Autoimmunity€¦ · • Autoimmunity arises most frequently to Tissue-specific antigens with only...
Transcript of Autoimmunity€¦ · • Autoimmunity arises most frequently to Tissue-specific antigens with only...
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Autoimmunity
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Self-tolerance• Lack of immune responsiveness
to an individual’s own tissue antigens
Central Tolerance
Peripheral tolerance
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Factors Regulating Immune Response
Antigen availability
Properties of the antigen
Genetics
Circumstances of antigen presentation
Cytokine millieau
Regulatory cells
Costimulation
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Susceptibility to Autoimmunity
Environmental and genetic factors play a key role in autoimmune
disease susceptibility
The best evidence comes from family and twin studies
High concordance in twins suggests shared genetic or environmental factors
If a disease is restricted to monozygotic twins then genetic factors are important
Insulin-dependent diabetes mellitus, rheumatoid arthritis, MS, SLE ~20% monozygotic twins show concordance compared with <5%
dizygotic twins.
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Mechanisms proposed for induction of Autoimmunity
• Release of “sequestered antigens”
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These Sites Sequester Self Antigens, But
Few Autoimmune Diseases Are Due
to Release Of Hidden Self Antigens
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Figure 13-13
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• Release of “sequestered antigens”
• Abnormal immunoregulation
Mechanisms proposed for induction of Autoimmunity
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Immunoregulatory T cells
• Immunoregulatory T cells release downregulating cytokines which turn-off potential immune responses.
IL-4
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Autoimmunity: a question of balance
Activating signals•MHC-II peptide•Cytokines (IFN-g)•CD40/CD40L•CD28/CD80,86
Downregulating signals•Cytokines (IL-10,TGFβ)•CD80,86/CTLA-4
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• Release of “sequestered antigens”
• Abnormal immunoregulation
• Bypass of helper T-cell tolerance
Mechanisms proposed for induction of Autoimmunity
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Bypass of helper T-cell tolerance
o Modification of antigen (via drugs, microorganisms)Me-Dopa altered synth. of Rh ag AIHAProcainamide nucleosomes -histone, -DNA SLE
o Cross reaction (Antigen mimicry)
o Shared epitopes
o Bystander activationLocal innate immune responses and expression of second signal and costimulatory molecules on tissue APCs in site of inflammation
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Cross-reacting Antigens(Molecular Mimicry)
•Viruses and bacteria possess antigenic determinants that are very similar, or even identical, to normal host cell components.
•This phenomenon, known as molecular mimicry, occurs in a wide variety of organisms.
•Molecular mimicry may be the initiating step in a variety of autoimmune diseases.
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Shared Epitopes• One of the most
popular theories concerning autoimmunity is that cross-reactive T cell clones emerge during an immune response against an infectious agent
Coxsackie B-induced myocarditis
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• Release of “sequestered antigens”
• Abnormal immunoregulation
• Bypass of helper T-cell tolerance
• Polyclonal lymphocyte activation
Mechanisms proposed for induction of Autoimmunity
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Polyclonal lymphocyte activation
• Endotoxins cause such activation independent of specific antigens
• Super antigens?
• Mitogens?
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• Release of “sequestered antigens”
• Abnormal immunoregulation
• Bypass of helper T-cell tolerance
• Polyclonal lymphocyte activation
• Somatic hypermutation
Mechanisms proposed for induction of Autoimmunity
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Figure 13-11
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• Release of “sequestered antigens”
• Abnormal immunoregulation
• Bypass of helper T-cell tolerance
• Polyclonal lymphocyte activation
• Somatic hypermutation
• Genetic Factors
Mechanisms proposed for induction of Autoimmunity
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Genetic Defects
• (a) MRL-lpr/lpr or gld/gld - Fas or FasL defect
SLE
• (b) Association with MHC Class II
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MHC Association withAutoimmune Disease
• Many autoimmune diseases show association with specific MHC genes.
The number of autoimmune patients carrying a HLA allele compared with the prevalence of that allele in the general population: Relative Risk Valuee.g. R.A. & DR4, SLE & DR3, IDDM & DQβ - single aa at pos n. 56, Asp protects, other aas IDDM
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Figure 13-20
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MHC Association withAutoimmune Disease
• Most self peptides are presented at levels too lowto engage effector T cells whereas those presented at high levels induce clonal deletion or anergy.
• Autoimmunity arises most frequently to Tissue-specific antigens with only certain MHC molecules that present the peptide at an intermediate levelrecognized by T cells without inducing tolerance
• The level of autoantigenic peptide presented is determined by polymorphic residues in MHC molecules that govern the affinity of peptide binding.
