Autoimmunity

Which of the following **self-tolerance** mechanisms help to prevent the **immune system** from responding to the body’s own healthy cells and tissues?

a) negative selection of B cells in the bone marrow and of T cells in the thymus

b) restriction of tissue-specific protein expression to the appropriate peripheral tissues

c) induction of anergy in primary lymphoid organs

d) suppression of autoreactive lymphocytes by regulatory T cells

a, d

Which of the following are NOT expressed by mast cells on their cell surfaces?

a) Toll-like receptors

b) Fc receptors for IgM

c) Fc receptors for IgG

d) Fc receptors for IgE

e) Fc receptors for IgA

b

Which type of disease is one in which the pathology is caused by an **adaptive immune response** directed against normal components of healthy tissue?

a) tolerance

b) allergic

c) type I hypersensitivity

d) autoimmune

d

What type of correlation exists between the capacity of the thymus to make new T cells and the incidence of rheumatoid arthritis?

a) an inverse correlation

b) no correlation

c) a direct correlation

a

Which **allotype** provides **dominant** protection against **type 1 diabetes** in **homozygotes** as well as **heterozygotes**?

a) DQ2

b) DQ6

c) DQ7

d) DQ8

b

Which of the following statements support the argument that the first step in the development of an **autoimmune disease** involves the loss of T-cell tolerance?

a) Most antibodies that mediate autoimmune disease are high-affinity IgG autoantibodies.

b) Mechanisms that delete self-reactive T cells are less efficient than those that eliminate autoreactive B cells.

c) Inflammation in tissues reduces the expression of MHC molecules, especially MHC class II.

d) Single HLA allotypes are associated with autoimmune disease.

a, d

Which of the following statements correctly describe the reasons why **autoimmune disease** are more prevalent in women than in men?

a) Women tend to make stronger adaptive immune responses to infection than men.

b) Estrogen and prolactin enhance adaptive immunity.

c) Testosterone enhances inflammatory responses.

d) Pregnancy promotes a switch from a predominantly TH2 response to a TH1 and TH17 response.

a, b

Which statement accurately explains why pyridostigmine is used to treat **myasthenia gravis**?

a) Pyridostigmine inhibits autoantibody-induced endocytic uptake of acetylcholine receptors.

b) Pyridostigmine binds to the antigen-recognition site on autoantibodies, preventing them from binding to the acetylcholine receptors.

c) Pyridostigmine increases Na+ influx at neuromuscular junctions, permitting muscle contraction.

d) Pyridostigmine inhibits the degradation of acetylcholine.

d

Which of the following **hypersensitivity reactions** is associated with **autoimmune disease** and is correctly matched with its cause?

a) type I: effector T cells

b) type II: mast-cell activation by antibody cross-linking

c) type III: immune-complex deposition

d) type IV: antibody against cell-surface or matrix antigens

c

Which of the following explain the relationship between peptidyl arginine deaminase (PAD) and increased susceptibility to autoimmune disease?

a) PAD produces peptide antigens to which the T-cell repertoire is not tolerant.

b) Citrullinated proteins are more unstable than proteins with unaltered arginine residues.

c) Increased PAD expression is always seen in rheumatoid arthritis.

d) PAD is expressed in healthy tissue but not in diseased tissues.

a, b

In pemphigus vulgaris and the milder variant pemphigus foliaceus, the ---- is affected by autoantibodies made against ---------- , which has five domains. Initially, the --- domain is targeted by autoantibodies, but this does not cause disease. Onset of pemphigus is seen when ---- binds to the EC2 and EC1 domains.

skin, desmoglein, EC5, IgG4

What is the term for the process by which the immune response broadens its specificity to target different antigen molecules?

a) systemic lupus erythematosus

b) lymphoid neogenesis

c) intramolecular epitope spreading

d) intermolecular epitope spreading

d

What is the term that describes the normal situation whereby the **immune system** does not attack the body’s own tissues?

a) hypersensitivity

b) autoimmunity

c) tolerance

d) inflammatory

c

In family studies investigating sibling pairs who both have **type 1 diabetes**, it has been shown that the highest percentage of affected pairs share how many HLA **haplotypes**?

