Chapter 16- Autoimmunity Flashcards
Autoimmune responses
Resemble normal immune responses to pathogens in that they are specifically activated by antigens- autoantigens (antigens from our own cells and tissues) give rise to autoreactive effector cells and autoantibodies. Diseases are classified as organ-specific or systemic. 5% of the population in Western countries has an autoimmune disease, and the rarity illustrates that the immune system has evolved multiple mechanisms to prevent self injury
Classification of autoimmune diseases
Autoimmune diseases are classified as type 2, 3, and 4, given that the tissue-damaging effects resemble the immune cells and factors seen with hypersensitivity reactions
Type 2 autoimmunity
Evolves autoantibodies against cell surface or matrix antigens. Examples- hemolytic anemia, myasthenia gravis, and rheumatic fever
Type 3 autoimmunity
Involves the formation of immune complexes. The soluble autoantigens are released and bind to the immune complexes, which are deposited in the tissues. Examples- bacterial endocarditis, systemic lupus erythematosus
Type 4 autoimmunity
T cells are the major effector cell causing the pathology. Examples- type 1 diabetes, rheumatoid arthritis, multiple sclerosis
Central tolerance
Takes place at the sites of lymphocyte maturation and development (thymus, bone marrow). Central tolerance works to eliminate new B and T cells that are specific for self antigens (autoreactive). Not all self antigens are present in the thymus, so autoreactive cells may escape their place of development
Central tolerance in the thymus
In the thymus, positive selection occurs to ensure that T cells can recognize self MHC, and negative selection removes those cells with a high affinity for self antigen
Central tolerance in the bone marrow
During receptor editing, B cells have the opportunity to produce a different light chain and re-form a B cell receptor that is no longer autoreactive
Peripheral tolerance
Takes place when central tolerance is not able to eliminate all autoreactive cells. Includes immunological tolerance and regulatory T cells
Immunological ignorance
When immune cells have affinity for a self antigen but do not sense or respond to it. If the antigen is inaccessible found in too low a concentration, or binds to weakly to a receptor to generate an activating signal, the cells specific for this antigen will not be stimulated and will die off
Regulatory T cells
Act to prevent the activation and expansion of autoreactive cells. There are 2 types- natural and induced. If there are mutations in FoxP3 or other factors, this regulatory mechanism can break down and autoimmunity can take place
Co-activating factors and autoimmune diseases
Co-activating factors can result in the activation of ignorant self-reactive cells. Inaccessible antigens, from immunologically privileged sites, like the eyes, gonads, or brain, can be released by tissue injury or inflammation. The eye is one example because lymphocytes don’t enter these organs, so auto-reactive T cells can’t enter and cause problems either. However, trauma to the eye can cause the release of intraocular protein antigens. The intraocular antigens are carried to the lymph nodes where they activate T cells. Then, effector T cells in the blood can travel to the eyes and make them both blind
Natural regulatory T cells
When thymocytes express a T cell receptor specific to a self antigen. The regulatory T cells are allowed to survive, and they are programmed in the thymus to express FoxP3 in response to self antigens
Change in effector CD4 T cell differentiation
When we rely on one type of T cells for an organ (which may be autoreactive), but differentiation switches to another T cell type, and these auto-reactive cells will cause disease. One example is type 1 diabetes mellitus, which depends on TH1 cells. Experimentally switching to TH2 cells inhibits disease. Psoriasis depends on TH17 cells, which cause inflammation
Induced regulatory T cells
When a naive T cell recognizes an antigen peripherally and is activated in the presence of cytokine TGF-β. This cytokine causes the activation of FoxP3, which causes the cell to differentiate into a regulatory T cell
Functions of regulatory T cells (2)
- Secrete inhibitory cytokines (IL-10, TGF-b)
- Suppress dendritic cell maturation and/or expression of co-stimulatory molecules
Autoimmune hemolytic anemia symptoms (7)
- Fatigue
- Shortness of breath
- Jaundice
- Rapid heartbeat and breathing
- History of multiple blood transfusions
- Dark urine
- Splenomegaly
Autoimmune hemolytic anemia diagnosis
Testing will reveal severe anemia- hemoglobin is very low. The normal range is 12-15.5, while the patient in this case study has a value of 2.7
Autoimmune hemolytic anemia pathology
