Autoimmunity Flashcards
What is autoimmunity?
The presence of immune responses against self tissues or cells.
What type of hypersensitivity reactions are autoimmune reactions?
Hypersensitivity types 2-4
What constitutes a harmless or harmful autoimmunity?
Harmless= low titres of auto antibodies or auto reactive T cells Harmful= high titres of auto antibodies or auto reactive T cells => significant tissue/organ damage and chronic inflammation
What are the 4 steps to developing an autoimmune disease?
1) Genetic susceptibility
2) Initiating event
3) Breakdown of self tolerance- loss of immune regulation and generation of autoreactive T and B cells
4) Autoimmune disease
What is a monogenetic auto immune disease and give an example
Single gene defect causing an autoimmune disease. Rare.
Example = IPEX syndrome
What are the genetic influences of most autoimmune diseases?
Complex genetic interplay involving multiple genes including HLA genes, genes determining sex and other immune response genes
What is IPEX syndrome?
Rare X linked genetic disorder of immune disregulation
What are the symptoms of IPEX syndrome?
Presents early in childhood with overwhelming systemic autoimmunity.
Severe infections, irretractable diahorroea, Eczema, very early onset type 1 diabetes
What is the treatment for IPEX syndrome?
Haematopoetic stem cell transplantation, immunosuppressive drugs and total parentral nutrition
What is the pathogenesis of IPEX syndrome?
Mutation of FOXP3 gene which is essential for development of regulatory T cells. This leads to failure of peripheral tolerance. X linked
What percentage of the CD4+ T cell population are T reg cells?
5-10%
What is the function of T reg cells?
Suppression of hyper reactive T cells via production of anti-inflamatory cytokines IL10, TGFbeta.
There fore if you have a mutation in the FOXP3 gene you do not produce functional T red cells => uninhibited T cell activation
What is tolerance?
Non responsiveness of lymphocytes to specific antigens
Why is tolerance important?
There is huge potential for the generation of auto reactive T and B cells due to the random shuffling of gene segments to generate different variable regions. These can be auto reactive or non functional.
What is central tolerance?
Deletion of self reactive lymphocytes in primary lymphiod tissue
What is peripheral tolerance?
Inactivation of self reactive lymphocytes in peripheral tissues that escape central tolerance. Involves T reg cells
Where are HLA genes found?
Short arm of chromosome 6
Which cells express MHC (HLA) class 1 proteins on their surface?
All nucleated cells
What are the HLA class 1 proteins?
HLA-A
HLA-B
HLA-C
Which cells express MHC (HLA) class 2 proteins on their surface?
Specialised antigen presenting cells
Dendritic cells, macrophages and B cells
What are the HLA class 2 proteins?
HLA-DP
HLA-DQ
HLA-DR
How many variants of each HLA molecule type does each individual possess?
2
HLA genes are incredibly polymorphic. Why is this important?
Maintain diversity
Different allele sequences bind to different proteins. Only a few peptides will bind to any specific HLA molecule
To maximise the net ability to bind peptides individual HLA molecules have significant allelic diversity
Why are autoimmune diseases more common in women?
Unclear reasons but there is different hormonal influences on lymphocyte function in males and females
What are the risk factors for developing an autoimmune disease?
Women of child bearing age
People with a family history (eg SLE or MS) different types of AI diseases can affect different members of the same family
People of cirtain race/backgrounds (eg DM type 1- white people, SLE in African/Americans)
For genetically predisposed individuals, what factors in the environment can trigger their autoimmune disease?
1) Infection:cross reactivity between antigens expressed on self and pathogen = molecular mimicry
2) Cigarette smoking
3) Hormonal changes
What is molecular mimicry?
T cells with cross reactive T cell receptors are activated by peptides donated by the pathogen that resemble or are identical to endogenous peptides => immune activation against self antigens triggered by the presence of a foreign antigen that shares molecular or antigenic properties with self.
Give an example of a disease caused by molecular mimicry and how if develops?