a) zero

b) one

c) two

c

The process involving the shift in immune response away from one region of an antigenic molecule and toward a different epitope of the same molecule is known as what?

a) intramolecular epitope spreading

b) antigenic shift

c) lymphoid neogenesis

d) tertiary lymphocyte reactivity

a

**Sympathetic ophthalmia** arises after one eye has been injured. Which statement best describes the nature of the immune response in this disease?

a. It causes damage only to the eye involved in the injury.

b. It causes damage to both eyes even if only one eye was injured.

c. It causes an autoimmune response directed at a range of nervous system tissues, resulting in a multiple sclerosis-like disease.

d. It causes no damage to the eyes because the eye is an immunologically privileged site.

b

Which of the following characteristics are shared by secondary and tertiary lymphoid tissues?

a. Their formation is driven by lymphotoxin.

b. They both are encapsulated.

c. They both contain lymphatic vessels.

d. They both carry out germinal-center reactions.

a, d

Individuals with **IPEX** must be treated with which of the following in order to survive?

a. immunosuppressive drugs

b. thyroid hormones

c. hematopoietic stem cells

d. injections of IFN-β1

c

How efficient are cryptic epitopes at inducing T-cell tolerance compared with noncryptic epitopes?

a. more efficient

b. just as efficient

c. less efficient

c

Which of the following **allotypes** modifies susceptibility to **type 1 diabetes** in individuals who express the DQα\*03:DQβ\*02:01 heterodimer?

a. HLA-DR4

b. HLA-DR3

c. HLA-DQ7

d. HLA-DQ6

a

Which of the following describes the function of insulin?

a. Insulin signals cells to take up glucose and incorporate it into carbohydrate and fats.

b. Insulin causes the liver to convert stored glycogen into glucose, which is then released into the bloodstream.

c. Insulin suppresses the release of gastrointestinal and pancreatic hormones in order to reduce the rate of glucose uptake during a meal.

a

Identify the statements that correctly compare **Graves’ disease** and **Hashimoto’s disease**.

a. Graves’ disease and Hashimoto’s disease are associated with the production of anti-thyroid antibodies.

b. Graves’ disease is mediated by a TH1 response, whereas Hashimoto’s disease is mediated by a TH2 response.

c. Although tertiary lymphoid tissue is formed in both Graves’ disease and Hashimoto’s disease, it is formed with more regularity in the latter.

d. Graves’ disease and Hashimoto’s disease cause hypothyroidism.

a, c

Which of the following accurately explain how the T-cell population is maintained in individuals who are 70 years of age or older?

a. Existing T cells become more resistant to apoptosis.

b. The thymus continues to sustain adequate levels of new naive T cells.

c. Tertiary lymphoid tissues develop in endocrine glands and give rise to new naive T cells.

d. Existing T-cell clones proliferate.

a, d

Pathogen with corresponding autoimmune diseases: Reiter’s syndrome

*Chlamydia trachomatis*

Pathogen associated with Lyme disease

*Borrelia burgdorferi*

Pathogen associated with reactive arthritis

*Shigella flexneri*

Pathogen associated with type 1 diabetes

Coxsackie A virus

Pathogen associated with rheumatic fever

*Streptococcus pyogenes*

What **autoimmune diseases** is not caused by autoantibodies specific for a signaling receptor?

a. Graves’ disease

b. multiple sclerosis

c. myasthenia gravis

d. type 2 diabetes

e. hypoglycemia

b

Which of the following is true of individuals with **Graves’ disease** treated by thyroidectomy?

a. They also require continued treatment with iodine-131.

b. They receive daily doses of synthetic thyroid hormones.

c. They live normal lives with proper diet and exercise.

d. They usually receive a thyroid transplant.

b

Which of the following produces insulin in the islets of Langerhans?

a. α cell

b. β cell

c. δ cell

b

Why do individuals with **autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy** (**APECED**) exhibit symptoms of a wide variety of **autoimmune diseases**?

a. The transcriptional repressor protein FoxP3 does not function properly.

