Mechanisms of Autoimmunity

Question 1

Autoimmunity

Answer 1

A failure of the mechanisms of tolerance to self antigens; generally due to inheritance of susceptibility genes and/or environmental factors. Often categorized based on type of hypersensitivity reaction.

Autoimmune diseases can be organ-specific or can affect many organs (and are then called systemic). Many people have autoimmune diseases ranging from the relatively benign (e.g., cold agglutinin antibodies) to more severe diseases such as rheumatoid arthritis, lupus, type 1 diabetes and multiple sclerosis.

Autoimmune disease has a 7-9% prevalence in the population and preferentially affects women.

Question 2

Physiologic or regulatory autoimmunity

Answer 2

Physiologic or regulatory autoimmunity occurs normally. For example, in the removal of aged red blood cells by reaction of IgG autoantibodies with senescent cell antigen. Without autoimmunity red cells would not be removed properly from circulation resulting in accumulation of red cells (polycythemia).

Question 3

Autoimmune Disease

Answer 3

A specific and sustained adaptive immune response directed against self which causes damage to the host. In systemic lupus erythematosis (SLE), for example, antibodies are formed against DNA, histones and other nuclear components. Since it is nearly impossible to eliminate self antigen, tissue damage occurs.

Question 4

Tolerance

Answer 4

Is the acquired and specific lack of immunological reactivity to a particular antigen. Tolerance is mediated by a combination of central tolerance and peripheral tolerance mechanisms.

Question 5

B Cell Tolerance

Answer 5

•Self-reactive, immature B cells are deleted in bone marrow or subject to clonal anergy (50%) or receptor editing in periphery, but 20% of all peripheral blood B cells are still auto-reactive.

Question 6

T Cell Tolerance

Answer 6

• Self-reactive, DP cells are deleted at the C/M junction in the thymus
• TCR with moderate affinity become Tregs to inhibit responses
• Anergy & Ignorance also come into play

Question 7

Are all self-reactive lymphocytes deleted? Why or why not?

Answer 7

• No-only strongly self-reactive T & B cells are deleted. Otherwise positive selection would not occur. (Why?)
• Not all self antigens are expressed (or at high levels) in thymus and bone marrow. Thus, some self-reactive T & B cells escape to the periphery

. • Negative selection is a moderate “pruning” process.

Question 8

How Does Autoimmune Disease Develop?

Answer 8

1. Development of autoimmune disease appears to involve genetic factors (e.g., HLA), hormonal milieu (e.g., estrogen) and environmental factors (e.g., heavy metals such as mercury or infection with various viruses).
2. Autoimmunity seems to develop spontaneously, but MHC-associated genetic predispositions do exist. Th cells are required for all forms of autoimmune disease. Generally autoimmune diseases are not monogenic in nature.
3. Infectious agents may play a role in inducing autoimmune disease through Antigenic Mimicry, which results in over-activation of the innate immune system. Epigenetics also involved.

Question 9

Commonly Accepted Mechanism of Autoimmune Disease Induction (in Most Cases)

Answer 9

1. An infectious agent causes disease. Tissue damage and inflammation result. Innate immune system is activated.
2. Recovery from disease due to T cell and antibody response.
3. A portion of a protein from the infectious agent may mimic a self protein.
4. Due to the MHC composition, some T cells specific for infectious agent’s protein also cross-reacts with self protein. In addition, ignorant T cells may now see the no longer sequestered antigen, especially nucleic acids.
5. T cell becomes “pathogenic”, responds to self antigen and recruits other immune cells. Epitope spreading can also occur due to release of sequestered antigen.
6. Tissue destruction.

Question 10

Factors Contributing to Autoimmune DIsease

Answer 10

!. Gender

2. Infections
3. Stress

Question 11

Factors Contributing to Autoimmune DIsease - Gender

Answer 11

• Estrogen induces (stimulates) IFN-γ production which causes an increase in HLA expression on APCs. Estrogen-induced IFN-γ may push Th2 autoimmune responses toward Th1, and cause an episode of autoimmune disease.
• 90% of all autoimmune dx is in women.
• Estrogens also interfere with B cell tolerance.
• X-chromosome inactivation also plays a role as does loss of mosaicism.

Question 12

Factors Contributing to Autoimmune DIsease - Infection

Answer 12

• such as the superantigen effect of Staphylococcus or Mycoplasma may activate T cells and cause them to secrete cytokines, and/or expand an autopathogenic T cell population due to prolonged inflammatory response.
• CMV and scleroderma
• HCV and mixed cryoglobulinemia (proteins (mostly Ig’s) that become insoluble at reduced temperatures)
• HBV and MS
• Coxsackievirus B4 and T1D
• Strep pyogenes and rheumatic fever
• Campylobacter jejuni and Zika virus with Guillain Barre syndrome
• Yersinia enterocolitica and Graves’ disease

Question 13

Factors Contributing to Autoimmune DIsease - Stress

Answer 13

•STRESS-induced stimulation of the hypothalamus and pituitary may lead to an increase in cytokine secretion, that may cause inflammation.