This disease arises when the patient produces autoantibodies against Rh blood group antigens. When RBCs are bound with IgG antibodies, they are rapidly cleared through uptake by FcγR-expressing macrophages in the spleen. When RBCs are bound with IgM, they fix complement and are cleared by CR1-bearing macrophages. Additionally, antibody-sensitized RBCs can also be lysed via formation of MAC. All of these mechanisms contribute to destroying RBCs faster than they can be produced. 50% of cases are idiopathic
Autoimmune hemolytic anemia treatment
Corticosteroids, IVIG, and splenectomy
Graves disease symptoms (8)
- A slowly enlarging, painless mass in the front of the neck
- Difficulty concentrating
- Heart palpitations
- Unintentional weight loss
- Bulging eyes
- Irritability
- Thickening skin
- Problems sleeping
Graves disease diagnosis
Testing will reveal elevated free levels of thyroid hormones
Treatment of Graves disease
Antithyroid drugs, radioactive iodine, and thyroidectomy
Graves disease pathology
Graves disease is the most common cause of hyperthyroidism in the US. It appears suddenly and may be triggered by infection. Occurs when autoantibodies bind to the thyroid stimulating hormone (TSH) receptor. It then stimulates excessive production of thyroid hormone (“hyperthyroidism”)
Myasthenia gravis symptoms
- Whole body weakness
- Tiring easily
- Difficulty speaking
- Drooping of both eyelids
- Trouble chewing and difficulty swallowing solid food
- Double vision
- Unsteady walking
Myasthenia gravis treatment
Acetylcholinesterase inhibitors and immunosuppressant drugs
Myasthenia gravis epidemiology
Prevalence is 4 in 10,000 individuals, found more frequently in females than in males. Patients are also more likely to have other autoimmune conditions, like rheumatoid arthritis or lupus
Myasthenia gravis pathology
Autoantibodies against a chain of the nicotinic acetylcholine receptor block the stimulation of muscle contractions. This results in internalization and degradation of the acetylcholine receptor. Patients develop an inability to sustain a maintained or repeated muscle contraction
Goodpasture syndrome diagnosis
Patients present with advanced acute renal failure. Testing reveals hematuria and proteinuria. A renal biopsy shows glomerulonephritis. Further tests reveal the presence of anti-glomerular basement membrane (anti-GBM) antibodies
Glomerulonephritis
Inflammation of the tiny filters (glomeruli) in your kidneys. The glomeruli are small ball-shaped structures made of capillaries. They are involved in the filtration of blood to form urine
Goodpasture syndrome
Where antibodies are formed against type 4 collagen and bind to the basement membranes of renal glomeruli. The antibodies ligate FcgR on monocytes and neutrophils, causing their activation, chemokine release, and further innate cell recruitment. The antibodies also activate complement, causing tissue damage
Goodpasture syndrome treatment
Immunosuppressive drugs, plasmapheresis alleviate the symptoms
Transfer of antibody-mediated autoimmune disease
IgG autoantibodies can cross the placenta (through the FcRn receptor) and cause disease in the fetus or newborn. In diseases such as Grave’s disease, Myasthenia gravis, thrombocytopenic purpura (anti-platelet antibodies), and SLE, antibodies are capable of crossing the placenta to cause transient autoimmunity. Symptoms disappear as maternal antibodies are catabolized, however, tissue damage can occur (e.g., heart tissue damage with SLE antibodies)
Epitope spreading
During a normal immune response against pathogens, we produce effector B cells and T cells against antigens produced by the pathogen. The antigens go away when the pathogen is cleared. However, self antigens are permanent because they are part of the individual. This means that autoreactive B and T cells will always have something to respond against. Chronic inflammation can cause tissue damage and release of additional self antigens. Epitope spreading the recruitment of new clones of B and T cells as self antigens continue to be released. There are 2 types of epitope spreading- intramolecular and intermolecular
Intramolecular epitope spreading
The immune response is targeting new epitopes on the same antigen that initiated the autoimmune response
Intermolecular epitope spreading
New autoantigens are released for the immune system to respond to. This is why some people with autoimmune diseases have multiple autoimmune conditions
Pemphigus vulgaris
Pemphigus vulgaris is a disease categorized by severe blistering of the skin and mucosal membranes. Patients produce autoantibodies against desmogleins- a cadherin in cell junctions that hold cells of the epidermis together. Autoantibodies then cause dissociation of the tight junctions. Initially “harmless” antibodies against the EC5 domain of desmoglein (Dsg-3) are produced. This domain does not cause disease
Pemphigus vulgaris and intramolecular epitope spreading
As antibodies against EC5 are produced, they can begin to allow uptake of the desmoglein molecule. There is an immune response against additional epitopes, like EC1 and EC2. Antibodies against these domains are pathological, causing lesions in the oral and genital mucosa.
