Janeway`s Immunology - Cal State LA

Download Report

Transcript Janeway`s Immunology - Cal State LA

MICR 304 Immunology &
Serology
Lecture 15
Autoimmune Diseases and
Transplantation Immunology
Chapter 14.1 -14.5, 14.7– 14. 19;
14.22.- 37
Overview of Today’s Lecture
• Horror autotoxicus
• Self tolerance and breach in self tolerance
• Genetic and environmental factors
contributing to autoimmune diseases
• Classification of autoimmune diseases
• Selected examples for autoimmune diseases
• Transplantation immunology
Horror Autotoxicus
• Term coined by Ehrlich when he
conceived the idea of antibodies
• Inherent problem of random creation
of antigen receptors
• Self reacting lymphocytes are
randomly and constantly generated
• Normally, autoreactive lymphocytes
are either removed by apoptosis or
tolerance is established
Discrimination of Self and Non-Self
Mechanism
Self antigens
Non-self antigens
Timing of antigen
receptor signaling
Strong signals in immature
developing lymphocytes in
central lymphoid organs
(central tolerance)
Activation of antigen
receptor in mature
lymphocytes in peripheral
(secondary) lymphoid
organs
Antigen
concentration
Continuous and high
Sudden increase of
previously low concentrated
antigen
Co-stimulatory
signals
Absent
Present
Layers of Self Tolerance
• Self tolerance depends on the concerted and synergistic action of a
variety of mechanisms
• Succession of checkpoints
Peripheral
Tolerance
Autoimmune Diseases
• Develop when multiple layers of self tolerance
are dysfunctional
• Response to endogenous self antigen that
leads to tissue damage
• Since antigen cannot be eliminated response
is sustained
• Results from a combination of genetic
susceptibility, break down of natural
tolerance mechanisms and environmental
triggers
Requirements of the Development
of Autoimmune diseases
Tolerance
Defects in Central Tolerance
Development
• Defective AIRE gene
– Transcription factor “autoimmune regulator”
– Allows thymic epithelial cells to express
peripheral genes
– Absence leads to lack of elimination of self
reactive lymphocytes and development of
severe autoimmune disease
Activation of Ignorant Lymphocytes
• Ignorance develops when self antigen is
monovalent or of low affinity for antigen receptor
• Under normal circumstances, no reaction to self
antigen.
• However, ignorant lymphocytes are potentially
self reactive under certain circumstances:
– High concentration of antigen
– Immune complexes with formation of multivalence
– In the context of inflammation and infection
• Co-stimulation through TLRs
When a Monovalent Selfantigen Becomes
Multivalent
• Example rheumatoid factor
– Anti-IgG antibodies
• Normally, B cells specific for Fc of
IgG are not activated as Fc of IgG is
a monovalent antigen.
• When immune complexes are formed
Fc moieties of complexed IgG
becomes multivalent.
• BCR of self-reactive B cells can be
cross linked.
• In the presence of co-stimulatory
signals self reactive B cells become
activated and begin to secrete antiIgG.
TLR Ligands Can Activate
Autoreactive B Cells
Increased liberation of host
DNA during infection with
tissue damage
+ Additional costimulatory signals
Unmethylated CpG DNA sequences are enriched in apoptotic cells.
Antigens in Immunologically Privileged
Sites Can become Target
Normally
• Immunologically privileged sites are not
under constant immune surveillance
• Extracellular fluid does not pass through
lymphatic system
• No naïve lymphocytes around those
tissues
• Presence of inhibitory cytokines like TGFb
• Expression of fas ligand in these tissues
Post trauma and infection
• Tissue barrier disrupted
• Access of self reactive lymphocytes to the
sites
• Infection/inflammation provide costimulatory signal
•  Immune response against self
• Example: sympathetic ophthalmia
Sympathetic Ophthalmia
Control of Autoimmune
Responses by Regulatory T Cells
• Regulatory T cells can suppress self reactive
lymphocytes that react to an antigen different
from those recognized by themselves.
• Regulatory tolerance = dominant immune
suppression = infectious tolerance
• The different antigens must be presented by
the same APC.
