Autoimmunity

Question 1

Autoimmunity

Answer 1

Physiological autorecognition with secondary epiphenomena. It is the failure of an organism in recognising its own constituent parts as non-self.

Question 2

Autoimmune disease

Answer 2

Immune response contributing directly to tissue / organ damage

PATHOLOGICAL PROCESS

Question 3

Prevalence of autoimmune disease

Answer 3

20%

Question 4

Causes of autoimmunity (genetic factors)

Answer 4

Human Leukocyte Antigen can correlate with certain diseases
Very seldom is there an individual, pin-pointable gene
Though in some instances the presence of single gene defects such as FAS/FasL, AIRE, FOXP3, Complement Genes (Lupus) can cause autoimmune disease

Question 5

Hormonal factors contributing to autoimmunity

Answer 5

Women more likely to be affected than men (as high as 10/1)

SLE 10x more common in women than men in reproductive years, but only 2x more common in early/later life

Question 6

Environmental factors contributing to autoimmune disease

Answer 6

UV sun exposure

Klebsiella pneumonia and Coxsackie B have been strongly correltated with ankylosing spondylitis and diabetes.

Question 7

Cell mediated autoimmunity (T and NK cells)

Answer 7

T cellsdestroy intracellular pathogens by killing infected cells and by activating macrophages but they also have a central role in the destruction of extracellular pathogens by activating B cells.

Interact with cells bearing the antigen they don’t recognize
Stop cells that could potentially lyse and release viruses

Question 8

Type 1 Diabetes

Answer 8

Auto-reactive T cells against Pancreatic Islet cell Antigens, leading to destruction and non-production of insulin

Question 9

Crohn’s Disease

Answer 9

Triggered by a foreign pathogen leading to APC presentation to TH
Autoreactive T cells against intestinal Flora antigens leading to lymphocyte infiltration of exocrine glands
Can be familial (NOD2 gene)

For reasons not clearly understood, pathogens make it past the mucosa in the gut, and are engulfed by APCs. The cytokine reaction from T-Helper cells is dysfunctional and exaggerated, leading to lots of Macrophages creating proteases and platelet activating factors, which causes inflammation

Question 10

Psoriasis

Answer 10

Autoreactive T-cells against Skin associated antigens

Question 11

Coeliac Disease

Answer 11

In coeliac disease B cells for transglutamine are helped by T cells recognising gliadin (an amino acid sequence in Gluten).

Secretory IgA in mucosal membrane (normally a marker of immune cell destruction, crosses to lamina proprieta.

Macrophages uptake these TTG antibodies, express MHCII antibodies (HLA-DQ2)

CD4+ TH Cells release IFNγ and TNF – destroying villi, CD8+ TC destroy damaged endomysial cells

Question 12

Antibody mediated autoimmunity

Answer 12

Antibody binds to targets leading to damage by Fc receptor macrophage with or without complement lysis. Can also lead to immune complex formation and deposition, activating phagocytes and causing damage.

Type II Hypersensitivity Reaction

Question 13

Goodpasture Syndrome

Answer 13

Genetic risk - HLA-DR15
Environmental risk – Infection/Smoking/Solvents (dry cleaning). Places likely to be damaged are lung and kidneys

IgG reactions to alpha 3 collagen (after some damage). C1 attaches to collagen and activates and cleaves other elements. This attracts granular cells which release their enzymes resulting in inflammation and tissue damage.

Question 14

Immune Complex Autoimmunity

Answer 14

Antigen-antibody/Immune complex formation and deposition, activating phagocytes and causing damage

Type III Hypersensitivity reaction

A fully differentiated B cell called a plasma cell secretes antibodies into serum, and has antibodies bound to it’s cell surface to act as receptors
When an antigen cross links 2 surface antibodies on the plasma cell, it absorbs it, and offers a piece of it to T Helper cells.
They join via stimulatory CD4 and CD40 Ligands and the B-cell releases cytokine which switch it’s Immunoglobulin class

Antibody binds to targets leading to damage by FC receptor macrophage and or complement lysis (AIHA, ITP, Anti-GBM)

Question 15

SLE

Answer 15

A failure of self-tolerance allows a B-cell to react to leaked DNA auto-antigen from a damaged cell

If a T-cell that is also specific to this, it begins to secrete anti-dsDNA antibodies to be produced

Question 16

Myasthenia Gravis

Answer 16

Myasthenia gravis is anautoimmune diseasewhich results fromantibodiesthat block or destroynicotinic acetylcholine receptorsat thejunction between the nerve and muscle.[1]This preventsnerve impulsesfrom triggeringmuscle contractions. Complement activation also causes local inflammation
ACH Receptor antibodies in 85%. Thymomas are cancers of the Thymus, and can cause autoantibody release
Treatment
Cholinesterase Inhibitors
Immunosupression
Thymoma

Question 17

Graves Disease

Answer 17

Autoantibodies against the Thyroid stimulating hormone receptor. Activates the TSH and over-produces Thyroid hormones

Question 18

Rheumatic Fever

Answer 18

infection with Group A beta-haemolyticstreptococci. Although rheumatic fever has been attributed to molecular mimicry for half a century no antigen has been formally identified (if anything too many have been proposed). Moreover, the complex tissue distribution of the disease (heart, joint, skin, basal ganglia) argues against a cardiac specific antigen. It remains entirely possible that the disease is due to e.g. an unusual interaction between immune complexes, complement components and endothelium.

Question 19

Multiple Sclerosis

Answer 19

T-cells specific to Myelin, cross the BBB and release cytokines
BBB damage, macrophage and Tc cell migration attacks Oligodendrocyte
Despite Treg cells allowing healing, eventually the damage become worse
Associated to HLA-DR2, and Vit D Deficiency

Question 20

Treatment of Autoimmune Disease

Answer 20

Immunosuppressive therapy

Anti-inflammatory therapy

Plasmapheresis

Stem Cell/Bone Marrow Transplant (?)

Replacement of lost physiological factor

Organ / tissue / mechanical graft

Question 21

Tolerance

Answer 21

A state of unresponsiveness of the immune system to self

Question 22

Central control of Tolerance

Answer 22

Thymus.

Inactivation of cells required for initiation of an immune response.

Question 23

Enhancement of central control of tolerance

Answer 23

IL-10 and TGF beta

Question 24

Inhibition of central tolerance

Answer 24

Leuktriene, IFN-Ɓ and TNF-Ɓ

Question 25

Peripheral control of tolerance

Answer 25

Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens,gut microbes, etc.)
Clonal deletion (apoptotic cell death); clonal anergy (functional inactivation without cell death); clonal ignorance (failure to recognize or recognition of antigens without costimulation); suppression of lymphocyte activation and effector functions by regulatory lymphocytes

Regulated by Treg cells

Question 26

HLA

Answer 26

Chromosome 6
Two alleles, 6 loci
Co-dominantly expressed

Themajor histocompatibility complex(MHC) is a set ofcellsurface proteins essential for theacquired immune systemto recognize foreign molecules invertebrates, which in turn determineshistocompatibility.

Question 27

Histocompatibility

Answer 27

Histocompatibility, or tissue compatibility, is the property of having the same, or sufficiently similar,allelesof a set ofgenescalledhuman leukocyte antigens(HLA).

Question 28

HLA molecules that increase chance of autoimmune disease

Answer 28

HLA-B27 - ankylosing spondylitis

HLA DR3 - addisons disease, graves disease, myasthenia gravis

Question 29

A working immune system has

Answer 29

Recognition (including past infections and self)
Interaction with foreign antigens
Response 
Elimination
Control & Regulation