Pemphigus vulgaris and intermolecular epitope spreading
Immune response to another desmoglein molecule (Dsg-1). This causes deep skin blistering
Systemic lupus erythematosus (SLE)
An immune complex mediated disease (type 3 hypersensitivity). Prevalence is 20-70 cases per 100,000 people. The patient produces autoantibodies against a wide range of cell-surface and intracellular antigens. A defect in apoptotic clearance leads to apoptotic material being taken up by APCs and development of anti-nuclear antibodies
Systemic lupus erythematosus (SLE) symptoms
Immune complex deposits result in glomerulonephritis, arthritis, hair loss, fatigue, butterfly-shaped rash. Type 3 autoimmune disease as immune complexes are produced
Criteria for SLE
Established in 1982 by the American College of Rheumatology, a patient must exhibit at least 4 of 11 signs/symptoms: Butterfly rash
Scaly rash on skin, Pericarditis or pleurisy, Oral Ulcers, Arthritis, Photosensitivity, Blood disorder (anemia, leukopenia, lymphopenia, or low platelets), Kidney disease, Antinuclear antibodies, Anti-ds DNA antibodies, or neurological disorder (seizures, psychosis)
SLE immunopathology
SLE consists of an immune response against nucleosomes, which are made up of histone proteins and DNA. If apoptosis is occurring normally, these antigens won’t be processed and presented. However, in people who have defects in the clearance of apoptotic cells, these molecules can be presented. CD4 helper T cells have a specificity for a certain peptide from the linker histone. Then, B cells specific for epitopes on the nucleosome bind to and endocytose the intact nucleosome. The histone peptide is presented to CD4 T cells, and the B cells are activated to make autoantibodies
Autoantibodies in HLE
B cells can be activated to make autoantibodies against histone or DNA self antigens
SLE and epitope spreading
Immune complexes formed in SLE may present different epitopes to different autoreactive T cells (histone proteins, etc.) which activates a wider range of T cells and broadens the immune response. This is an example of intermolecular spreading
Cryptic epitopes
When B cells internalize an autoantigen and present novel, previously hidden peptides to autoreactive T cells. The “hidden” immune response then becomes detectable as the new antigens are presented.
T cells contribute to autoimmunity by (2)
- Provide help to autoreactive B cells
- Direct effector function- cytokine release, cytotoxicity
How can we prove the existence of autoreactive T cells?
Difficult to prove due to MHC restriction. CD4 epitopes are also easier to identify than CD8. The epitopes are identifiable by adding cells or tissues containing autoantigens to cultures of patient’s T cells
Hashimoto’s thyroiditis
The most common cause of hypothyroidism in the US. The thyroid gland is infiltrated with B and T cells (CD4 TH1 helper T cells) and the normal architecture of the thyroid is destroyed. It is reorganized to resemble secondary lymphoid tissue. Patients lose the capacity to make thyroid hormones
Hashimoto’s thyroiditis symptoms
Symptoms appear slowly- fatigue, weight gain, constipation, increased sensitivity to cold, dry skin, depression, muscle aches
Hashimoto’s thyroiditis treatment
Synthetic thyroid hormones
Type 1 diabetes
Make up 5-10% of all diabetes cases. The insulin-producing beta cells are targeted and destroyed by CD8 T cells, which suggests that the autoantigen is unique to b cells (i.e., insulin). On biopsy, the pancreas exhibits insulitis- infiltration of lymphocytes in the islet. One complication is diabetic ketoacidosis due to a lack of insulin and elevated glucagon
Type 1 diabetes symptoms
Frequent urination, increased thirst, increased hunger, and weight loss, blurry vision, feeling tired, and poor wound healing
Multiple sclerosis
A T cell mediated, destructive immune response to CNS myelin antigens, including Myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG). There is a dissolution of the myelin sheath surrounding nerve cell axons and inflammatory infiltrates along blood vessels. Lesions and plaques develop in the white matter of the brain
Multiple sclerosis symptoms
Various neurological symptoms- muscle weakness, ataxia, blindness, paralysis. Patients experience acute attacks followed by relapses, and undergo a steady decline where they become less responsive to therapies
Multiple sclerosis immunopathology
The CNS is a tightly regulated environment, but with MS there is a breakdown of the blood brain barrier. Activated autoreactive T cells bind to VCAM on the vascular endothelium, and migrate out of the blood vessel into the CNS. TH17 and TH1 cells infiltrate the CNS and secrete cytokines IL-17 and IFN-g. These cytokines exacerbate inflammation, and autoreactive B cells produce autoantibodies
Rheumatoid Arthritis
Found in 1-3% of the US population, and women are 3 times more likely to develop it than men. It is a chronic disease characterized by inflammation of the synovium (lining of joints). This inflamed synovium leads to cartilage damage and then bone erosion. There is an increased incidence of RA with age, possibly due to senescence and thymic involution
Rheumatoid Arthritis symptoms
Chronic pain, loss of function, and disability
Rheumatoid arthritis immunopathology
RA was first thought to be solely autoantibody mediated, but it is a T cell mediated disease. An unknown trigger causes the initial inflammation in the synovial membrane, but is attracts leukocytes to the tissue. Autoreactive CD4 T cells activate macrophages, resulting in the production of pro-inflammatory cytokines and sustained inflammation. The cytokines can also increase the production of molecules that work to break down the joint and cause degradation of the bone. People with certain HLA molecules (HLA-DR) are more likely to develop RA
Rheumatoid factor
The autoantibodies produced by B cells in RA- consists of IgM, IgG, and IgA antibodies. These antibodies are not the major factor causing disease, but can be used diagnostically
Environmental factors associated with RA
Smoking is an environmental factor associated with RA. Smoking induces the expression of PAD and the production of citrullinated proteins, especially in people with HLA-DR4.