b. The normal array of tissue-specific proteins is not expressed in the thymus.

c. The signaling molecule BTK is not expressed, leading to an increased number of autoreactive B cells.

d. Unregulated angiogenesis (blood-vessel generation) causes extensive vascular penetration of endocrine glands and other tissues.

b

Which factor dominates all others in the predisposition to **autoimmune disease**?

a. the environment in which the individual is raised

b. the microbiota that colonizes the individual

c. the race of an individual

d. the individual’s HLA genes

e. the sex of an individual

d

Which of the following are associated with an increase in the relative risk of developing **rheumatoid arthritis**?

a. smoking

b. B cells specific for citrullinated self peptides

c. T cells specific for citrullinated self peptides

d. number of HLA-DR susceptibility alleles

e. healthy teeth and gums

f. appearance of rheumatoid symptoms soon after the production of antibodies against citrullinated self proteins

a, b, c, d

The mechanism that operates in **SLE** in which autoreactive **B cells** make antibodies to DNA (a macromolecule not recognized by T cells) is analogous to the immune response induced by which of the following?

a. TLR ligands

b. conjugate vaccines

c. adjuvant

d. T-independent antigens

b

Which of the following statements support the argument that the first step in the development of an **autoimmune disease** involves the loss of T-cell tolerance?

a. Single HLA allotypes are associated with autoimmune disease.

b. Most antibodies that mediate autoimmune disease are high-affinity IgG autoantibodies.

c. Mechanisms that delete self-reactive T cells are less efficient than those that eliminate autoreactive B cells.

d. Inflammation in tissues reduces the expression of MHC molecules, especially MHC class II.

a, b

Which of the following is true of individuals with a deficiency in the transcription factor **AIRE**?

a. Treg cells fail to develop in these individuals.

b. Their CD8 T cells develop poorly, predisposing these people to virus infection.

c. The negative selection of their T-cell repertoire is incomplete.

d. Few cases of autoimmunity occur because these people express reduced amounts of inflammatory cytokines.

c

Which statement is correct regarding the presence of acidic amino acid residues at positions 70 and 71 in the DRβ chain of the DRB1\*04 **allotype**?

a. They confer susceptibility to rheumatoid arthritis.

b. They are associated with the same level of susceptibility to rheumatoid arthritis as all of the other subtypes of HLA-DR4.

c. They make the localized charge environment within the peptide-binding groove more positively charged.

d. They do not increase an individual’s susceptibility to rheumatoid arthritis.

d

Which of the following are true statements regarding the period prior to the onset of symptoms in individuals who will eventually be diagnosed with **type 1 diabetes**?

a. Antibodies against specialized proteins of the pancreatic β cells are detectable.

b. Insulitis occurs in the pancreas.

c. Pancreatic β cells undergo hyperproliferation.

d. T-cell tolerance to pancreatic β-cell proteins is broken.

e. They will experience hypoglycemia.

a, b, d

The inflammation and tissue damage observed in celiac disease are associated with which of the following?

a. cell death induced by natural killer (NK) cells

b. pro-inflammatory cytokines made by macrophages

c. immune-complex deposition in gut-associated lymphoid tissue

d. IgE-mediated type I hypersensitivity to gluten

b

Under certain conditions, antigenic determinants on molecules that are usually inaccessible to the **immune system** are revealed. What is the name given to these antigenic determinants?

a. cryptic epitopes

b. discontinuous epitopes

c. linear epitopes

d. repeated epitopes

a

Myasthenia gravis is caused by antibodies antagonistic to the acetylcholine receptor. Which of the following is the consequence of this interaction?

a. hypoglycemia

b. progressive muscle weakness

**c. h**yperthyroidism

d. glomerulonephritis

b

APECED is caused by defective alleles in the AIRE gene and is common in certain populations, such as Finnish people. There are a range of common symptoms, including dystrophic fingernails, shown here. However, only one symptom is universally seen in all Finnish individuals with APECED. What is it?

a. hypothyroidism

b. vitiligo

c. candidiasis

d. type 1 diabetes

c

What is the term for an occurrence that can cause an immune response directed against both a pathogenic antigen and a **self antigen** that resembles it?

