Week 12 - Autoimmunity and Tolerance Flashcards by Guy Ben Arie

Natural Autoimmunity (Good autoimmunity)

B1 cells (CD5+) produce polyreactive, low affinity binder IgM natural autoantibodies that recognize conserved molecules.

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Heat Shock Proteins, Enzymes (CyteC), Membrane Proteins (Beta2m), Cytoplasmic Proteins (Actin), DNA, IL1, Albumin, IgG.

These are all examples for shared ______ of Human and Microbes that are possibly recognized by _______ ________.

These are all examples for shared Antigens of Human and Microbes that are possibly recognized by Natural Autoimmunity.

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Natural Autoimmunity is apart of the process of the development of ______ since over time the reaction gets less and less _______ with the exposure.

Natural Autoimmunity is apart of the process of the development of Tolerance since over time the reaction gets less and less powerful with the exposure.

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Pathological autoimmunity develops if the

immune _______ is broken or insufficient.

Pathological autoimmunity develops if the

immune tolerance is broken or insufficient.

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Immune tolerance which is unresponsiveness to a given antigen could be either :

Peripheral or Central

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T cells that recognize self peptide MHC
complexes with high avidity, undergo
clonal deletion (apoptosis) in a process called _______ ______ this is part of the ______ _________

T cells that recognize self peptide MHC
complexes with high avidity, undergo
clonal deletion (apoptosis) in a process called Negative Selection this is part of the Central Tolerance.

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In Negative Selection, T cells with weak or intermediate TCR avidity get to the ________ .

In Negative Selection, T cells with weak or intermediate TCR avidity get to the periphery.

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Peripheral tolerance mechanisms:

Anergy

Inability to respond to stimuli in the absence of costimulation

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Peripheral tolerance mechanisms:

Ignorance

low avidity TCR binding

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Peripheral tolerance mechanisms:

Antigen Segregation - Immunoprivileged sites

Brain, Testis, Thyroid, Pregnant Uterus (In general no Lymphatic drainage)
For example BBB is the segregating entity of the Brain

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Peripheral tolerance mechanisms:

Antigen Segregation - Molecules Involved in its sites

Immunosuppressive cytokines e.g. TGF-Beta , IL 10

- FasL expressed by Cells allow for Avoidance from T cell

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Release of hidden (cryptic) antigens from immune privileged sites - Give an example and What could be the consequence.

Injury of the eye causes the release of its protein antigens to the Blood and eventually lymphatic system.
Possible attack on Eye tissues by T cells can happen.

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Peripheral tolerance mechanisms:

Cytokine Devations, by Helminths Response, Allergy or cell mediated Immune response could (3 Examples) -

Damage immune tolerance and lead to:

Rheumatoid Arthritis, Crohn’s or Multiple Sclerosis

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Peripheral tolerance mechanisms:

Regulatory T cells - CTLA4

Aka CD152 , is a protein receptor that acts as an “off” switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.

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Peripheral tolerance mechanisms:

Regulatory T cells - PD-1

Programed Cell Death Protein-1 (CD279) - Promotes apoptosis in antigen-specific T-cells in lymph nodes and reduces apoptosis in regulatory T cells.

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Peripheral tolerance mechanisms:

Regulatory T cells and TH3 cells- FOX3P

Master regulator transcription factor upregulating regulatory T-cell function, and may inhibit transcription of key genes following stimulation of T cell receptors.

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Peripheral tolerance mechanisms:

Regulatory T cells - Cytokines Released

IL-10 and TGF-beta (immunosuppressive)

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Peripheral tolerance mechanisms:

TH3 cells - Cytokines Released

IL-10 and TGF-beta (immunosuppressive)

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Peripheral tolerance mechanisms:

Tr1 cells - Cytokines Released

IL 10 (immunosuppressive)

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Peripheral tolerance mechanisms:

Clonal exhaustion

Activation induced T cell death (AICD),

apoptosis is mediated by Fas FasL interaction.

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Autoimmune diseases - 6 General Principles for all of them

MB5UFC

Multifactorial: Polygenic +Environmental factors
B cell , T cell , immune complex mediated
5% of the adult population
Usually in adulthood
Frequent in women
Characterized by Exacerbations and Remissions

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Genes determining autoimmune disease susceptibility

MHC, AIRE, FAS, PD, CTLA4, Inhibitory Fc receptors

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Cross reactivity (molecular mimicri)

Viral and bacterial peptides might mimic self peptides causing Autoimmunity

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Bacterial Example for Molecular Mimicry

Streptococcal antigens → similar to endocardial antigens → inflammation , valve deformity → Rheumatic fever.

