Autoimmune Diseases Flashcards
Immune Tolerance
Lack of response to antigen because it was previously introduced to lymphocytes
Central Tolerance
Occurs in Bm and thymus
Mechanisms
Deletion of self reactive
Receptor editing of B cells
Development of regulatory T cells
(Defficieny of T regs –> autoimmune diseases)
Peripheral Tolerance
Clonal Anergy: lach signal 2 B7–> inactivate
Deletion
Suppression via T regs secreted IL 10 and TGF-Beta
Supress self-reactive, pathogenic lymphocytes, block MO activation
Mucosal Tolerance
- Ignorance of ag by immune system (anergy)
- Deletion of T cells that respond to inhaled/ingested AG
- Generation of T reg cells to control and or modulate inflammatory responses
- Considerable overlap of mechanisms
Autoimmune Diseases
- Failure of self tolerance and subsequent adaptive immune responses against self antigens
- Most are complex polygenic traits with inheritance of multiple genetic polymorphisms
- Interplay of
- Genetic factors: HLA
- Infections (molecular mimicry)
- Enviromental factors (mercury)
- Leads to break down of self tolerance
Autoimmune diseases initiation and pathophysiology
- Tolerance breakdown
- Self and non self recognition failure
- Generation of autoreactive B and T cells
- Auto-AB or autoreactive T cells attack body
- Inflammation, tissue damage
- Hypersensitivities II, III, IV
- Complement activation
Complement activation and AID development
- Uncontrolled complement activation leads to inflammation
- common in autoimmune diseases
- Deficiency in complement proteins
- C1q, C2, C4
- seen in 10% SLE
- Defective immune-complex clearance and apoptotic cells
Ab-dependent Cytotoxic HS (II)
3 mech
- IgG and IgM bind cell surfave antigens
- activating cytotoxic immune response killing target
- 3 mechanisms for this cytotoxicity
- Complement-mediated lysis
- Cell injury by inflammation
- Phagocytosis of antibody coated cells
Imm-complex HS (III) Mechanism
- Ab-ag imm complex usually removed by phagocytes and complememnt
- Persisting complexes percipitate into tissue and organ causing inflammation
- Immune-Complex Mediated Disease (
- persistent ag
- Self ag: SLE and RA
- Immune complex formation and deposition in blood vessel causes vasculitits causing
- Platelet aggregation and complement activation
- Microthrombi formation
- C5a C3a recruitment of PMNs damage to vessel wall
Type III HS Autoimmune diseases
2 examples
SLE
Vasculititis
Type IV DTH
Examples
- T cell mediated, primarily Th CD4
- Encountered in
- Contact dermatitis
- Tuberculin-type Hypersensitivity
- Granulomatous formation (TB, leprosy)
- Allergic rxn to bacteria virs fungi
- Graft rejection
- Autoimmune diseases
Type II HS autoimmune diseases
Idiopathic thrombocytopenic purpura
Autoimmune Hemolytic Anemia
Graves disease
Myasthenia gravis
Insulin receptor Ab syndrome
Type IV Autoimmune diseases
- Insulin-dependent diabetes mellitus
- Hasimotos disease
- Rheumatoid Arthritis
- Multiple sclerosis
How are auto-antibody diseases characterized
Presence of autoantibodies in serum
Deposition of autoantibodies in tissue
What dictates how pathogenic autoantibodies are
Affinity
Charge
Concentration
Characteristics of Anti-DNA antibodies charge
Anti-DNA antibodies are weakly positive
Bind negatively to glomerular of kidney
Anti-DNA Abs are prevalent and diagnostic in SLE
Anti-DNA Ab
Lupus Nephritis
Complement fixing autoantibodies
Autoimmune anemias
thrombocytopenia
Tissue-specific autoantibodies
SLE
RA
Type 1 diabetes
Autoantibodies to cell surface receptors
Graves Disease
Myasthenia gravis
Autoimmune Hemolytic Anemia
Antigen
Mech
clinical
- Ag- RBC membrane proteins
- Mech- Opsonization and phagocytosis of RBC
- Clinical- Hemolysis, anemia
Autoimmune thrombocytopenic purpura
Ag
Mech
Clinical
- Ag- Platelet mebrane
- Mech- Opsonization and phagocytosis of platelets
- Clinical- bleeding
Acute rheumatic fever
Ag
Mech
Clinical
- Ag- Strep Ag cross reacts with myocardial Ag
- Mech- inflammation, macrophage activation
- Clinical- Myocarditis, arthritis
Myasthenia Gravis
Ag
Mech
Clinical
- Ag- Acetylcholine receptor
- Mech- Ab inhibits Ach binding
- Clinical- Muscle weakness, paralysis
Graves Disease
Ag
Mech
Clinical
- Ag- Thyroid Stimulating Hormone (TSH) receptor
- Mech- Ab- mediated stimulation of TSH receptors
- Clinical- Hyperthyroidism
How does tissue-specific autoantibodies destroy tissue