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Self Level Sets Tolerance Degree
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Other Genetic Factors
Genetic defects in:
• Antigen clearance & presentation ( C1q)
• Signaling (TCRζ)
• Co-stimulatory molecules (CTLA-4)
• Apoptosis (Fas & FasL)
• Cytokines (IL-2)
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• Release of “sequestered antigens” • Abnormal immunoregulation
• Cross-reactivity (molecular mimicry)• Bypass of helper T-cell tolerance• Polyclonal lymphocyte activation
• Somatic hypermutation
• Genetic Factors
• Danger theory
Mechanisms proposed for induction of Autoimmunity
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• Proposes anti-self B & T-cells always present
• AIR is due to release of “danger signals”
• Response to tissue damage, necrosis or cell distress, e.g. infection or injury
• Inflammation response to danger signals mediated by effector mols. inc. cytokines.
• BUT can stimulate AIR without tissue damage, e.g. immunisation with self-ag
Mechanisms proposed for induction of Autoimmunity
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• Release of “sequestered antigens” • Abnormal immunoregulation
• Bypass of helper T-cell tolerance• Polyclonal lymphocyte activation
• Genetic Factors• Somatic hypermutation
• Danger theory
• Hormonal status
Mechanisms proposed for induction of Autoimmunity
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Sex-based Differences in Autoimmunity
• Differences can be traced to sex hormones
- hormones circulate throughout the body and alter immune response by influencing gene expression- (in general) estrogen can trigger autoimmunity and testosterone can protect against it
• Difference in immune response
- ♀ produce a higher titer of antibodies and mount more vigorous immune responses than ♂
- ♀ have higher levels or CD4+ T-cells and serum IgM
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Antigen Structures in Different Type Autoimmune Diseases
Organ specific autoimmune disease:Specific organ limited Ags
systemic autoimmune diseases:Ubiquitous Ags (nuclear and cytoplasmicantigens as autoantigens)
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Mechanisms of Autoimmune Damage
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Mechanisms of Autoimmune Damage
• Autoimmunity is initiated in the same way as adaptive immune responses
• Clinical outcome is determined by– self Ag(s)
– the mechanism of tissue damage
• The mechanism of tissue damage is classified by the scheme adopted for hypersensitivity reactions.
• More than one type of hypersensitivity may be involved
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Mechanisms of Autoimmune Damage
• Tissue injury is caused by a response to self Ag Chronic diseases
• The Ag cannot be removed so the response persists
• Epitope spreading Progressive diseases• Tissue damage can be mediated by the
effector mechanisms of both T cells and B cells (antibodies)
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Figure 13-7Epitope spreading
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Autoimmune responses resemble hypersensitivity reactions
• Type II: Antibodies (Abs) against cellsurfaces/extracellular matrix
• Type III: Soluble immune complexesdeposited in tissues
• Type IV: Effector T cells
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Type II HypersensitivityAutoimmunity
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Figure 13-27 part 1 of 3
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Pernicious A
nemia
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Type III HypersensitivityAutoimmunity
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Figure 13-27 part 2 of 2
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Figure 13-27 part 3 of 3
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Type IV Hypersensitivity
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Figure 13-6
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Graves’ Disease
•Abs against the TSH receptor mimic the natural ligand
•leads to chronic overproduction of T3/T4 insensitive to regulation
•Results in hyperthyroidism
•Individuals suffer from heat intolerance,nervousness, weight loss, outwardly bulging eyes
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Myasthenia Gravis
• Abs bind to the Ach receptor on muscle cells,
resulting in their endocytosis and degradation
• Results in loss of muscle sensitivity to neuronal stimulation, progressive muscle weakness
• Often characterized by droopy eyelids, double vision
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Systemic Lupus Erythematosus (SLE)
• Multisystem autoimmune disease
• Abs against DNA, histones, ribosomes form immunecomplexes with Ags released from damaged cells
• B-cell hyperreactivity is a feature of LE, caused by
excess T-helper activity
• Affects skin, kidneys, serosal surfaces, joints,
CNS and heart (deposition of Immune complex)
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Rheumatoid arthritis• Non-suppurative proliferative synovitis which leads
to descruction of articular cartilage and progressive disabling arthritis
• 3-5X more common in women than in men
• Initiated by activation of T-helper cells which produce cytokines and activate B cells to produce antibodies
• 80% of patients with rhematoid factors (antibodies against Fc portion of IgG)
• precise trigger which initates destructive immune response is not known
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Insulin-dependent diabetes mellitus (IDDM)
Selective destruction of insulin-producing β cellslocated within the islets of Langerhans by T cells
Several autoantigens are recognized by both Absand T cells, including insulin and glutamic aciddecarboxylase (GAD)