• Defects in regulatory T cell activity are
associated with certain autoimmune diseases
– Multiple sclerosis
Etiology of Autoimmune
Diseases
Genetic Factors
• Single gene defects
described
• Association with MHC
genotype
– B27, DR2, DR3, DR3/DR4
• Family and twin studies
Environmental factors
• Heterogeneous
geographic distribution
of autoimmune diseases
• Triggered by infectious
agents
• Trauma
• Drugs
• Hormones (estrogen,
progestron)
Gene Defects Associated with
Autoimmune Diseases
• Predisposition to most autoimmune diseases due to combined
effects of multiple genes including
– Cytokines
– CTLA-4, an inhibitory T Cell surface molecule
– Complement factors
• Small number of autoimmune diseases with a single gene
mutation
– Fas
• Block in apoptosis
• Failure of apoptotic death of self reactive B and T lymphocytes
• Autoimmune lymphoproliferative syndrome
– AIRE (autoimmune regulator gene)
•
•
•
•
•
Transcription factor
Regulates expression of tissue specific antigens by DC in thymus
If absent decreased expression of self antigens in thynmus
Defective negative selection of self reactive thymocytes
Autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy
Manifestations of APECED
Autoimmune polyendocrinopathy- candidaiasis-ectodermal dystrophy
Association of HLA Serotype and Sex with
Susceptibility to Autoimmune Diseases
Hip joints
Eyes
Kidneys
CNS
Thyroid
Muscles
Systemic
Pancreas
Small joints
Skin
Thyroid
Predisposition to Type I Diabetes Mellitus
Asp
Uncharged aa
DR3/DR4
How Microbes and their Products
can Trigger Autoimmune Diseases
Hormones and Autoimmune
Diseases
• The biggest difference
in gender is observed
between menarche and
menopause
• Relatively more
females affected
during the years of
cycling
• Intensified during
pregnancy in affected
women
Autoimmune Diabetes Mouse Model
Classification of Autoimmune Diseases
Based on Mechanism of Tissue Damage
• Type II: Antibodies
against cell surfaces
– Autoimmune hemolytic
anemia
– Autoimmune
thrombocytopenic
purpura
– Goodpasture (basement
membrane in kidney)
– Pemphigus vulgaris
– Graves disease (TSHRec.)
– Myasthenia gravis (ACHRec.)
– Acute rheumatic fever
• Type III:
Antibody:Antigen
Complexes
– SLE (nuclear antigens)
– Rheumatoid arthritis
• Type IV: T cell mediated
– Diabetes mellitus
(insulin)
– Rheumatoid arthritis
– Multiple sclerosis
Classification of Autoimmune
Diseases by Localization
Antigen expressed
only in the
affected organ
Abundant ubiquitous
antigen
Secondary Effects of
Autoimmune Reactions
• Deposit of immune
complexes
• Complement activation
triggering inflammation
• Removal of complement
-covered antigen by
erythrocytes
• Sequestration in spleen,
liver
Autoimmune Hemolytic Anemia
• Autoantibodies against
surface molecule of
erythrocytes
• IgG and IgM cotaed
eruthrocytes are rapidly
cleared
– IgG: Phagocytosis
– IgM: complement
actvation and then
phagocytosis or
hemolysis
• Anemia
IgG
IgM
Myasthenia Gravis
• Autoantibodies against
acetylcholine receptor
• Receptor inactivation and
degradataion
• Muscle weakness
• Repetitive movements very
difficult!
