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Autoimmune diseases in general - Diagnostics / Clinical / Therapy; A specific autoimmune disease: Coeliac Disease; Hypersensitivity in general - Types / Mechanisms

44 important questions on Autoimmune diseases in general - Diagnostics / Clinical / Therapy; A specific autoimmune disease: Coeliac Disease; Hypersensitivity in general - Types / Mechanisms

Give an example of an autoimmune disease study

1) Mice injected with myelin basic protein and complete Freand's adjuvant develop EAR and are paralyzed

2) the disease is mediated by Th1 cells specific for myelin basic protein

3) disease van be transmitted by transfer of Tcells from affected animal

How do AID (autoimmune diseases) work?

Under control of the AIRE protein, thymic medullary cells express tissue specific proteins, deleting tissue-reactive Tcells. In the absence of AIRE, Tcells reactive to tissue-specific antigens mature and leave the thymus.

A trigger makes the Tcell respond by producting cytokines with cytotoxicity. This leads to inflammation and tissue damage, which can be a co-activator.

Meanwhile, the Tcell activates Bcells to produce antibodies, also leading to inflammation and tissue damage

What does AIRE stands for, and what does it do?

Autoimmune regulator induces promiscuous expression of tissue-specific genes in the medullary thymic epithelial cells (mTECs)

How do you break self tolerance?

1) release autoantigens (heart, testis, eye) apoptosis-defects (SLE)

2) 'errors' in the thymus

3) local activation immuneresponse / reduced Treg

4) T helper bypass

What does an AIRE mutation result in?

Autoimmune Poly Endocrinopathy Candidiasis Ectodermal Dystrophy

What are the new auto-antibodies in APECED, and what do they do?

anti-cytokines -> Neutralizing anti-IL17 inhibits Candida clearance. IL-17 is essential in elimination of candida infections

What can Treg mutations (Foxp3, CTLA-4) result in?

Immunodysregulation

Polyendocrinopathy

Enteropathy

X-linked

Experimental Foxp3 deletion:

Name 2 types of T helper bypass

cross reactivity (mimicry):

-micro-organisms-tissue (streptococ-myocard)

-micro-organisms-HLA (klebsiella- HLA B27

modified 'self

- drugs: eg. methyldopa

-viral infections

-gliadin complexes with tissue transglutaminase

How would you diagnose Graves' diseases?

Symptoms: Hyperthyroidism; Ophthalmopathy

Lab: TSH low, T4 high

Immune diagnostics: anti-TSH-R antistoffen

Therapy; - radio active Jodium (131I) or surgery - hormonal therapy to restore thyroid hormone levels

How would you diagnose Hashimoto disease/.

Symptoms: Hypothyroidism; Thyroiditis; Goiter (struma)

Immune diagnostics: High titres anti-TPO; Biopsy: lymphocytic infiltrate

Therapy: - hormone suppletion (levothyroxin, synthetic T4)

What is the Prevalence of thyroid autoimmune disease: Prevalence hypothyreoïdism and Prevalence hyperthyreoïdism?

Prevalence hypothyreoïdism : 5,8 per 1000 individuals

Prevalence hyperthyreoïdism : 1,9 per 1000 individuals

Prevalence hypothyreoïdismin

young men (25-44-yr): 0,8 per 1000

old men (>75 yr): 7,9 per 1000

young women (25-40 jr): 7,0 per 1000

old women (>75 jr): 22,5 per 1000

Which receptor autoantibodies causing blockage or
stimulation in Pernicious anemia, Myasthenia gravis and Graves’ disease?

Pernicious anemia (vit B12 deficiency): Vit B12 binding site on intrinsic factor

Myasthenia gravis (muscle weakness): Acetylcholine receptor

Graves’ disease (hyperthyroidism): TSH-receptor

Name 5 genetic factors for immune dysregulation:

- HLA-type

- AIRE mutations

- Antigen clearance

- Signaling

- Costimulation

- Cytokines

Name 3 Environmental factors for immune dysregulation±

Infection

Drugs

Damage

How would you diagnose Type 1 diabetes?

Diagnosis: Type 1 Diabetes

Destruction of insulin producing β cells in the pancreas by cytotoxic T cells

Insulin ↓ Hyperglycaemia

Therapy: Insulin injections

Immune diagnostics: Early in disease: Island Cell Antibodies (ICA). ICA Disappear soon after diagnosis.

auto-antigens: - Insulin - Glutamic acid decarboxylase (GAD65) - ICA512 - IA-2β / phogrin

What are the steps for Indirect immune fluorescence test on pancreas?

1. Cryo-sections from human pancreas

2. patient serum

3. rinsing

4. anti-human Ig-FITC

5. rinsing

6. evaluation by fluorescence microscope

Name 3 pathogenic effects of antibodies (SLE)

1. DNA-antibodies precede disease activity

2. Transplacental transfer of antibodies (SS-A or SS-B) may cause neonatal lupus / cardiac heart block

3. Therapeutic effects of plasmapheresis and immunosuppression

What is the clinical test for coeliac disease? What can you see on this?

Duodenum biopsy:

- increased IEL (Intra Epitheliale Lymfocyten) numbers

- villous atrophy

- crypt hyperplasia

- infiltrated mucosa (lamina propria)

What intolerance have coeliac disease patients?

intolerance for gluten, present in wheat, rye and barley

Gliadin = ethanol soluble protein fraction of wheat gluten causing CD

What are the genetic factors of coeliac disease?

