Autoimmune Disorders Flashcards
When does autoimmunity become a disease?
Breakdown in mechanisms that keep benign autoimmunity in check
What is central tolerance?
Removal of self-reactive T and B cells in the thymus and bone marrow respectively
What is peripheral tolerance?
Anergy inactivation of B and T cells when they bind to self-antigens in the absence of co-stimulatory signals
Fas-mediated apoptosis
What has provided direct proof of autoimmunity as a disease?
AI is transmissible from mother to baby via placenta (IgG)
Most AI involves autoreactive T-cells - observed in animal experiments
What has provided indirect proof of autoimmunity as a disease?
Disease recreation in animal models via experiments
Spontaneous AI occurrence in animals of AI seen in humans
These factors are helpful in diagnosis of autoimmune disease
High IgG and deposition of immune complexes in certain tissues
High number of infiltrating immune cells to affect tissue
HLA molecules presenting self-peptides to T-cells —> no self-tolerance
Decreased symptoms with immunosuppressive therapies
What factors contribute to autoimmune disorders?
Genetic
Environmental
Immune regulation
How do genetic factors contribute to autoimmunity?
HLA alleles
non-HLA genes (deficiency in pro-apoptosis molecules, overexpression of pro-inflammatory cytokines, complement deficiency)
How do environmental factors contribute to autoimmunity?
Drugs modifying self-antigen
Modified environmental antigens
Trauma
Microbial antigens may mimic self-antigens or cause polyclonal B-cell activation
This sex is more likely to develop autoimmune disorders
Females
Pregnancy may improve or worsen some AI diseases
What is relative risk?
Risk of contracting a disease based on a person having a certain HLA type vs someone who doesn’t have that HLA type
This HLA is strongly associated with ankylosing spondylitis and is helpful in diagnosis of the disease
HLA-B27, class I gene
How is tolerance to foods (highly antigenic) maintained?
Oral tolerance Immune unresponsiveness to oral or nasally encountered antigens
Initiated when antigen encounters GALT
Dendritic cells most active in GALT
Large antigen dose —> some entering systemic circulation —> T cell anergy when no co-stimulatory interactions
Low dose —> locally induced tolerance r/t cytokines in GALT —> differentiation into TH2 and Treg for specific antigen
This condition is related to a failure of oral tolerance to gluten
Celiac disease
What sites in the body are immunoprivileged?
Brain
Testicles
Fetus and placenta
Eyes
What mechanisms protect immunoprivileged tissues?
Lack of lymphoid drainage
BBB
Presence of immunosuppressive cytokines (TGF-beta, FasL expression)
How can immunoprivileged sites be compromised?
Trauma —> antigen from site into circulation —> T-cell presentation by APCs
What happens to autoreactive B cells that escape into the periphery?
Deleted or become anergic in absence of T-helper cells
What is molecular mimicry?
Epitope of microbial antigen mimics that of self-antigen —> self reactivity
What is the mechanism of molecular mimicry? (T and B cell role)
- T-cell cross reactivity with microbial epitope —> self-reactive B cell activation —> anti-self antibody production
What causes rheumatic heart disease?
- S.pyogenes cross reactivity with heart valve myosin —> autoimmune response
Tell me about Myasthenia Gravis (sensitivity type, target)
Type II hypersensitivity
Ach receptor antagonist
Tell me about Graves disease (sensitivity type, target)
Type II hypersensitivity
TSH receptor agonist
Tell me about SLE (sensitivity type, mechanism)
Type III hypersensitivity
Immune complex deposition
What is the half-life of IgG? Implications for MG and Graves?
IgG half-life = 21-28 days
IgG is the autoantibody in MG and Graves and can cause transient disease in the newborn
Severe disease tx with plasmapheresis
Immune complexes in SLE often composed of…
Ab + soluble DNA
What is the principal lab test for dx of SLE?
High titer of autoantibodies vs DS DNA
Autoimmune diseases are mainly what type of hypersensitivity?
Type IV hypersensitivity - T cell mediated
Tell me about rheumatoid arthritis (hypersentitivity, location, cells/cytokines involved)
Type IV
Synovial fluid chronic inflammation
Fluid infiltration by CD4, CD8, B-cells, plasma cells, and macrophages
Cytokines: TNF-am IL-1 —> fibroblast, macrophage, chrondrocyte production of proteinases and other enzymes
Tell me about Type I diabetes (hypersensitivity, location, cells/cytokines involved)
Type IV
B-islet cells of pancreas
CD8 cells mainly; CD4, macrophages also
Cytokines: TNF-a, IL 1, IFN-a
Tx of AI diseases
NSAIDS
Immunosuppressive drugs
Cytokine production inhibitors
Cytotoxic drugs
Immunosuppressive drugs and action
Steroids
Hydroxychloroquine
Anti-inflammatory. Alter Tcell and neutrophil movement and communication; decrease # of immune cells, decrease cytokine production
Cytokine production inhibitors and uses
Cyclosporin and Tacrolimus: interfer with IL2 synthesis
Rapamycin: blocks IL2-ILR signal
Cytotoxic drugs and action
- Azathrioprine, methotrexate,
- Nucleotide synthesis inhibitors
Biologics - mechanism, types, side effects
Function: biological response modifiers or targeted immune modulators
Types:
TNF-a antagonists
IL1 antagonists
MAB
IF-b
- Side effects: TNF-a inhibition may reactivate TB, certain viruses