• In particular eye bulb muscles
affected
• Life threatening when muscles
for respiration are affected
• Can be transferred to fetus
Grave’s Disease
• Autoantibodies
against receptor for
thyroid stimulating
hormone (TSH)
• Activate receptor
leading to excessive
thyroid hormone
production
Systemic Lupus Erythematosus (SLE)
• Auto-antibodies against nuclear
components (DNA, histones,
ribosomes, snRNP, etc)
• Immune complexes activate
complement
• Complexes transported via Fc-rec. on
phagocytes or via complement rec.
on erythrocytes to spleen/liver for
sequestration
• Excess complexes are deposited in
small blood vessels
• Local inflammation in skin, joints and
kidneys, multi-organ damage
• May lead to activation of self reactive
T lymphocytes
T-Cell Mediated Autoimmune
Disease: Diabetes Mellitus Type I
• Insulin Dependent
Diabetes Mellitus (IDDM)
• Early, sudden onset
(adolescence)
• Initially mediated by
autoantibodies against bNormal
cell antigen
• Later phases include
cytotoxic T-cell response
IDDM
Immunohistochemistry
Insulin = brown
Glucagon = black
Autoimmune Transfer
•
•
•
•
From mother to fetus through placenta
Often during pregnancy increased disease activity
Child is born with symptoms of mother’s disease
Graves’ disease, myasthenia gravis
Diagnostics of Autoimmune
Diseases
• Elevated general inflammation markers
– Erythrocyte sedimentation rate
– CRP (C-reactive protein)
• Detection of autoantibodies
– Immunofluorescence
• Incubate tissue sections with patient serum (indirect assay)
• Detect bound patient antibodies with fluorescent secondary
antibodies (direct assay)
–
–
–
–
Ouchterlony (Double immunodiffusion)
ELISA
Western blot
Radioimmunoprecipitation
Antinuclear Antibodies: EpitopDependent Staining Patterns
Homogenous staining
Speckled staining
(red is counter stain)
Therapeutic Approaches of
Autoimmune Diseases
• Plasmapheresis
• Organ specific
– remove circulating
antibodies
– short term
• Immunosuppression
– Steroids
– Cyclosporin A
– Insulin in DM
– Acetylcholine
esterase inhibitor in
Myasthenia gravis
Transplantation Immunology
Tissue Commonly Transplanted
and Graft Survival
Graft Rejection
• Graft rejection is an immunological
response mediated primarily by T-cells
• Major antigens involved : MHC complex
• Minor antigens: Minor H antigens
– Allelically variable non-MHC proteins
– Presented via MHC I molecules
– Rejection is slower
Graft Rejection is Specific
•
•
•
•
Graft APC migrate to host lymph node
Present graft antigen to host T cells
Host T cell activation
Migration of activated anti graft T cells to the grafted tissue and
destruction
Alloantigens in Grafted Organs are
Recognized in Two Different Ways
• Passenger
leukocytes in
grafts
• Donor APC, bear
allogenic MHC
and costimulatory
factors
• Activate
alloreactive
recipient T cells
Graft
(donor)
Recipient
• Recipient APC
take up donor
antigen
• Recipient T cells
are activated by
recipient APC
Hyperacute Graft Rejection
• Recipient has preexisting ABO
antibodies
– Previous blood transfusions
– ABO antigens also present on
leukocytes, endothelial cells
• During surgery antibodies bind
to endothelial vessels of graft
• Immediate activation of
complement, blood clotting
• Can be prevented by cross
matching donor and recipient
Graft versus Host Disease
• Major problem in allogenic
bone marrow transplantation
• Mature T cells, which
contaminate bone marrow,
recognize tissue of recipient
• Severe inflammatory disease
– Rashes
– Diarrhea
– Liver disease
Mixed Leukocyte Culture
• To detect tissue incompatibilities
• Mix leukocytes form potential donor with irradiated
leukocytes from potential recipient and vice versa
• If mismatch donor leukocytes will proliferate and lyse
host cells and vice versa
The Fetus is an Allograft that is
Typically Not Rejected
• Fetus is detected as mothers
generate antibodies against
father’s MHC proteins
• Placenta sequesters fetus from
maternal T cells
• Trophoblast is major protective
layer
– Does not express MHC I and II
– Expression of non-classical MHC
molecules that bind to inhibitory
NK cell receptors
– Active tryptophan depletion
– Secretion of inhibitory cytokines
(IL10, TGFb, IL4)
Additional Resources
Accessed 5/21/2008
http://www.mayoclinicproceedings.com/images/7508/7508cr4-fig1.jpg
http://www.bio.davidson.edu/Courses/Immunology/Students/Spring2003/Super/handsofRA.jpg