Question 14

Age and Autoimmunity

Answer 14

• The aged immune system is prone to autoimmune responses and an increase in autoimmune disease.
• Increased autoantibody titres are observed after 60yrs and RA almost only develops in females after menopause. Also, polymyalgia rheumatica and giant cell arteritis (GCA) only occur after age 50 years.
• Homeostatic proliferation and repertoire skewing (e.g., antiCMV) may select for T cells that recognize self antigens preferentially.
• Other factors include decreased Treg generation, unstable peripheral tolerance, lymphopenia, changes in intracellular signaling mechanisms.

Question 15

Autoimmune Diseases Wax and Wane

Answer 15

• regulatory T cells (CD4+ T regulatory and CD8+ T suppressor cells) prevent the response of autoimmune cells.
• Type of immune response, Th1 (cellular) vs. Th2 (humoral) is also important. Th1 responses are often associated with more severe autoimmunity, and the “diversion” of the autoimmune response from Th1—>Th2 can prevent some autoimmune diseases.

Question 16

Th17 and Autoimmunity

Answer 16

• Th17 cells are now thought to also be of significance in many autoimmune and inflammatory diseases, because of IL6 and IL1 secretion.
• TH17 cells appear to be intimately involved in psoriasis and Crohn’s disease, and possibly involved in inflammatory bowel disease (IBD) and rheumatoid arthritis (RA).
• Interestingly, deficiencies in either IL17 or its receptor results in chronic mucocutaneous candidiasis syndrome (loss of barrier protection), so IL17 cannot be eliminated completely.

Question 17

Autoimmune diseases can have characteristics of more than ome hypersensitivity reaction, but the classification is based on the [] presentation or propoased mechanism of pathogenesis.

Answer 17

Autoimmune diseases can have characteristics of more than ome hypersensitivity reaction, but the classification is based on the initial presentation or propoased mechanism of pathogenesis.

Question 18

Systemic Autoimmunity

Answer 18

A. pathology is evident in a number of organ systems

B. e.g., connective tissue diseases such as SLE, scleroderma, Sjogren’s

Question 19

Organ-specific Autoimmunity

Answer 19

A. only affects specific tissues in which the target antigen is found

B. e.g., thyroiditis (thyroid), diabetes (islets), Addison’s (steroid producing cells of ovary & adrenal)

Question 20

SLE

Answer 20

• This is a common autoimmune disease in which there are inflammatory destructive changes in many organ systems and in which anti-nuclear antibodies of many different specificities occur.
• This disease occurs at a frequency of 6 per 100,000 in low risk groups and 35 per 100,000 for higher risk groups such as Native Americans. It is most frequent in black females where it has a frequency of 1 per 250.
• The frequency in females is 10-20-fold greater than in males (in general).

Question 21

SLE Symptoms

Answer 21

• The disease is characterized by a rash of fixed erythema forming the “red wolf” pattern on the face.
• It is exacerbated by exposure to sunlight.
• Symptoms include oral ulcers and pain in joints.
• The symptoms tend to ‘wax and wane’.

Question 22

SLE Pathogenesis

Answer 22

• High levels of autoantibodies to native DNA (anti-dsDNA, ANA), denatured DNA, soluble ribonucleoproteins and RBC (anti-Smith) are characteristic features of the disease.
• Levels of complement tend to be decreased in patients experiencing an episode because of the formation of immune complexes.
• The buildup of these complexes in the kidney can lead to kidney failure
• Type III

Question 23

SLE Treatment

Answer 23

• Immunosuppressive drugs such as corticosteroids and cyclophosphamide improve symptoms and survival.
• SLE is considered a type III hypersensitivity.
• There is also a newly approved (2012) therapy for SLE called belimumab (Benlysta) that is a human monoclonal antibody against the B cell survival factor, BLyS. However, recent data indicates it may not be efficacious for African American patients

Question 24

Rheumatoid Arthritis

Answer 24

• This is a chronic inflammatory disease of connective tissue that is characterized by symmetrical multiple joint swellings, particularly of the fingers and wrist.
• The disease tends to ‘wax and wane’ in severity.
• The frequency of the disease is two-three-fold higher in women than in men.
• Inciting event is unknown (Superantigen?)

Question 25

RA Symptoms

Answer 25

•characterized by symmetrical multiple joint swellings, particularly of the fingers and wrist.

