Autoimmunity
When the lymphocytes begin to recognize self-antigen and mount an immune response.
Assorted Features
Multiple Sclerosis (CNS)
EBV/Mono infection (mononucleosis) is frequently associated with autoimmune disorders. EBV & Herpes family (HHV1 and HHV6) can infect and persist silently inside B cells for the lifetime in infected patients.
Hashimoto's thyroiditis (thyroid)
Hyper/hypoactivity of thyroid (more commonly hypo). Often associated with other autoimmune diseases.
Graves disease (thyroid)
Hyperactive thyroid.
Myasthenia gravis (muscle)
Auto-antibodies against Ach Receptors at the NMJ (Type II). See here for treatments: Cholinergic Drugs > Cholinesterase Inhibitors (Parasympathetic)
Dermatomyositis (muscle)
Inflammation, more in kids.
Pernicious anemia (stomach)
Antibodies interfering with the stomach’s B12 absorption.
Addison's Diseases (adrenal)
Auto-antibodies.
Insulin-dependent Diabetes Mellitus (pancreas)
Learning that there may be an infectious trigger very early on in children leads to induction of auto-antibodies to pancreatic islet cells.
Goodpasture syndrome (kidney/lungs)
Antibody for the basement membrane leading to glomerulonephritis and hemorrhaging in the lungs.
Systemic lupus erythematosus (kidney)
Scleroderma (skin)
Rheumatoid arthritis (joints)
Genetic Risks
Twin studies
If one identical twin has lupus there is a 30% chance the other will as well.
Human Leukocyte Antigen (HLA) risks
Certain HLA markers are associated with an increased relative risk of developing autoimmune disorders.
B27: Ankylosing Spondylitis
DQ2/DQ8: Coeliac disease
DQ6.02: Narcolepsy
Polygenic traits
The two major genes that relate to autoimmune responses are HLA-DQ and DR.
Regulation of Autoimmune Response
AIRE
An autoimmune regulator gene. Aire makes a protein called AIRE that helps destroy tissue-reactive T cells. Without AIRE, the T cells that are reactive to self-antigens are able to mature and leave the thymus.
Antigen segregation
Immune cells can’t be reactive to self-antigens if they don't contact them with a physical barrier (e.g., the blood brain barrier).
Peripheral anergy
When immune cells can’t function at their full potential because of the absence of a co-stimulus. A weak signal means the immune response to a self-antigen does not trigger a full response.
Regulatory cells
These cells (like Treg) can suppress cytokines and intracellular signals, reducing immune response. They are able to maintain self-tolerance by suppressing other self-reactive lymphocytes.
Cytokine deviation
These cells secrete IL-4, IL5, and IL-13 (allergic responses) as well as IL-10 (anti-inflammatory). The TH2 response balances out the TH1 response (which is more inflammatory). By favoring the TH2 response, inflammatory cytokine secretion is limited.
Clonal exhaustion
How self-directed cells are destroyed. Cells undergo programmed cell death (apoptosis) and this process takes out potentially problematic clones.
Sequestering
Immunologically privileged sites are places in the body that are surrounded by physical barriers that limit exposure to lymphocytes. The extracellular fluid from these sites does not travel via the conventional lymphatic system.
The four immunologically privileged sites are the brain, eyes, testes, and uterus (+ fetus). The downside is that treatment for to these sites is harder if there is inflammation (like in the case of eye diseases).
Molecular mimicry
When antigens cross-react with something they were not supposed to react with normally. This happens when a protein sequence (antigen) in a pathogen that is recognized by an antibody is also present in a human tissue. The antibodies produced by the B cell will react with both non-human and human tissues.
Vaccines can be a type of molecular mimic.
Clinical pearl: Group A Streptococcus
Antibodies to the Streptococcus pyogenes will also attack cardiac myosin, leading to rheumatic fever. They can also recognize dopamine receptors, which leads to post-strep Sydenham Chorea and presents with “clicky” speech and abnormal movements.
Clinical pearl: Celiac disease
When gluten enters the small intestine of a patient with celiac disease, antibodies are created. Antibodies to gluten also recognize endomysial tissue transglutaminase (tTG). This results in the flattening of the villi and makes the gut more permeable to even more gluten and inflammatory mediators.
