13. immune system

Question 1

do autoimmune diseases effect females or males more

% population effected by autoimmune diseases

Answer 1

females

5%

Question 2

categories of autoimmune diseases

what does this depend on?

Answer 2

organ specific

systemic

nature of autoantigens recognised

Question 3

mechanisms that prevent autoimmune diseases

Answer 3

central tolerance

peripheral tolerance

Question 4

central tolerance

Answer 4

• Generated in the primary lymphoid organs

• For immature lymphocytes, strong interaction with antigen induces apoptosis (death) rather than activation
• Leads to clonal deletion of immature autoreactive lymphocytes that interact with autoantigens in the primary lymphoid organs

not perfect

monogenic autoimmune disease called ‘Autoimmune Polyendocrine Syndrome type-1 (APS-1)’ in which there are mutations in the AIRE gene (autoimmune regulator).

Question 5

peripheral tolerance

Answer 5

• Ignorance - tissue antigens that are not exposed to lymphocytes (i.e. are sequestered), or are presented in such small amounts that they cannot activate lymphocytes.
• Inhibition of autoreactive T cells by regulatory T cells (Treg)- express transcription factor Foxp3
  • ​mutations cause IPEX gene
• Checkpoints’ control autoreactive T cell activity
• APC cells express checkpoint molecules (PDL) interact with PD-1 on t cells- switches off t cells

Question 6

Susceptibility to autoimmune diseases:

Answer 6

• Environmental - infections may either increase the risk (trigger or exacerbate), or decrease the risk (eg. Hygiene Hypothesis)
• Genetic - some individuals have a greater risk than others (eg. sex, HLA type)

Increasing incidence in UK due to lifestyle hygiene hypothesis

Question 7

Sex associations:

Answer 7

males have testosterone- immunosuppressive

men have less effective immune responses

Question 8

HLA associations

Answer 8

HLA II genes occur more in those with autoimmune diseases

some genes encoding HLA can affect- different HLA bind to different peptides

HLA-DR4 alleles are associated with rheumatoid arthritis

Question 9

Rheumatoid arthritis (RA)

Answer 9

primarily targets synovial joints

Rheumatoid factor (RF) is anti-IgG(Fc) autoantibodies:

IgM factor has worse prognosis

• Occurs in some other autoimmune diseases during chronic infection and in healthy individuals -not specific for RA
• IgM RF (particularly high titre) indicative of more aggressive disease with relatively poor prognosis

Not a specific maker for RA

Question 10

Anti-citrullinated protein antigen (ACPA) antibodies

Answer 10

• Present in about 85% of RA patients -quite sensitive for RA
• Rare in other diseases and healthy individuals -highly specific for RA
• Citrulline is an amino acid formed by the enzymatic de-imination of arginine in proteins.
• Citrullinated proteins (eg. fibrin) occur in synovial membranes of affected joints in RA
• ACPA is prognostic of more aggressive, erosive disease in RA
• The presence of ACPA in patients with undifferentiated arthritis indicates probable progression to RA

Question 11

Synovitis in RA

Answer 11

Lymphocytic infiltration of synovium, and cytokine production, play an important part in the damage to joints in RA. Understanding this has led to novel targeted treatments in RA using cytokine-neutralizing monoclonal antibodies and other ‘biologics’.

Question 12

Identified risk factors for ACPA-positive RA

Answer 12

HLA-DR shared epitope

important structural features in their peptide binding clefts;

May favour presentation of autoantigenic peptide to autoreactive T cells.

PTPN22 (R620W)

Protein tyrosine phosphatase that reduces T cell signaling;

Trp620 variant has enhanced enzymatic activity, raising the threshold for T cell signaling; associated with multiple autoimmune diseases

May lead to:

• less clonal deletion of autoreactive T cells
• less Treg activity

Smoking

May induce citrullination of lung proteins

Genetic and environmental factors interact to determine an individual’s overall risk of developing RA.