5% -15% CD in 1ste degree relatives

70% -75% concordance of CD in monozygotic twins

98% of coeliac patients is carrier of HLA-DQ2 or DQ8

40% of general population is carrier of DQ2 or DQ8

1% of DQ2/8 carriers develop coeliac disease

HLA-DQ2: DQA1*05 en DQB1*02

HLA-DQ8: DQA1*03 en DQB1*0302

Why are gluten peptides “a two-edged sword”?

1. ‘Toxic’ stimulus:

Activation of mucosal epithelium and innate immune system

-> IL-15, increased gut permeability, IEL activation

-> DC activation, increased IFN-α production

2. Immunogenic stimulus:

Activation of adaptive immune system

-> gliadin specific T cells and B cell activation

Gluten specific T cell activation depends on the enzyme tissue transglutaminase (TG2) - T cells from duodenal biopsies only react to gliadin if gliadin is pretreated with TG2

What is/does Tissue transglutaminase (tTG of TG2)?

- enzyme in lamina propria

- involved in woundhealing

- cross-links extracellular matrix proteïns

- uses gluten (40% glutamin) als substrate,

forms complexes and generates new immunogenic epitopes

What is the coeliac disease pathogenesis of Tcell activation?

TG2 in lamina propria binds to APC. This presents it to a Tcell via the HLA-DQ2 TCR. The Tcell produces IFN-gamma and IL-21.

This leads to Slijmvlies afwijkingen: Epitheliale apoptose, Vlokatrofie, Crypt hyperplasie, IEL lymfocytose, transglutaminase release. And to the functional defects: Malabsorptie, Permeabiliteit ↑

What is the coeliac disease pathogenesis of Bcell activation?

TG2 in lamina propria binds to Tcell that activates Bcell. The Bcell produces TGA, DGPA, AGA and antibodies.

What are the 3 key molecules in the pathogenesis of coeliac disease?

• HLA-DQ2 and DQ8

- present the deamidated gluten peptides to CD4+ T cells.

- ca 90% of celics is DQ2 and 6% DQ8

• Gluten derived petides

- proline rich (36%) > resistant to enzymatic degradation

- glutamine rich (15%) > substrate for transglutaminases

- provide T cell epitopes

- gliadinpeptides trigger innate immune response (IL-15)

• Tissue Transglutaminase (TG2)

- deamidates gluten peptides > negatively charged peptides, fitting

in HLA-DQ2 and DQ8 molecules

What do Gliadine specific T cells do?

stimulate B cells

against both gliadin and TG2 (-> auto-antibodies)

How and which antibodies are being used as diagnostic parameters in CD

• IgA most specific (IgG only relevant in IgA deficiency)

• present in mucosa, faeces, blood and saliva

• directed to

- Gliadin AGA

- Endomysium EMA

- tissue Transglutaminase tTGA

Antibodies to endomysium or TG2 in serum from coeliac patients are stained on esophagus cryosections

How do you get allergic (skin)?

1st contact infection / vaccination (sensitization) -> Tcell activation.

2nd contact skin test (challenge) -> Tcell (re)activation = inflammatory cytokines

What kind of diagnostic is used in a type IV reaction?

patch testing

What can evoke a delayed reaction upon skin contact? (type IV)

Metals and small chemicals can evoke delayed reactions upon skin contact,

but also proteins, like tuberculin (Mantoux test) or even tumor antigens can do so in sensitized patients.

delayed type (DTH)

IgE mediated Ig mediated T cell mediated

Ø erythema

Ø induration

What is Active Specific Immunotherapy (ASI)?

Used in colon carcinoma patients. After surgery the patients'Tumor recieves enzymatic dissociation cryopreservation radiation (200 Gy). Then after 4,5,6 and 26 weeks, BCG (danger signal) and 10^7 autologous tumor cells are injected.

How is a type I allergy mediated, recognizable and diagnosed?

IgE mediated, recognizable bt the "wheal and flare": white centre with red circulair spot. diagnosed with skin prick test.

Which phases has a type I reaction? At which times?

Immediate phase after about 30 minutes and late phase after 8-10 hours.

Name 8 clinical manifestations of type I hypersensitivity

conjunctivitis

rhinitis

urticaria

bronchitis

gastroenteritis

asthma

atopic eczema

systemic anaphylaxis

What are the characteristics of a type I reaction?

Immediate type, IgE mediated, after 15 - 30 min, Ø wheal

What are the characteristics of a type III reaction?

Arthus, Ig mediated, 4-8 hrs, diffuse reaction

What are the characteristics of a type IV reaction?

Delayed type DTH, Tcell mediated, 24-48 hrs, Ø erythema, Ø induration

How can you measure the Kinetics of type III reaction=

Kinetics of type III reaction 1. inhalation (provocation test) 2. Injection in skin

All types of hypersensitivity reactions result from adaptive
immune responses, with the following pattern:

1. Sensitization -> specific T cells / antibodies

2. Challenge/provocation -> local reaction

3. Chronic phase -> disease

What cells are involved in a type III reaction?

Soluble Ag-Ig complexes

Complement activation, granulocytes

Give an example of a type II cell- or matrix associated antigen reaction

some drug allergies (penicillin)

Give an example of a type II cell-surface antigen reaction

chronic urticaria (antibody against FC(e)R1alpha

Give an example of a type IV Th2 cell mediated reaction

Chronic asthma, chronic allergic rhinitis

Which type of reactions are the following diseases:
thyroid (M Hashimoto):thyroid (M Graves’): Myasthenia gravis: Diabetes type I: Celic disease:
lupus erythematosus: reumatoid arthritis:

thyroid (M Hashimoto): IV
thyroid (M Graves’): II
Myasthenia gravis: II
Diabetes type I: IV
Celic disease: IV

lupus erythematosus: III
reumatoid arthritis: IV

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