Autoimmunity Flashcards
What two key features lead to autoimmunity?
- Failure of self-tolerance (self-reactive B or T cells)
2. Tissue destruction due to inflammation
What is the difference between autoimmunity and autoimmune disease?
autoreactive Ab or self-reactive T cells cause autoimmunity, but they will not cause disease unless there is inflammation (due to type II, III, or IV hypersensitivity)
What are the 5 major symptoms of inflammation?
- Heat
- Redness
- Swelling
- Pain
- loss of function
Are autoimmune diseases usually acute or progressive (chronic)?
What two things tend to cause acute/transient autoimmunity?
They are chronic and worsen with time, although there can be acute flares.
Acute/transient autoimmune disease is caused by drugs or infection
What is central tolerance?
Censoring of B or T cells in the primary lymphoid organs to make sure they are not self-reactive
What is peripheral tolerance?
censoring in secondary lymphoid organs
How does central tolerance of B cells work in the bone marrow?
B-cell editing - at the light chain locus
Anergy- if weakly reactive
Deletion- via apoptosis if strongly reactive
How does central tolerance of T cells work in the thymus?
High avidity–> deleted (negative selection)
No avidity–> deleted (neglect)
Low avidity–> survives and proliferates
AIRE presents tissue from the body that isn’t circulating through the thymus so T-cells will not be reactive to it
What are the three major ways peripheral tolerance are maintained?
- Sequester Ag
- Privileged sites
- regulatory cells (Treg, TGFb, IL-10)
What are 4 ways that antigens can be sequestered in the periphery to maintain tolerance?
- potentially autoreactive T and B may not gain access to the autoantigen tissue because it is not inflamed (lack addressins)
- There may not be MHC II molecules on the autoantigen tissue
- Most cells in the body lack CD80/86 which give signal 2 to the T-cell
- B-cells unactivated by Tcell CD40L undergo apoptosis via FAS/FASL
What are “immune privileged” sites of the body?
eyes, brain, uterus, testes
What are 3 ways that the body ensures B and T cells are not activated in immune privileged sites?
- physical barrier- BBB to block entrance of B and T
- Suppressive cytokines (IL-10, TGF-B)
- FASL expression on privileged sites to initiate apoptosis if B or T cells breach the physical barrier/get past suppressive cytokines
What cells in the body regulate autoreactivity of T and B cells? What TF activates these cells? What cytokines does it produce?
CD25, FOXP3 derived Treg cells supress the immune system by secreting IL-10 and TGF-B
Patients with mutations in AIRE develop what disorder?
APECED (APS1) where there is autoimmunity in endocrine glands due to the failure of self-antigens to be presented in the thymus
Patients with mutations in FAS/FASL develop what disorder?
ALPS- autoimmune lymphoproliferative syndrome because there is an accumulation of B and T cells that fail to be deleted (by fas)
What molecule downstream of fas can also cause ALPS?
caspases
Patients with defects in FOXP3 develop what disorder?
IPEX- because of defects in Treg function
Why does trauma increase the chance of an autoimmune response?
It breaches physical barriers and releases sequestered or privileged site antigens
What are the 4 ways infections can increase the chance for autoimmune disease?
- infection upregulates MHCII, CD80/86 to activate T and B cells
- engage TLR to activate innate immune system
- damage barriers- release privileged Ag
- Molecular mimicry
What is molecular mimicry?
B or T cells recognize epitopes on pathogens that are very similar to host epitopes. Activated pathogens thus kill the pathogens, but also kill self proteins
What self protein do streptococcus A proteins resemble? What does this cause?
cardiac myosin–> rheumatic heart disease
What self proteins do campylobacter jejuni proteins resemble? What problem does this cause?
Myelin gangliosides and glycolipids on neurons–> Guilain Barre Syndrome (neural disease)
What is sympathetic opthalmia?
Trauma to the left eye cause inflammation in the right eye 3 weeks later because there is a release of intraocular protein to the other eye
What are 4 examples of breach of a physical barrier causing autoimmunity?