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Viral Examples for Molecular Mimicry: | Poliovirus - Protein in virus and What is mimicked

Poliovirus | VP2 - ACh receptor

Viral Examples for Molecular Mimicry: | HIV - Protein in virus and What is mimicked

HIV | p24 - IgG Constant Region

Viral Examples for Molecular Mimicry: | Measles - Protein in virus and What is mimicked

Measles | p3 - Myelin Basic Protein

__________ (e.g. bacterial toxins) bind the MHC II molecules and the T cell receptors from the outside, thus, a high number of T cell clones can be activated in a ___ _______ way.

Superantigens (e.g. bacterial toxins) bind the MHC II molecules and the T cell receptors from the outside, thus, a high number of T cell clones can be activated in a non specific way.

Autoimmune Diseases Associated with Brain: (3 examples)

Multiple Sclerosis Guillain Barre Syndrome Autism

Autoimmune Diseases Associated with Thyroid: (3 examples)

Thyroiditis Hashimoto's Disease Graves's Disease

Autoimmune Diseases Associated with GI: (3 examples)

Celiac's, Crohn's, UC, T1DM

Autoimmune Diseases Associated with Blood: (3 examples)

Leukemia, SLE, Hemolytic Dysglycemia

Autoimmune Diseases Associated with Lungs: (3 examples)

Fibromyalgia | Wegener's Granulomatosis

Autoimmune Diseases Associated with Bone: (3 examples)

Spondylarthritis ankylopoetica RA Polymyalgia Rheumatica

B1 cells (CD_+) produce polyreactive, low affinity binder IgM natural ____________ that recognize conserved molecules.

B1 cells (CD5+) produce polyreactive, low affinity binder IgM natural autoantibodies that recognize conserved molecules.

The natural autoantibodies are arranged in a network of hierarchy for binding : from antigen up to the most conserved antibody. How is this network called?

idiotype/anti-idiotype network

What transcription factor allows the promiscuous gene expression of tissue antigens in the thymus?

Autoimmune Regulator (AIRE)

5 most important autoantibodies in autoimmune disorders: 1) ___ 2) ANCA 3) Anti-phospholipid antibodies 4) Rheuma factor 5) ACPA

5 most important autoantibodies in autoimmune disorders: 1) ANA 2) ANCA 3) Anti-phospholipid antibodies 4) Rheuma factor 5) ACPA

5 most important autoantibodies in autoimmune disorders: 1) ANA 2) ____ 3) APS: Antiphospholipid antibodies 4) Rheuma factor 5) ACPA

5 most important autoantibodies in autoimmune disorders: 1) ANA 2) ANCA 3) APS: Antiphospholipid antibodies 4) Rheuma factor 5) ACPA

5 most important autoantibodies in autoimmune disorders: 1) ANA 2) ANCA 3) ___ 4) Rheuma factor 5) ACPA

5 most important autoantibodies in autoimmune disorders: 1) ANA 2) ANCA 3) APS: Antiphospholipid antibodies 4) Rheuma factor 5) ACPA

5 most important autoantibodies in autoimmune disorders: 1) ANA 2) ANCA 3) APS: Antiphospholipid antibodies 4) _________ ______ 5) ACPA

5 most important autoantibodies in autoimmune disorders: 1) ANA 2) ANCA 3) APS: Antiphospholipid antibodies 4) Rheuma factor 5) ACPA

5 most important autoantibodies in autoimmune disorders: 1) ANA 2) ANCA 3) APS: Antiphospholipid antibodies 4) Rheuma factor 5) ____

5 most important autoantibodies in autoimmune disorders: 1) ANA 2) ANCA 3) APS: Antiphospholipid antibodies 4) Rheuma factor 5) ACPA

``` Methods for the determination of autoantibodies: __ ELISA CIE=counterimmunoelectrophoresis Multiplex assays ```

``` Methods for the determination of autoantibodies: IF ELISA CIE=counterimmunoelectrophoresis Multiplex assays ```

``` Methods for the determination of autoantibodies: IF _____ CIE=counterimmunoelectrophoresis Multiplex assays ```

``` Methods for the determination of autoantibodies: IF ELISA CIE=counterimmunoelectrophoresis Multiplex assays ```

``` Methods for the determination of autoantibodies: IF ELISA ___ Multiplex assays ```

``` Methods for the determination of autoantibodies: IF ELISA CIE=counterimmunoelectrophoresis Multiplex assays ```

``` Methods for the determination of autoantibodies: IF ELISA CIE=counterimmunoelectrophoresis _______ _____ ```

