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Autoimmune disease and allergy

33 important questions on Autoimmune disease and allergy

Summarize the mechanisms of inflammation briefly

Bacteria enters barrier; innatecells express vasoactive and chemotatic factors (IL2, TNFalfa); endothelial activation; neutophil migration (roling L selectine on neu, adhesion via e-selectin on endothelial with integrin on neu),

Inflammation can be induced by allergens.

How can a allergic reaction be recognized in the airways? (experiment saline/control and ragweed/allergen)

When allergen is added, specific cells are attrackted to the tissue.
Eosinophils. in this case.

What are the four types of hypersensitivity reactions?

I: typical allergy; mediated by IgE; IgE bounded to antigen binds mast cells; granules with histamine and cytokines.
II: Antibody mediated hypersensitivity; mediated by IgG and IgM; surface antigens are recognizes by complement and ctls.
III: Immune complex mediated hypersensitivity; antigen bound in immune complexes attrackt neutrophiles.
IV: Delayed hypersensitivity; mediated by tcells; no antibodies involved.

What can induce a hypersensitive reaction?

Infectious agents (TB-mantoux).
Environmental antivens (grass pollen)
Auto-antigens

Explain the linkage between diseases ms, crohn, asthma and diabetes

Auto-immune and inflammation diseases have genetic overlap; same genetic background; genes in the clustersare involved in the primary or secondary immune regulation (treg, th17).

Shared genes among distinct diseases may lead to common early diagnosis criteria and therapeutic strategies (anti TNFalfa).

Explain the difference between allergy and atopy.
How can atopy lead to allergy?

Atopy: The genetic tendency to develop the classic allergic diseases. Atopy involves the capacity to produce IgE in response to common environmental proteins such as house dustmite, grass pollen, and food allergens (allergen + genetic factors are present)

Allergy = Atopy + Tissue factors.

For disease, certain changes in the target organ are needed.
Also; triggers (for changes in target organs?)

What are the similarities and differences between psoriasis and atopic dermatitis?

There is genetic linkage; same genes are associated; genes predict skinn inflammation.
The immunereaction is different.

What levels of dearrangment can can cause allergys/immunemediated disease?

Immune regulatory genes
Atopy genes
Tissue factors

What factors determine atopic dermatitis versus allergic asthma?

Immune regulatory genes are the same (7p, 11p), atopy genes are the same (5q31-33, 12q), tissue factors are different (3q21, 1q21 for AD and ADAM33 and 20p13 for asthma)

Which factors determine allergic dermatitis versus psoriasis?

Immune regulatory genes are the same (7p, 11p), atopy genes are the different (5q31-33, 12q in AD and psoriasis gen 19p13 in psoriasis), tissue specific genes are the same (3p21, 1q21)

Psoriasis never had atopy (?). Specific psoriasis gene cause hyper activation of endothelia.

Two groups of genes are differentially regulated in atopic dermatitis compared to the healthy control group. Which groups of genes?

Genes for migration (to the skin) are upregulated.
Genes for proliferation, apoptosisn and polarization are downregulated..

This causes more cd4 tcell migration to the skin .

What is the effect of downregulation of GADD45a mrna and TNFAIP mrna in CD4 tcells in atopic dermatitis?

GADD45a: Is normally a negative regulator of t cell activation.
TNFAIP3: Is a global negative regulator of inflammation.

When mrna is downregulated; more tcell activation and more inflammation!

Which specific gene expression profiles are important to determine multifactorial atopic disease?

The gene expression profiles in CD4 tcells determine the disease (only in AD or in all atopic diseases?)

How can we distinguish a inflammed skin from a healthy skin under the microscope?

Non-lesional (not inflammed): No tcells.
Lesional: Infiltration of tcells in the epidermis.

What happens when there are too much th1 cells? And too much th2? What can cause disbalance?

Too many th1 cells leads to autoimmunity.
Too many th2 cells leads to allergy

Tregs normally regulate this balance. Hygiene theory; too much hygiene; less triggers for Treg; less tregs; disrupted balance; switch and Th2 expansion.

What are the different Th subsets and what diseases do they cause when upregulated?
Which cells regulate the Tcell differentiation?

Dendritic cells produce cytokines that are important in CD4 differentiation. When pathogens are recognizes, the dc produces:

TGFbeta; Treg
IL6; Th17 (TGFbeta also stimulates Th17)
ICOS-ligand; Th2 (IL4 also stimulates Th2)
IL12; Th1 (IFNgamma also stimulates Th1)

In the picture, the names shown above the cells represent the intracellular enzymes that react on the cytokines and induce differentiation intracellular.

What is the difference between acute allergic disease and inflammational allergic disease (?)

Inflammational allergic disease go on, even when you remove the allergen.

Which cells and other components are involved in a hypersensitivity reaction? What is the exact mechanism? (type I allergy)

Mastcells in skin/gut/lungs (basophils in blood)
Bcell (IgE)
APC
Tcell
Allergen
Cytokines (IL4,5,13 Tcells, histamine mastcells, LTL4, RAF, TNFalfa...)

Picture notes: Tcell not only produces IL4, but also IL13 and IL5.
IL13 activates skinn cells (tissue).
IL5 induces eosinophil differentiation; those cells are important for chronic inflammation.