- sympathetic opthalmia
- vasectomy (broken barrier allows anti-sperm Ab to be released–> infertility)
- lens surgery
- smoking–>Goodpasture’s disease in lungs/kidneys
How do drugs trigger autoimmunity?
- drugs generate neoepitopes out of self-antigens that trigger B and T cells for the new epitopes.
(Penicillamine and m-DOPA) - Bind to RBC and act as haptens–> autoimmune hemolytic anemia
What are the four disorders associated with autoimmunity due to Type II hypersensitivity?
- Graves- overactive TSH-R
- Myasthenia Gravis- blocked AchR
- Goodpasture’s Disease- anti-NC1 domain of type IV collagen
- Autoimmune hemolytic anemia (AIHA)
What is the autoantigen for AIHA?
What is the consequence?
Autoantigen against:
Factor I–> complement-mediated lysis of RBC
Rh+–> opsonization and destruction of RBC by phagocytes
What is the autoantigen for Goodpasture’s syndrome?
What is the consequence?
What is a major cause?
Ab against the NC1 domain of type IV collagen in lungs and kidney–> glomerulonephritis and pulmonary hemorrhage
Often caused by smoking
What is the autoantigen for Grave’s Disease?
What is the consequence?
Antagonistic reaction of TSH-R (thyroid stimulating hormone receptor)–> hyperthyroidism
What is the autoantigen for Myasthenia gravis?
What is the consequence?
Anti-AchR which leads to progressive muscle weakness because less AP can be transferred at the neuromuscular junction
What are the two types of Ab for autoimmune hemolytic anemia?
What is each directed against?
- Warm agglutinins- IgG directed against Rh+ antigen on RBC
2. Cold agglutinins- IgM to the I antigen on RBC
How do warm agglutinins cause hemolytic anemia?
warm = IgG against Rh+ which coat the RBC with Ab and clear them by opsonization by splenic macrophages
How do cold agglutinins cause hemolytic anemia?
IgM Ab lead to complement-mediated lysis of RBC by binding to I antigen–> Hb in the urine increases
What clinical sign would let you know that the patient had hemolytic anemia due to cold agglutinins?
Increased Hb in the urine
What is meant by transient autoimmunity?
When the mother’s IgG crosses the placenta, it can cause autoimmunity in the baby including:
- myasthenia gravis
- lupus
- hemolytic anemia
- graves
What Ab are involved in neonatal lupus?
What is the clinical presentation?
anti-Ro and anti-La cause congenital heart block
When do neonatal autoimmune diseases usually subside?
3-6 months because the mothers autoimmune IgG will nadir
What are examples of autoimmune disorders with type 3 hypersensitivity?
- Rheumatoid arthritis
2. SLE (lupus)
What is the autoantigen in rheumatoid arthritis?
What is the consequence?
Rheumatoid factor (IgM antiFC) –> immune complexes gather in joints
What is the autoantigen in SLE?
What is the consequence?
Ab against chromatin, DNA and ribonucleoproteins –> immune-complex mediated glomerulonephritis, vasculitis, arthritis
What type of immune complex is NOT pathogenic? Why?
large immune complexes because they are easily bound to FcR and complement and can be cleared
What type of immune complex is not easily cleared from the body and gets deposited where circulation is sluggish? (what are these sites)
small immune complexes get deposited in:
- kidney
- Joints
- choroid plexus
- ciliary bodies
What causes the autoimmune response when small ICs get deposited in sluggish circulation areas?
Fc and C3b are unable to be phagocytosed because they are stuck in the vascular wall.
Frustrated neutrophils release toxic mediators
What are examples of autoimmunity with type IV hypersensitivity?
T1D, Hashimoto’s thyroiditis, RA, MS
What cell is targeted by CTL in an autoimmune fashion in T1D? What is the consequence?
Pancreatic B cells leading to B-cell destruction and lack of insulin
What is the autoantigen for Hashimoto’s thyroiditis? What is the consequence?
Thyroglobulin and thyroid peroxidase–> hypothyroidism and goiters