Question 26

RA Pathogenesis

Answer 26

• . RA is associated with HLA-DR4.
• Rheumatoid factor (antibodies which are usually of the IgM class and are specific for the constant region of IgG; IgM-antiIgG) occur in approximately 70% of patients.
• The synovial membranes are infiltrated by neutrophils, macrophages, (T and B) lymphocytes and plasma cells in a localized inflammatory process.
• “Pannus”, or vascular granulation tissue, forms and erodes the cartilage of the joints.
• The cause is unknown, but it may be precipitated by infections with viruses or mycoplasma.
• RA is now considered to be a type IV hypersensitivity due to involvement of T cells.

Question 27

RA Treatment

Answer 27

•Sarilumab is a human monoclonal antibody against the interleukin-6 receptor for treatment of RA, but with significant AEs.

Question 28

Graves DIsease

Answer 28

• This is a localized organ-specific autoimmune disease that results in hyperthyroidism (over-reactivity of the thyroid gland).
• The disease is ten times more common in females than in males.

Question 29

Graves DIsease Symptoms

Answer 29

• Goiter
• Nervousness
• Tremor
• Rapid pulse

Question 30

Graves DIsease Pathogenesis

Answer 30

• Patients with this disease can have IgG autoantibodies to the receptor for thyroid stimulating hormone (TSH) that mimic the stimulatory effect of the hormone.
• Low TSH
• A type II hypersensitivity

Question 31

Graves DIsease Treatment

Answer 31

• Surgery, 131I
• Thyroid hormone replacement

Question 32

Hashimoto’s Disease

Answer 32

•This is another organ-specific disease directed against the thyroid gland.

Question 33

Hashimoto’s Disease Symptoms

Answer 33

•This is a disease which may initially manifest as goiter and lead to hypothyroidism

Question 34

Hashimoto’s Disease Pathogenesis

Answer 34

• Autoreactive CD4+ T helper cells, CD8+ CTL, and B cells producing autoantibodies to a number of thyroid antigens including thyroglobulin and peroxidase occur.
• Significant lymphoid infiltration and tissue destruction is observed upon microscopic examination of the thyroid gland.
• Hashimoto’s disease is considered to be a type IV hypersensitivity.

Question 35

Hashimoto’s Disease Treatment

Answer 35

• thyroid hormone replacement

Question 36

Multiple Sclerosis

Answer 36

• Disease mediated by TH1 (and possibly TH17) cells specific for myelin basic protein (MBP) causing de-myelination of nervous tissue.
• Etiology is unknown, but the disease ‘waxes and wanes’. Males and females are affected nearly equally

Question 37

Multiple Sclerosis Symptoms

Answer 37

• Impaired coordination, loss of balance, weakness or spasticity, altered speech patterns, altered reflexes, altered eye movement due to optic nerve damage, oligoclonal bands (antibodies) in CSF, MRI to detect demyelinating lesions in brain

Question 38

Multiple Sclerosis Pathogenesis

Answer 38

• Disease is associated with HLA-DR2. Th1, CTL and macrophage infiltrates are found upon examination of the brain in MS patients.
• Th17 cells may be involved in MS (e.g., in disease induction) but do not appear to be involved in the relapse-remitting form of the disease.
• MS is considered to be a type IV hypersensitivity.

Question 39

Multiple Sclerosis Treatment

Answer 39

• Drugs that alleviate individual symptoms (e.g., prednisone & methotrexate)
• IFN-β 1a, 1b which induces monocyte apoptosis • Anti-CD20 mAbs have now shown the most promise in halting and reversing the effects on nervous system (ocrelizumab & ofatumumab) without lots of AEs
• Also in use are an integrin inhibitor (Tysabri) and a CD52 inhibitor (Lemtrada/alemtuzumab) which can have severe AEs
• Autologous MSC infusions have also shown promise

Question 40

Type I Diabetes

Answer 40

• CD4 and/or CD8 T cells specific for pancreatic beta cells resulting in development of antibodies to beta-cell antigens (GAD), insulin and pancreatic antigens.
• accumulation of sugar in blood (hyperglycemia) and in the urine with symptoms of diabetes, including accumulation of ketones in blood (ketosis) from utilization of fats as energy source, also known as diabetic keto acidosis (DKA) resulting in convulsions and coma

Question 41

Type I Diabetes Symptoms

Answer 41

Whole body: excessive thirst, fatigue, hunger, or sweating

Gastrointestinal: nausea or vomiting

Urinary: bedwetting or excessive urination

Also common: blurred vision, fast heart rate, headache, sleepiness, or weight loss

Question 42

TYpe I Diabetes Pathogenesis

Answer 42

• CD4 and/or CD8 T cells specific for pancreatic beta cells resulting in development of antibodies to beta-cell antigens (GAD), insulin and pancreatic antigens.
• The destruction of beta cells by T cells (type IV hypersensitivity).
• Th1 and TH17 cells play roles in T1D pathogenesis.

