MICR 304 Immunology & Serology Lecture 15 Autoimmune Diseases and Transplantation Immunology Chapter...
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Transcript of MICR 304 Immunology & Serology Lecture 15 Autoimmune Diseases and Transplantation Immunology Chapter...
MICR 304 Immunology &
Serology
MICR 304 Immunology &
Serology
Lecture 15Autoimmune Diseases and
Transplantation ImmunologyChapter 14.1 -14.5, 14.7– 14. 19; 14.22.-
37
Lecture 15Autoimmune Diseases and
Transplantation ImmunologyChapter 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
PeripheralTolerance
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 anti-IgG.
TLR Ligands Can ActivateAutoreactive B Cells
Increased liberation of host DNA during infection with
tissue damage
+ Additional co-stimulatory signals
Unmethylated CpG DNA sequences are enriched in apoptotic cells.
Antigens in Immunologically Privileged Sites Can become
TargetNormally• 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
TGF• 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 co-
stimulatory 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
Environmental factors• Heterogeneous
geographic distribution of autoimmune diseases
• Triggered by infectious agents
• Trauma• Drugs• Hormones (estrogen,
progestron)
Genetic Factors• Single gene defects
described• Association with
MHC genotype– B27, DR2, DR3,
DR3/DR4
• Family and twin studies
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 APECEDAutoimmune polyendocrinopathy- candidaiasis-ectodermal dystrophy
Association of HLA Serotype and Sex with Susceptibility to Autoimmune
Diseases
Hip jointsEyes
KidneysCNS
ThyroidMuscles
SystemicPancreas
Small jointsSkin
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 (TSH-
Rec.)– Myasthenia gravis
(ACH-Rec.)– 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
LocalizationAntigen 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
IgMIgG
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 -cell antigen
• Later phases include cytotoxic T-cell response
Immunohistochemistry Insulin = brown
Glucagon = black
Normal IDDM
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: Epitop- Dependent Staining
Patterns
Speckled staining(red is counter stain)
Homogenous staining
Therapeutic Approaches of Autoimmune Diseases
• Plasmapheresis – remove circulating
antibodies– short term
• Immunosuppression– Steroids– Cyclosporin A
• Organ specific– 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
• Passenger leukocytes in grafts
• Donor APC, bear allogenic MHC and co-stimulatory factors
• Activate alloreactive recipient T cells
• Recipient APC take up donor antigen
• Recipient T cells are activated by recipient APC
Graft(donor)
Recipient
Alloantigens in Grafted Organs are Recognized in Two Different
Ways
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, TGF, IL4)
Additional Resources
Accessed 5/21/2008http://www.mayoclinicproceedings.com/images/7508/7508cr4-fig1.jpg
http://www.bio.davidson.edu/Courses/Immunology/Students/Spring2003/Super/handsofRA.jpg