Immuno: Autoinflammatory and Autoimmune diseases Pt.2

Question 1

Which autoimmune conditions are often seen in IPEX?

Answer 1

“Diabetes, dermatitis, Diarrhoea”
* Enteropathy
* Diabetes mellitus
* Hypothyroidism
* Dermatitis (Eczema)

Question 2

What does ALPS stand for?

Answer 2

Autoimmune lymphoproliferative syndrome

Question 3

Which mutations cause ALPS?

Answer 3

Mutations in the FAS pathway leading to defects in apoptosis of lymphocytes

This leads to a failure of lymphocyte tolerance (as autoreactive lymphocytes don’t die by apoptosis) and failure of lymphocyte homeostasis (you keep producing lymphocytes)

Question 4

Describe the clinical phenotype of ALPS.

Answer 4

• High lymphocyte count
• Large spleen and lymph nodes
• Autoimmune disease (usually cytopaenias)
• Lymphoma - over time

Question 5

What is the best known chromosomal region that is implicated in Crohn’s disease?

Answer 5

IBD1 on chromosome 16

Question 6

Which gene in this region is associated with Crohn’s disease?
(Chromosome 16)

Answer 6

NOD2 (aka CARD15)

Abnormalities are associated with increased risk of Crohn’s, Blau syndrome and some forms of sarcoidosis

Question 7

Where is NOD2 found and what is its role?

Answer 7

Cytoplasm of myeloid cells

Acts as a microbial sensor

(recognises muramyl dipeptide)

Question 8

Outline the treatment approaches to Crohn’s disease

Answer 8

• Corticosteroids
• Azathioprine
• Anti-TNF-alpha antibodies
• Anti-IL 12/23 antibodies

Question 9

What is the strongest genetic association of ankylosing spondylitis?

Answer 9

HLA-B27

NOTE: othes include IL23R, ERAP1, ANTXR2 and ILR2

90% heritability

Question 10

Where does ankylosing spondylitis tend to manifest?

Answer 10

At sites with high shear forces (i.e. entheses, SI Joint)

Question 11

What are the treatment options for ankylosing spondylitis?

Answer 11

• NSAIDs
• Immunosuppression (anti-TNF-alpha and anti-IL17)

Question 12

List the autoimmune diseases associated with the following HLA polymorphisms:

1. DR3
2. DR3/4
3. DR4
4. DR15

Answer 12

1. DR3
   
   • Graves’ disease
   • SLE
2. DR3/4
   
   • Type 1 diabetes mellitus
3. DR4
   
   • Rheumatoid arthritis
4. DR15
   
   • Goodpasture’s syndrome

Question 13

Name and state the function of 2 genes that are involved in T cell activation and are often mutated in polygenic autoimmune disease.

Answer 13

• PTPN22 - suppresses T cell activation
• CTLA4 - regulates T cell function (expressed by T cells)

Question 14

What are three forms of peripheral tolerance?

Answer 14

• T cell require costimulation to become activated (costimulatory molecules are upregulated in infection and inflammation)
• Regulatory T cells
• Immune privileged sites

Question 15

Outline the Gel and Coombs effector mechanisms of immunopathology.

Answer 15

Type I: Anaphylactic hypersensitivity - immediate hypersensitivity which is IgE-mediated

Type II: Cytotoxic hypersensitivity - antibody reacts with cellular antigen

Type III: Immune complex hypersensitivity - antibody reacts with soluble antigen to form an immune complex

Type IV: Delayed-type hypersensitivity - T cell mediated response

NOTE: autoimmunity is most common with type II hypersensitivity

Question 16

Effect of Type II Hypersensitivity

Answer 16

• Activate complement
• Activate NK cells
• Opsonin for phagocytosis

Question 17

List some inflammatory mediates involved in type I responses that are:

1. Pre-formed
2. Synthesised

Answer 17

1. Pre-formed: Histamine, Serotonin, Proteases
2. Synthesised: Leukotrienes, prostaglandins, bradykinin, cytokines

Question 18

Outline the pathophysiology of IgE-mediated type I responses.

Answer 18

IgE binds to a foreign antigen (e.g. pollen)

The Fc portion binds to mast cells and basophils leading to degranulation

NOTE: this mechanism is implicated in eczema

Question 19

How does antibodies binding to cellular antigens lead to cell death?

Answer 19

Antibody-dependent cellular cytotoxicity:
antibodies can activate complement (by binding to C1) or bind to NK cells and macrophages resulting in phagocytosis

Question 20

What is sometimes considered a type V hypersensitivity reaction?

Answer 20

Antibodies activate or block cellular receptors (e.g. Graves’ disease, myasthenia gravis)

Question 21

Name the autoantigen in the following diseases:

1. Goodpasture’s disease
2. Pemphigus vulgaris
3. Graves’ disease
4. Myasthennia gravis

Answer 21

1. Goodpasture’s disease = non-collagenous domain of basement membrane collagen IV
2. Pemphigus vulgaris = Epidermal cadherin
3. Graves’ disease = TSH receptor
4. Myasthenia gravis = nicotinic acetylcholine receptor

Question 22

What are the consequences of immune complex formation in type III hypersensitivity reactions?

Answer 22

Immune complexes can deposit in blood vessels

(especially in the kidneys (nephritis), joints and skin (purpura)

They activate complement and inflammatory cells through their Fc portion

Classic example - SLE

Question 23

What is the autoantigen in:

1. SLE
2. Rheumatoid arthritis

Answer 23

• SLE: DNA, histones, RNP
• Rheumatoid arthritis: Fc portion of IgG

Question 24

Give some examples of type IV hypersensitivity mediated diseases and state the autoantigen involved.

Answer 24

• Insulin-dependent diabetes mellitus: pancreatic beta-cell antigen
• Multiple sclerosis: myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein

Question 25

How can coeliac cause immune deficiency?

Answer 25

• Protein losing enteropathy
• Immunoglobulins are proteins - hence, the loss of circulating antibodies will reduce immunity.
• May be diagnosed by performing faecal alpha-1 antitrypsin levels

Can occur with IBD, Coeliac, SLE