Infection and autoimmunity
Pathogens can induce inflammation and tissue disruption, which can cause the release of sequestered autoantigens. Pro-inflammatory cytokines can also impair regulatory T cells
Molecular mimicry
An immune response against a pathogen epitope can cause a cross-reaction with self molecules. This results in an autoimmune response
Rheumatic fever
A generally transient autoimmune response that follows sore throat, scarlet fever, and impetigo. Characterized by damage to the heart valves and kidneys. Damage may be permanent in some individuals and cardiac function can be impaired
HLA and predisposition to autoimmunity
HLA is the dominant genetic factor in autoimmunity. It accounts for 50% of genetic predisposition. Some haplotypes are more prevalent in certain races, like HLA-DQ2 in Caucasians
Rheumatic fever immunopathology
When a person is infected with streptococcal bacteria, their immune system produces antibodies against the cell wall of the bacteria. However, some of these antibodies can cross-react with antigens expressed on the heart valves. This is another example of molecular mimicry, where antibodies cross-react with similar antigens
Factors influencing susceptibility to autoimmunity
Other genes, like those involved in signaling, co-stimulation, and apoptosis may be involved. Gender, age (thymus shrinking) and environmental factors may play a role
IVIG
Pooled human immunoglobulin, which achieves complete saturation of the FcgR receptor. The saturation may prevent the activation of macrophages. This results in suppression of autoantibodies
Anti-idiotypic antibodies
Antibodies that bind to antigen-binding site of another antibody (remember antibodies are proteins). May prevent them from binding to self antigens
Plasmapheresis
When components of blood plasma are filtered and returned to the donor. This process depletes the autoantibodies and immune complexes, as in Goodpasture’s syndrome, myasthenia gravis, and lupus. There is only a transient benefit, so this treatment must be coupled with corticosteroids. Side effects include a risk of infection (we may be removing beneficial antibodies) and clotting problems
immunosuppressives
Similar drugs are used for allergy and preventing transplant rejection. They impact the expression of several immune genes (20%). Side effects include toxicity and the development of tolerance
Rapamycin
An immunosuppressive that targets the mammalian target of rapamycin (mTOR), which is the central regulator of mammalian metabolism and physiology. It impacts cell proliferation and growth. Rapamycin also appears to increase the number of regulatory T cells
Antibody therapies
Experimentally generated monoclonal antibodies that can deplete and block function. Antibodies can be humanized to prevent rejection
Anti-TNF-a (Humira)
Blocks/neutralizes ability of TNF-a to induce inflammation- it is effective against RA, colitis, and Crohn’s disease. Humira has a long half life (12-14 days) but needs to be combined with methotrexate to suppress T and B cell activation. There are concerns about increased susceptibility to infections due to treatment, such as latent virus and bacterial infections
Ex vivo-Expanded Autologous Polyclonal Regulatory T Cell Therapy
T cells are isolated from the blood of patients, and the cells are expanded ex vivo. They are assessed for FoxP3 expression and suppressive activity prior to transfer back into patient. Tested in patients suffering from adult type I diabetes (n= 14); more studies needed
Citrullinated proteins
PAD enzyme converts arginine to citrulline residues, which are neutral in charge. The loss of surface charge makes the proteins more susceptible to proteolysis. Peptides containing citrulline residues are then presented to CD4 T cells in RA
