Immunopathology III (Autoimmunity) Flashcards
Define the mechanisms that lead to immunological tolerance.
• Ignorance: Antigen is inaccessible to immune system
• Thymus
o Negative Selection: T-cells are destroyed before reaching the periphery
• Outside the Thymus
o Anergy: T-cells encounter antigen but are ineffective
o Tregs: Suppress other lymphocytes
o T-cells destroyed in the periphery as\before they encounter antigen
Describe positive selection and negative selection.
• Positive Selection
o T-cells must recognize MHC\peptide through TCR
• Negative Selection
o T-cells that have VERY high affinity of MHC are killed
o Negative selection is incomplete (even in normal individuals)
Name possible mechanisms in autoimmunity.
- Molecular mimicry
- Escape of auto-reactive clones
- Release of “sequestered antigen”
- Epitope spreading (Damage releases even more antigens)
- Polyclonal B-Cell activation
List genes/loci known or strongly suspected to be associated with autoimmunity in humans.
• HLA DR3-A1-B8
o Auto-immune hepatitis:
• PTPN22
o Protein Tyrosine Phosphatase
o Rheumatoid Arthritis & Type I Diabetes
o Autoimmune Disease
• NOD2
o Crohn Disease (IBD)
o Encode cytoplasmic sensor of microbes
- Can’t sense microbes well
- Tissue invasion by microbes
• Cytokine receptors
o Multiple sclerosis
o IL-2R alpha – CD25
o IL-7 receptor alpha
o Control maintenance or development of TregsDescribe mechanisms by which infection can lead to autoimmunity.
• Adjuvant Effect
o Up-regulation of co-stimulators of APC
o Break tolerance for self-antigens
• Molecular Mimicry
o Rheumatic Heart Disease caused by Streptococcal proteins
• Polyclonal B-cell Activation
o Augment production of autoantibodies
• Poly-clonal B-cell activation
o Production of autoimmune antibodies
o EBV & HIV
• Tissue Injury
o Release self-antigens
o Activate T-cells
o Alter self-antigens
Describe the role of regulatory T cells in controlling autoimmunity.
• Treg cells
o Sub-population of CD4 or CD25
o Low affinity IL-2 receptor = CD25 (receptor is also found on other cell types)
o FoxP3
o Higher affinity than conventional affinity but not so high that it is negatively selected against in the thymus
o If this population of T-cells depleted = pathogenic autoimmunity
• Tolerance to a specific antigen can be transferred actively from one individual to another
• Other populations of cells have regulatory or suppressive activity
• Mechanism
- Produce certain cytokines (IL-10 and TGF-B1)
- Cell contact is required
- CTLA-4 (intracellular initially and then expressed on the surface)
- FasL
- Granzyme
Identify diseases mediated by antibodies and diseases mediated by T cells
• DISEASES MEDIATED BY ANTIBODIES
- Organ specific
o Autoimmune hemolytic anemia
o Autoimmune thrombocytopenia
o Myasthenia gravis
o Graves disease
o Goodpastures Disease
- Systemic Autoimmune Disease
o Systemic Lupus erythematosous (SLE)
- Diseases caused by autoimmunity or by reactions to microbial antigens
o Polyarteritis nodosa
• DISEASES MEDIATED BY T-CELLS
- Organ specific
o Type 1 diabetes
o Multiple sclerosis
- Systemic autoimmune disease
o Rheumatoid arthritis
o Systemic sclerosis
o Siogren syndrome
- Diseases caused by autoimmunity or by reactions to microbial antigens
o Inflammatory Bowel Disease
• Crohn disease
• Ulcerative colitis
o Inflammatory myopathiesSystemic Lupus Erythematosus.
• Symptoms
o Malar rash
o Discoid rash
o Photosensitivity
o Oral ulcers
o Arthritis
o Serositis
o Renal disorders
o Neurological disorders
o Hematological disorder
o Immunological (anti-DNA antibody)
o Antinuclear antibody
• Etiology
o Genetic Factors
• Genetic complexity
• ↑ familial association
• HLA associations: HLA-DQ alleles
• Deficiency in complement cascade (C2, C4 & C1q)
• Favors tissue deposition of Ag-Ab complexes and no complement to clear it away
• In mice at least 20 different loci
o Immunological Factors
• Defective elimination of self-reactive B cells
• Specific nucleosomal antigens activate CD4+T-cells
• Nuclear DNA\RNA engage TLRs
• Over reaction to type 1 interferons
• Increased cytokines = augment B cell
o Environmental Factors
• UV light exposure (DNA damage)
• Sex hormones (greater frequency of flair ups in women during reproductive years)
• Drugs can induce SLE-like symptoms
Activation of Helper T-cells and B-cells and results in production of pathogenic autoantibodies.
Rheumatoid Arthritis Symptoms
o Fatigue o Weight loss o Myalgias o Excessive sweating o Low-grade fevers o Morning stiffness o Lymphadenopathy
Rheumatoid Arthritis Etiology
o Genetic
• Complex
• MHC: HLA-DRB1 allesl
• PTPN22 allele
o Environmental
• Cyclic Citrullinated proteins (CCP) (arginine converted to citrulline)
• Unknown perhaps viral or bacterial antigens
o Immunological
• Inflammatory synovitis mediated by CD4+ T-cells
• Th17: Recruit neutrophils
• Th1: Macrophage activation
• 80% of patients have Rheumatoid Factor (IgM)
• Autoantibodies to Fc portions of IgG
• Not causative but a marker for disease
• Production of Anti-CCP antibodies and T-cell response = chronicity
• Many cytokine mediators
• TNF – TNF angonists used in treatment
• IL-1, 6, 17, 23
• PGE2
• GM-CSF
• NO
• TGF-beta
• MMPs
• RANKL
Rheumatoid Arthritis Pathogenesis
o Inflammatory cells infiltrate the synovial stroma
o ↑ vascularity due to vasodilation & angiogenesis
o Fibrin aggregates form
o Neutrophils accumulate in joint space
o Pannus Formation
• Mass consisting of
• Synovium
• Stroma
• Granulation tissue
• Fibroblasts
• Grows over the cartilage and causes erosion
• Once cartilage is destroyed = fibrous ankylosis = pannus bridge between boob
Type I diabetes mellitus
- Destruction of β cells of pancreatic islet
- CD4+ & CD8+ cells
- Proceeded by production of anti-insulin antibodies