a. intermolecular epitope spreading

b. molecular mimicry

c. original antigenic sin

d. opportunistic infection

b

Strep throat, an infection caused by *Streptococcus pyogenes*, is associated with an **autoimmune disease** known as what?

a. bacterial endocarditis

b. rheumatic fever

c. systemic lupus erythematosus (SLE)

d. rheumatoid arthritis

e. hemolytic anemia

b

What is the term for tissue that resembles secondary lymphoid organs but forms by lymphoid neogenesis?

a. tertiary lymphoid tissue

b. islets of endocrine tissue

c. erythema nodosum

d. secondary endocrine tissue

a

The genetic disease called **immune dysregulation, polyendocrinopathy, enteropathy, X-linked disease** (**IPEX**) manifests because of a functional impairment of what subset of T cells?

a. TH2

b. TH17

c. Treg

d. TH1

c

Which of the following explains why **celiac disease** is often referred to as an **autoimmune disease**?

a. There are many characteristics in common in the immune mechanisms causing autoimmune disorders and celiac disease.

b. The immune response is made in response to something introduced into the gastrointestinal tract of the body.

c. The immune response is characterized by an absence of inflammation.

d. The immune response is specific for a self antigen.

a

Diagnosis of **celiac disease** involves the detection of what?

a. gluten-specific T cells in the peripheral blood

b. anti-transglutaminase antibodies

c. HLA-DQ6 and HLA-DQ9 allotypes

d. rotavirus

b

What is **celiac disease** triggered by?

a. food containing gluten

b. commensal microorganisms

c. opportunistic microorganisms

d. smoking-induced citrullinated gut proteins

a

What is the term for a ligand that mimics the natural ligand of a particular receptor and activates that receptor when bound?

a. competitive inhibitor

b. receptor agonist

c. activating receptor

d. receptor antagonist

b

Auto Immunity

• Immune response of auto Ab against self Ag

• Humoral or cell mediated immune response against the components of the own cells/tissues.

Autoantibody

Altered cell (Auto Ag) - elicits the productions of Antibody

Auto or self antigens

• Antigens present in one's own cells

• Altered by the action of bacteria, viruses, chemicals or drugs

Autoimmune diseases

is a group of disorders in which tissue injury is caused by humoral (by auto-antibodies) or cell mediated immune response (by auto-reactive T cells) to self-antigens

What type of immune response is involved in autoimmunity?

Adaptive

Autoimmune response

• Highly-specific pathogen-mediated process

• B-cells (humoral immunity) & T-cells (cellular immunity)

• Distinguish between self- & non-self

• Develop immune repertoire “immunological memory”

What type of hypersensitivity reaction does not resemble every autoimmune disease?

a. Type I

b. Type II

c. Type III

d. Type IV

e. All

a

Which of these is not a cause of autoimmune diseases?

a. sequestered or hidden antigens

b. neo antigens

c. molecular mimicry

d. loss of immunoregulation

e. exposed antigens

e

Prevalence of autoimmune diseases

Thyroid - >3% adult women

RA - 1% general pop

Primary sjogren - 0.6-3% adult women

SLE - 0.12% general pop

MS - 0.1% general pop

T1D - 0.1% children

Primary biliary cirrhosis - 0.05-0.1% middle and elderly women

MG - 0.01% general population

What is the autoantibody target of T1D?

Pancreatic Beta cells

What is the autoantibody target of Grave’s disease and Hashimoto’s thyroiditis?

Thyroid proteins and cell antigens

What is the autoantibody target of vitiligo?

Tyrosinase

What is the autoantibody target of Pemphigus vulgaris?

Desmoglein

What is the autoantibody target of MG?

ACh receptor

What is the autoantibody target of Lambert-Eaton syndrome?

Voltage-gated calcium ion channels

What is the autoantibody target of haemolytic anaemia?

IgG/IgM binding to RBCs

What is the autoantibody target of thrombocytopenic purpura?

Platelet glycoproteins

Why are endocrine glands a common target for organ specific autoimmunity?