Individuals with DQ2/DQ8 HLA proteins have an increased relative risk for celiac disease.
Type II Hypersensitivity
Antibody mediated, where IgG or IgM are directed against host cells. Leads to destruction of healthy cells. Self-reactive B come from defective central tolerance when negative selection fails. Intrinsic antigens are what the host cell makes, while extrinsic antigens are from some medications (e.g. penicillin).
This is the culprit in ABO mismatch.
Mechanism 1A: Complement System
IgG and IgM activates complement proteins which will kill the host cell that's bound to the antigen that's complexed with the immunoglobulins.
For example, a penicillin allergy. Penicillin binds to a red blood cell and activates complement. The chemotactic factors attract neutrophils, which kill the RBC. This can result in hemolytic anemia, thrombocytopenia, or neutropenia.
Antibodies binding to intrinsic antigens on collagen in kidney glomeruli or lung alveoli can also cause Goodpasture's syndrome.
Mechanism 1B: Complement System + MAC
After activation of complement results in the membrane attack complex on host cells.
Mechanism 2: Phagocytosis
IgG antibodies coat the target cell and bind C3b. This complex marks the cell for opsonization.
In the spleen, macrophages recognize IgG antigens and phagocytose
In the liver, Kupffer cells (liver macrophages) recognize C3b antigens and phagocytose
Mechanism 3: Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
NK cells recognize IgG/C3b and bind the Fc part of the antibody, and kill the cell via perforins, granzymes, and granulysins.
Mechanism 4: Antibody-Mediated Cellular Dysfunction
Antibody binds to the cell and impairs physiologic function just by being annoying and present.
Antibodies specific to acetylcholine receptors in muscle result in myasthenia gravis.
Antibodies specific for receptors which stimulate thyroid hormone production can result in Graves' disease (hypothyroidism).
Pattern Recognition Receptors
Pathogen-Associated Molecular Patterns (PAMPs) and Damage-associated Molecular Patterns (DAMPs) can activate primitive pattern recognition receptors. Toll Like Receptors (TLRs) are one such subclass.
In autoimmunity, self-antigens activate the receptors as if they were PAMPs or DAMPs. EBV, HHV1, and HHV6 have PAMPs, which activate TLRs, producing an inflammatory response.
Some autoimmunity to self-antigens can actually be adaptive. Lymphocytes can bind with low level affinity to self-antigens. For example, B cells with specificity for DNA can bind to soluble fragments of DNA, cross-link, and endocytose the DNA into the cell. This is why massive cell death (and lots of self-DNA getting released) can lead to an inflammatory response.
Spreading
When an antibody starts to recognize an epitope that is different from the initial antigen. This is different from molecular mimicry because in mimicry the antibody responds to the same epitope in different areas (both human and non-human), but in epitope spreading the antibody recognizes proximate epitopes.
Systemic lupus erythematosus (SLE)
Elevated antinuclear antibody (ANA) is associated with SLE. ANAs will bind to chromatin and if antibodies fluoresce around the nucleus then it is most likely ANA. An elevated ANA is seen in 95-98% of patients with SLE.
If a patient has a positive anti-dsDNA, it is safe to say they have lupus.
Random note: A mouse with lupus that is treated with estrogen will get sicker more quickly and more severely.
Sjogren's Syndrome
A Gell-Coombs type III reaction where immune complexes are deposited into the dermal-epidermal junction.
Patients with Sjogren’s syndrome can have anti-Sjogren’s syndrome A (anti-SSA) or anti-Sjogren’s syndrome B (anti SSB). These code for anti-Ro particles (A) and anti-RnP particles (B). Anti-Ro antibodies can react with sun activated epithelial cells (photosensitivity).
The RnP is a cytoplasmic particle composed of Ro and La particles. It helps process RNA and moves between cell surface and nucleus.
Both anti SSA/SSB can be present without symptoms and can cross the placenta. exposure to anti-Ro antibodies can cause congenital heart block in infants (adults do not express the same epitope).