``` Methods for the determination of autoantibodies: IF ELISA CIE=counterimmunoelectrophoresis Multiplex assays ```

ANA

Anti-Nuclear Autoantibodies: autoantibodies that bind to contents of the cell nucleus. antigen: double stranded DNA, histone, topoisomerase, RNP, Centromere (Cenp‐B)

Anti-CCP/ACPA

Anti-cyclic Citrullinated Protein Antibody

APS

Antiphospholipid syndrome antibody panel - | antigens: cell membrane proteins and proteins involved in blood coagulation

Rheuma factor: Antibody against the Fc fragment of IgG

ANCA

Anti-neutrophil cytoplasmic antibodies P-ANCA: Perinuclear (Strong Cations) C-ANCA: Cytoplasmic (Weak Cations)

``` The most important Targets of APS Autoantibodies: Cardiolipin Phosphatidylserine ________________ Prothrombin Lupus anticoagulant (LA) ```

``` The most important Targets of APS Autoantibodies: Cardiolipin Phosphatidylserine β-2-glycoprotein I Prothrombin Lupus anticoagulant (LA) ```

``` The most important Targets of APS Autoantibodies: Cardiolipin Phosphatidylserine β-2-glycoprotein I ________ Lupus anticoagulant (LA) ```

``` The most important Targets of APS Autoantibodies: Cardiolipin Phosphatidylserine β-2-glycoprotein I Prothrombin Lupus anticoagulant (LA) ```

``` The most important Targets of APS Autoantibodies: Cardiolipin Phosphatidylserine β-2-glycoprotein I Prothrombin __________ ```

``` The most important Targets of APS Autoantibodies: Cardiolipin Phosphatidylserine β-2-glycoprotein I Prothrombin Lupus anticoagulant (LA) ```

``` The most important Targets of APS Autoantibodies: Cardiolipin ____________ β-2-glycoprotein I Prothrombin Lupus anticoagulant (LA) ```

``` The most important Targets of APS Autoantibodies: Cardiolipin Phosphatidylserine β-2-glycoprotein I Prothrombin Lupus anticoagulant (LA) ```

``` The most important Targets of APS Autoantibodies: ________ Phosphatidylserine β-2-glycoprotein I Prothrombin Lupus anticoagulant (LA) ```

``` The most important Targets of APS Autoantibodies: Cardiolipin Phosphatidylserine β-2-glycoprotein I Prothrombin Lupus anticoagulant (LA) ```

What is the testing methods for APS?

ELISA or Functional Testing

RA: about 80% sensitivity of patients show sensitivity to:

RA-specific antibody, which is more specific than RF. Often positive in the early (non-specific) stage of RA. Part of the new RA classification criterion. Positivity is a poor prognostic factor.

Anti-cyclic citrullinated protein (anti-CCP)

Antimitochondrial antibodies (AMA) - What diseases?

Primary biliary cirrhosis (PBC), but rarely it may also be positive in other autoimmune hepatitis

Anti-smooth muscle (F-actin) antibody (SMA) - What diseases?

positive in autoimmune hepatitis, but it can also be positive in many other liver diseases

Anti-microsomal antibody (LKM-1) - What diseases?

antibody against cytochrome P450 2D6 protein – characteristic to type 2. autoimmune hepatitis

Liver specific proteins (LSP) - What diseases?

characteristic to type 2. autoimmune hepatitis

Symptomes are„butterfly” erythema, Pleuritis, Nephritis, Joint pain, Cardial complaints, Neurological symptoms with ANA+ What could be the diagnosis?

SLE

Muscle weakness, diplopia, swallowing difficulty (dysphagia) with Anti-AChR+. What could be the diagnosis?

Myasthenia Gravis

Dryness of the eyes and mouth with Anti-SSA+ and Anti-SSB+ What could be the diagnosis?

Sjögren’s syndrome

Rigid, swollen, painful joints especially in the morning with ANA+, RF+ positivity, Anti-CCP+ What could be the diagnosis?

Rheumatoid arthritis

What is the role of Anti-dsDNA in SLE?

Predictive Marker

What is the role of Anti-Sm/RNP/Rho/La in SLE?

Diagnosis

What are the changes that occur in C3,C4 and CH50 while therapy for SLE is taking place?

Exacerbation at first, ease and finally ascending

Citrullination: Enzyme

Peptidyl-arginine deiminase (PAD) enzymes (post transcriptionally)

Peptides may undergo Citrullination:

fibrin, vimentine, enolase

90% of the Caucasian patients are HLA B27 positive in which autoimmune disease?

Bechterew’s disease (ankylosing spondylitis)