Autoantibodies are depositied in tissue
Complement is activated (C3 and C5) resulting in inflammation
Phagocytes are recruited to tissue with Auto-ab-Ag complex
Phagocytes release proteolytic enzymes and toxic radicals
Autoimmune Hemolytic Anemia
Mech
- Complement-fixing Autoantibody
- IgG or IgM autoantibodies activates complement
- Complement occurs on RBC where autoantigen are
- May cause RBC lysis by Membrane Attack Complex
- Induce phagocytosis of RBC via C3b on RBC
- (Type II)
*
How do autoantibodies to receptors work and examples
Bind to cell membrane receptors and interfere with endogenous ligand binding to receptor
Graves disease: TSH to TSH receptor
Myasthenia: Ach to Ach receptors
Mechanisms of T cell mediated Tissue Injury and autoimmune disease
- Self ag activates T cells to cause tissue damage and autoimmune disease
- Cell injury mediated by T helper T cells via DTH is seen in
- Type 1 diabetes, RA and MS
- Cell killing via CD8 T cells
- Autoimmune diseases with T cell mediation may also include auto-abs and immune complexes, it is the T cell mediation that plays a dominant role
Type 1 Diabetes
Ag
Clinical
T cell mediated
Ag- Islet cell
Clinical- impaired glucose metabolism, vascular diseases
Rheumatoid Arthritis
Ag
Clinical
T cell mediated
Ag- Synovial fluid Ag
Clinical- Inflammation and erosion or joints and bones
Multiple Sclerosis
Ag
Clinical
T cell mediated
Ag- Myelin protein
Clinical- Demyelination of CNS, sensory and motor dysfunction
Hasimotos Disease
Ag
Clinical
T cell mediated
Ag- Thyroglobulin
Clinical- Destruction of thyroid gland, hypothyroidism
Molecular Mimicry
- Induction of autoantibodies by cross-reactive antigens
- Autoreactive B cells recognize both self-ag and cross reactive foreign ag
- Cross-reactive foreign ag triggers Th cell activation and cytokine production
- B cells proliferate, differntiate and secrete autoantibodies
- the antibodies bind to the pathogenic structures and control infection
- Residual auto-abs bind to self ag and trigger autoimmune disease
Molecular Mimicry in Rheumatic Fever
Auto-Abs to heart valve Ag is developed after group A Streptococcal infection of throat
Carb Ags on strep cell wall cross-react with a heart valve Ag
Strep infection is controlled via Abs
Later these Ab then bind the heart valve ag
Leading to inflammatory disease of the heart valves: rheumatic fever
Other Molecular Mimicry Diseases
Coxsackie virus B4 nuclear protein similar to pancreatic islet cell Ag glumate decarboxylase: Causes Type 1 Diabetes
Campylobacter jejuni glycoproteins similar to myelin-associated gangliosides:causes Guillain-Barre syndrome
Link between RA and Periodontitis
Link established through protein citullination or deamination in host
Patients with periodontitis have citullinated proteins in gingiva
This is due to post translational modification of arginine to citruline
P. gingivalis generates citrullinated peptides
Host creates antibodies against CCP
Citrullinated auto antigens are found in the synovial fluid of RA
Therefore infection with P. gingivalis leads to generation of CCP, loss of self-tolerance, anti-CCP Abs, development of RA
Periodontitis and autoimmune atherosclerosis
Heat shock protein from P. gingivalis may have a link between the two
HSP causes TNF production
Anti-TNF treatment in RA patients benefited RA and periodontal condition
Omega-3-fatty acids reduces swollen, tender joints in RA, may be beneficial for periodontitis
Dietary polyphenols may also be useful
How does an autoimmune disease develop?
- Self ag is not expressed in thymus or at low concentration
- Affinity of TCR for self-Ag: MHC complex is too low
- Concentration of self-ag: MHC complex in the thymus is too low
- Allow autoreactive T cells to leave thymus
- Once in periphery can induce immune response to self-ag
- Genetic predisposition
How to diagnose autoimmune disease
- Involves determination of auto-ab
- Anti-DNA Ab in SLE, anti-Rh factor Ab in RA
- Examination of tissue biopsies for deposits of Ab and complement proteins
Treatment of Autoimmune diseases
NSAIDS, COX-2 inhibitors and corticosterids: Block inflammation
Cyclophosphamide prevents proliferation B cells: reduces auto-Ab producetion, used in SLE
Anti-TNF-a mAb: control inflammation, used in Chrons disease and RA
Anti-CD20 mAb: eliminates B cells used in RA, SLE