Question 43

Type I Diabetes Treatment

Answer 43

• Some attempts to treat with stem cells, islet transplants and artificial pancreas.
• Mostly treated with exogenous insulin injections

Question 44

Treatments for Autoimmune Disease - Corticosteroids

Answer 44

A. Decreases inflammation caused by cytokines (IL-1, 3, 4, 5, 8, TNFα, GM-CSF), as well as decreasing Nitric Oxide, Prostaglandins, Leukotrienes, Adhesion Molecules, and Chemotaxis

B. Increases apoptosis of lymphocytes

C. Side Effects: fluid retention, weight gain, increased blood sugar, osteopenia, hyperactivity

Question 45

Treatments for Autoimmune Disease - NSAIDs

Answer 45

A. Aspirin, Ibuprofen, Acetaminophen

B. Side Effects: GI and liver damage

Question 46

Treatments for Autoimmune Disease - Cyclosporin A, Tacrolimus, Rapamycin

Answer 46

A. Reduce production of IL-2 from T cells

B. Side Effects: renal toxicity

Question 47

Treatments for Autoimmune Disease - Anti-TNFα biologicals

Answer 47

A. Infliximab (Remicade)

B. Etanercept (Enbrel)

C. Adalimumab (Humira)

D. Certolizumab (Cimzia

E. Side Effects: susceptibility to infections and development of malignancies

Question 48

Treatments for Autoimmune Disease - IVIG

Answer 48

A. Is often administered to patients with positive results

B. Its immunosuppressive effects are due to the presence of N-linked glycans on the IgG Fc portion of the antibodies

C. Glycans bind to lectin expressed on myeloid regulatory cells to suppress inflammation

D. Results in reduced antigen presentation & inhibition of antigen-specific T cell responses via Treg induction

E. Also shown to induce production of anti-inflammatory, IL10-producing macrophages

F. Side Effects: potential development of immune complexes; expensive

Question 49

Treatments for Autoimmune Disease - Recent Therapeutic Developments - Belimumab

Answer 49

•There is an approved (2012) therapy for SLE called belimumab (Benlysta) that is a human monoclonal antibody against the B cell survival factor, BLyS (it may not work for African American patients, however).

Question 50

Treatments for Autoimmune Disease - Recent Therapeutic Developments - Ustekinumab

Answer 50

•A mAb directed against IL12/IL23 called ustekinumab (Stelara) for patients with psoriasis, psoriatic arthritis and Crohn’s disease, and an anti-IL23 mAb called tildrakizumab for psoriasis (2015)

Question 51

Treatments for Autoimmune Disease - Recent Therapeutic Developments - Brodalumab, Secukinumab, Risankizumab

Answer 51

•There is an anti-IL17R mAb (brodalumab, 2012) which is extremely effective vs. psoriasis, as is a mAb versus IL17A (secukinumab or Cosentyx, 2015) and anti-IL23 mAb Risankizumab/Skyrizi (2020, may be the best).

Question 52

Treatments for Autoimmune Disease - Recent Therapeutic Developments - Olokizumab and Tocilizumab

Answer 52

•Olokizumab and Tocilizumab bind to interleukin 6 and act as anti-IL-6 therapeutic aimed at inflammatory disease e.g. rheumatoid arthritis (RA). The latter is now FDA-approved for CRS after CAR-T therapy (2017).

Question 53

Treatments for Autoimmune Disease - Recent Therapeutic Developments - Ocrelizumab

Answer 53

•Ocrelizumab (anti-CD20) is the most effective therapy for MS now (2016).

Question 54

Treatments for Autoimmune Disease - Recent Therapeutic Developments - Dupilumab

Answer 54

•On Mar 2017 Dupilumab approved (humanized IgG4-anti-IL4Ra shared by IL4 and IL13 receptors) by FDA to treat moderate to severe atopic dermatitis.(eczema).

Question 55

Hygiene Hypothesis

Answer 55

•Epidemiologic observations suggest that exposure to microbes early in life is associated with the prevention of asthma and certain autoimmune (inflammatory) diseases. That is, children born to parents living on or near farms display much lower levels of asthma and IBD that those born to parents living in cities. Similar results are seen in mice living in specific pathogen free (SPF) vs. germ-free conditions (the “dirt is good” hypothesis). This observation may be due to levels of Treg (good) and iNKT (bad) cells stimulated by the presence or absence of the microbes. Early stimulation of the innate immune system decreases the predisposition to autoimmune disease.

Question 56

TNF-α, IL-1, IL-6

Answer 56

Begin Acute Phase Response

Question 57

IL-2

Answer 57

Induces T cell, NK and (minor) B cell proliferation

Question 58

IL-4, 5

Answer 58

Induces IgG1 and IgE, eosinophil production (IL-5)

Question 59

IL-10

Answer 59

suppresses TH1 and TH17 responses

Question 60

IFN-γ

Answer 60

up-regulates MHC class I and II expression