Express tissue-specific proteins

Good blood suppy

How does the selective destruction of insulin-producing β-cells in the pancreas in T1D occur?

• Autoantibodies target insulin, glutamic acid decarboxylase and specific β-cell proteins.

• CD8+ T cells mediate cell destruction

What is Grave’s disease?

Hyperthyroidism due to over production of thyroid hormone

Consequence of over production of thyroid hormone in GD

* Enlargement of thyroid
* Heat intolerance and anxiety
* Exophthalmos

What triggers GD?

* Bacterial/viral trigger
* Produces Abs to Thyroid Stimulating Hormone Receptor (TSHr)

What is not increased in hyperthyroidism?

a. T3 (triiodothyronine)

b. T4 (thyroxine)

c. TRH

d. TSH

c, d

What is stimulated in hyperthyroidism?

Persistent TSHr

What is not a treatment of hyperthyroidism?

a. thyroidectomy

b. anti-thyroid drugs (carbimazole)

c. Radioiodine-121

d. Radioiodine-131

c

What is not increased in hypothyroidism?

a. TSH

b. T3 (triiodothyronine)

c. T4 (thyroxine)

B, C

What is a treatment of hypothyroidism?

a. thyroidectomy

b. Replacement therapy (Lthyroxine/ Liothyronine)

c. anti-thyroid drugs (carbimazole)

d. Natural desiccated thyroid (NDT)

e. Radioiodine-131

b, d

What is Hashimotos disease?

Reduced thyroid function due to production of antibodies to thyroid oxidase – Cytotoxicity

Consequence of Hashimoto’s

Thyroid gland enlargement (goitre)

Reduced metabolic rate

What causes MG?

Antibodies to the AChR & MuSK (Muscle-Specific Kinase)

Typical symtoms of MG

. Skeletal muscle weakness – worsens with activity

. Symptoms subside after periods of rest

. Facial muscles affected (Speech/vision)

What causes Lambert-Eaton syndrome?

Antibodies to the voltage-gated Ca2+ channels

Consequence of Lambert-Eaton syndrome?

Decreases Ca2+ influx into nerve terminal = proximal and distal muscle weakness and ataxia

In LEMS what antibodies block calcium influx, leading to reduced ACh vesicle release from the presynaptic membrane; therefore, reduced ACh is available to bind to postsynaptic ACh receptors?

Voltage gated calcium channel antibodies

Treatment of LEMS blocks the efflux of potassium ions, prolonging the duration of depolarisation. Longer depolarisation keeps the pathologically affected calcium channels open longer, increasing calcium ion influx and intracellular calcium concentration and thereby improving the ability of the ACh vesicles to fuse and release neurotransmitter.

Treatment with 3,4-diaminopyridine

What is haemolytic anaemia?

Organ specific autoimmune disorder in which IgG and IgM autoantibodies bind to RBCs and activate complement

What happens to RBCs in haemolytic anaemia?

become spherocytic and are phagocytosed by macrophages

Erythrocyte destruction

Symptom of haemolytic anaemia?

Fatigue

What causes Thrombocytopenic purpura?

Antibodies (IgG) to platelet surface glycoproteins leading to low platelets

Symptoms of Thrombocytopenic purpura?

Abnormal bleeding

Bleeding, bruising, rash (pupuric)

Haematomas – mucous membranes

Pemphigus symptoms

Blistering of skin

Which autoimmune condition is not a type II response?

a. haemolytic anaemia

b. graves

c. MG

d. Rheumatoid arthritis

e. Pemphigus

d

Which is a type III RESPONSE?

a. haemolytic anaemia

b. SLE

c. MG

d. Rheumatoid arthritis

e. Pemphigus

b

Which of these is not a type IV response?

a. T1D

b. RA

c. Grave’s

d. MS

c

Autoimmune diseases corresponding to type II

caused by antibodies that bind to either components of the cell surface or the extracellular matrix

Autoimmune diseases corresponding to type III

caused by soluble antigen:antibody complexes that deposit in blood vessel walls.

Autoimmune diseases corresponding to type IV

caused by effector T cells