibodies
 May result from
o immune response against self antigens
o immune response against microbial antigens
 Eg. Crohn’s diseases
 Allergy
 harmful immune responses to non-infectious antigens that cause
tissue damage and destruction
 Can be mediated by IgE antibodies and mast cells -- type I
hypersensitivity
o acute anaphylactic shock
OR
 Can be mediated by T cells -- type IV
hypersensitivity
 Autoimmunity
 immune response against self antigen
o inflammatory
 can be both systemic or organ-specific
 pathogenesis includes a combination
of;
o susceptibility genes
o environmental triggers
 features;
o chronic
o self-perpetuating
 hypercytokinemia and sepsis
 overstimulation of immune response
 triggered by either;
o failure to regulate responses to correct level
OR
o pathogens entering the wrong compartment (Sepsis)
 often in a positive feedback loop
 tolerance
o how lymphocyte responses are regulated
 As extent of elimination of pathogen increases, the responses against the
pathogen decreases
 Specific T-cells are re-activated
 Those that have become inert
 This fact is often the basis of cancer therapies vx
o immune tolerance
 self tolerance
 all individuals are tolerant of their self antigens
 a breakdown of self tolerance = autoimmunity
 therapeutic potential of inducing tolerance
  prevent graft rejection
 treat autoimmune disease
 treat allergy

o
o Central tolerance
 destroy self reactive T or B cells before they enter circulation
 either eliminated or
made harmless
 B cells
 antigens cross-link
their IgM
o leads to
apoptosis
 T cells
 need to select the T cells capable of binding to self MHC (this is
needed to antigen recognition)
o if doesn’t
 useless  apoptosis
o if too high affinity binding
 dangerous
 negative selection  apoptosis
o if low affinity binding
 useful
  positive selection  survival signals
 autoimmune regulatory (AIRE)
o specialised transcription factor
 allows thyminic expression of
genes expressed in peripheral
tissues
 promote self tolerance in T
cells (which develop in the
thymus)
o mutations can lead to
 multi-organ autoimmunity/ autoimmune
polyendocrinopathy syndrome type I
o peripheral tolerance
 destroy or control any self reactive T or B cells which enter the circulation

 types;
 anergy
o when the T cell sees MHC/peptide ligand without
appropriate costimulatory proteins
 this T cell them becomes ANERGIC
o Anergic T-cell;
 less likely to be stimulated in the future even if co-
stimulation is present
o naïve T cell needs costimulatory signals in order to become
activated
 ignorance
o antigen may be present in TOO LOW a concentration to
reach the threshold for T cell receptor triggering
o often in immunologically privileged sites
 where immune reactions are suppressed because
they could cause more harm than good
  Eg.
 Eye
 Brain
 Antigen induced cell death/deletion
o Activation through the T cell receptor can result in apoptosis
o caused by the induction of expressed on the death ligand
 CD95
 FasL
 role of cytokines
o T-helper cell subset functions;

Cytokines present in the milieu

determine which type of T cell

recognise peptides on MHC-II

molecules in antigen presenting cells
(instigate and shape adaptive
immune response)

 TH1
 pro-inflammatory
 boosts cellular immunity response
 intracellular control of pathogens;
o viruses
o some bacteria
 formation/differentiation
o triggered by;
 IL-12
 IL-18
o Transcription factors essential for differentiation and
function;
 T-bet
 STAT-4
 Secretes;
o IFN-γ
 Tumor Necrosis factor is also an important cytokine involved
 TH2
 important in defence against large multicellular organisms
o e.g.
 helminths
 promote
o eosinophilia
o mastocytosis
o this goblet cell hyperplasia
 important cytokines involved;
o IL-4
o IL-5
o IL-13
  transcription factors essential for differentiation and function;
o Gata-3
o STAT-6
 TfH
 essential for generation of isotope switched antibodies
o antibody class switching
 resides in B cell follicles
 produces;
o IL-21
 TH17
 important for the control of bacteria
 linked to several inflammatory conditions
o arthritis
o IBD
 secretes IL-17
o in autoimmune diseases eg. Arthritis
 IL-23 promotes expansion of these cells
 TH0/ Treg
 Anti-inflammatory, limit the immune response
o Necessary to maintain tolerance
to self-antigens
o Inactivate;
 Dendritic ccells
 Responding lymphocyte
 Only present in mammals
 Regulatory;
o activation
o effector
 CD4+
 Express transcription factor FoxP3
o Mutations in FoxP3;
 IPEX syndrome –
Polyendocrinopathy
Enteropathy X-linked
 Immune
dysregulation
 Symptoms;
o Alopecia
o Nail dystrophy
o Eczematous dermatitis
 In mice  causes scurvy
o Blocking Foxp3 in immune cells
causes the same effect as if it had
been blocked in the whole body
 Cell surface receptors;
o High # IL-2 receptors
o Low # IL-7 receptors
 (Immune-suppressive) Cytokines secreted;
o IL-10
 Anti-inflammatory
 Shuts down production of other interleukins
 Viruses can hijack this to supress immune response
o TGFβ
o IL-35
 Regulation in pregnancy;
o Pregnancy as a parasitic infection
o Exposure to new antigen expressed in context of foreign
MHC I
 Types of Treg;
o iTreg (Inducible regulatory cells)
 Develop from mature CD4+ T cells exposed to
antigen in the periphery
 May be generated in all immune response
 Limit collateral damage
 Has no role in the thymus
o nTreg (Natural regulatory T cells)
 Development requires recognition of self-antigens
during T-cell maturation
 In the Thymus
 Resides in peripheral tissues to prevent harmful
reactions against self