The IgE mastcell interaction stays upon 6 months!

Left; sensitazation phase, lot of people have this.

How is type I hypersensitivity treated (astma, hooikoorts, non inflammed!)?

Anti-histamines work for sniffy nose and scratchy eyes but not in case of astma and eczeem (all type I). Allergen reduction also doesnt really work.

What are the characteristics of atopic dermatitis (atopic eczema)?

Itch, chronic recurrent, age dependent localization, runs in families.

Histology: Spongiosis (holes in the skinn), infiltrated tcells, ancanthosis (diffuse epirdermal hyplasia=thickening of the skinn).

What is the difference between an intracutaneous test and atopy patch test (mechanism, outcomes etc).

In ICT, neutrophiles are atrackted and less mast cells are measured.

Damage because of injection causes the neutrophile influx, so this has nothing to do with the disease mechanism. ICT shows a drop in mast cells; this is because degranulation takes place and therefore the mast cells are not shown.

Acute vs. chronic allergic reactions:

Picture

What is the difference between auto-immunity and auto-immune disease?

Auto-immunity is the breakdown/failure of self-tolerance (very common).
Auto-immune disease is a disease as a result of tissue damage due to autoimmune reactions

What mechanisms of selftolerance do you know?

Central tolerance: elimination of autoreactive b and t cells.
Peripheral tolerance: no costimulation for autoreactive t and bcells; autoreactive t and b cells are stimulated towards apoptosis. + regulatory cells can inhibit lymphocytes.

What is central tolerance (tcells) and where does it occur? Which protein is essential in central tolerance?

Aim: T cell repertoire has to be both MHC-specific and self-tolerant.
Where: In the thymus (tcells)

Positive selection: 90% of the tcells are lost. Double positive tcells that bind self HLA are selected.
Negative selection: 50% of the tcells are lost. Tcells with strong binding to self HLA and specific self antigen are eliminated.

AIRE: Autoimmuneregulator: Gene responsible for expression of tissue autoantigens in the medular epithelial cells. (AIRE deficiency APS1 leads to auto-antibodies against certain tissue types).

What is central tolerance for bcells and where does it occur?

Self reactive bcells are going into apoptosis or receptor editing takes place and the cell is checked for autoreaction again.

Explain why central tolerance is not perfect

Sometimes the antigen is not presented on AIRE or the concentration is too low.
Antigen produced due to AIRE is not processed by the APC correctly.

Only antigens that are produced by AIRE are tested. When this doesnt occur correctly, autoreactive t and b cells will enter the periphery.

Explain two ways how the innate immune system is involved in autoimmunity due to activation autoreactive cells by inflammation

During infection, pro-inflammatory cytokines are released, leading to tissue damage en release of auto-ag. These auto-ags are phagocytosed by APCs and presented to autoreactive tcells. Since the APC is already activated by the infection causing inflammation, co-stimulatory molecules are expressed and cytokines. This is called bystander activation.
Molecular mimicry: the pathogen epitopes resemble auto-antigen; antibodies produced against pathogen after infection also recognize self-antigen,

Explain how the innate immune system is involved in autoimmunity by disrupted clearance of apoptotic debris

Normal process: Apoptotic cells are cleared in a anti-inflammatory way. Receptors on the macrophage interac with ligands on apoptotic cells. After uptake of the apoptotic cell, the macrophage releases anti inflam cytokines such as TGFbeta.

Disease: Too many apoptotic cells induce disrupted macrophagereceptor-ligand interactions. Now, immature dc's take up the apoptotic cell instead of the macropgafes.
Anti-inflammatory cytokines are not released. In presence of pro-inflammatory cytokines, the dc matures into an auto ag presenting cell, able to activate auto-ag specific tcells.

Explain how the innate immune system is involved in autoimmunity by activation netosis

This is also the case in SLE:

Specific autoantibodies bond to neutophiles, inducing netosis. (SLE=higher rates of NET).The pDC can uptae the self DNA and induce upregulation of IFNalfa.; leading to auto-immunity?

Name some characteristics and examples of type II autoimmune disease

Antibodies against cell-surface or matric antigens; immune complexes of antibodies and complement bind to the antigen. Mainly IgM and IgG.
Example: Grave disease: Autoantigen thyroid stimulating hormone receptor is attacked, leading to hyperthyroidism; overproduction of thyroid hormone

Mind you; the circulating antibodies have stimulating activity on the receptor!!
Other examples are: acute rheumatic fever, pemphigus vulgaris (antibodies bind skin) and goodpasture syndrome. (anti GBM binds kidney).

Name some characteristics and examples of type III and IV autoimmune disease

Type III is characterized by reaction due to formed immune complexes. Type IV is characterized by tcell mediated reaction. An example is SLE. Immune complexes in the circulation bind the endothelial cells. The recognized auto antigen is DNA/RNA.
Type IV is characterized by the tcell mediated reaction. An example is diabetis: cytotoxic tcells react on pancreatic beta cell antigen.

Explain the role of genetics in auto-immune disease

Monogenic disease in case of AIRE mutation, but more common multiple genetic factors.

For example SLE: mutations in different pathways such as immunecomplex processing, immune signal transduction and IFN pathways.

The question on the page originate from the summary of the following study material:

Klinische I&I

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