Acute Rheumatic fever after streptococcal infections
1) Group A strep presents as a sore throat- expresses large amounts of M protein
2) Large amounts f IgG produced against M protein during normal adaptive immune response
3) Antibodies against M can bind to structurally similar proteins present on cardiac muscle cells
4) Antibody induced injury to heart valves and sarcolema
How does reactive arthritis develop after a bacterial infection?
1) Inflamation secondary to bacterial infection develops several weeks after a GI or GU infection
2) Usually one joint or several in the lower limb
3) susceptibility is associated with inheritance of cirtain MHC class 1 alleles- HLA-B27
What is a sequestered antigen and how can they cause an auto immune disease?
Sequestered antigens are those which cannot interact with the immune system during development as they are anatomically sequestered and therefore the lymphocytes for these antigens are not deleted.
1) These antigens are treated as foreign when they enter the circulation.
Give 3 examples of sequestered antigens and the diseases the can cause?
1) Lens of eye antigens- post traumatic ureitis
2) Sperm antigens- aspermatogenisis
3) CNS antigens- encephalitis
How can super antigens cause autoimmunity?
They cause NON SPECIFIC activation of T cells => polyclonal T cell proliferation and some of the antibodies attack self = Toxic shock syndrome
Give 2 examples of super antigens?
1) Staphleococcal proteins
2) Clostridium endotoxin
How can auto immune diseases be classified?
Clinical classification- organ specific or multi organ system disease
Pathological classification: Gel and coombs classification (hypersensitivity reactions
Give examples of autoimmune diseases caused by type 2 mechanisms?
1) Blood cells
2) Kidney
3) Nervous system
4) Endocrine system
5) Skin
1) Blood cells- Autoimmune haemolytic anaemia
2) Kidney- Good pastures syndrome
3) Nervous system- Myasthesia Gravis or Guillan Barre syndrome
4) Endocrine system- Graves disease
5) Skin- Pemphigus Vulgaris
Where do autoantibodies bind in autoimmune haemolytic anaemia?
RBCs
Where do autoantibodies bind in Good pastures syndrome?
Glomerula basement membranes
Where do autoantibodies bind in Myatheisia Gravis?
ACh receptors
Where do autoantibodies bind in uillan Barre Syndrome?
Peripheral nerve glycoproteins
Where do autoantibodies bind in Graves disease?
TSH (thyroid stimulating hormone receptors
Where do autoantibodies bind in Pemphigus Vulgaris?
Epithilial cell cement
What are the symptoms of graves disease and what can it cause?
Heat intolerance, sweating, palpitaions, dyspnoea on exertion, weight loss, fatigue, eye irritation, dryness, blurring, tearing
Hyperthyroidism and the swelling og muscle and tissue behind the eye
What is Good Pastures syndrome and what are the clinical features?
Rare autoimmune disease where autoantibodies attack the basement membranes in the lungs and kidneys leading to bleeding from the lungs and kidney failure
Glomerulonephritis (=> RBC in urine) and pulmonary haemorrage
What self antigen is thought to cause good pastures syndrome?
Alpha 3 subunit of type 4 collagen
What is the management for auto immune diseases caused by type 2 hypersensitivity reactions?
1) Plasmapheresis with the aim to remove the pathogenic antibody
2) Immunosupression- Rebound antibody production can limit effectiveness of plasma phoresis soa strong immunosupressive agent is given to switch off antibody production by B cells
What is plasmapheresis?
1) Patients blood removed by a cell separator
2) Cellular contents returned to patient
3) Plasma replaced by fresh frozen plasma or pooled immunoglobulin
4) Approximately 50% of plasma removed each time
Give an example of an autoimmune disease mediated by type 3 hypersensitivity?
Systemic Lupus Erthematosus SLE
A prototypic multi system auto immune disease
What are the clinical features of SLE?
Buttery face rash Mouth ulcers Poor peripheral circulation Arthritis Fever Muscle Aches Photosensitivity
Where do autoantibodies bind in SLE?
Nuclear antigens
What is the age of onset of SLE?
20s and 30s (90% of cases female)
What causes SLE?
Preformed immune complexes deposit in vascular beds and cause injury which activate the complement cascade through the classical pathway
The vascular beds are determined by the physical nature of the complexes and this determines the clinical manifestations
WHat are the clinical manifestations of SLE?
Vasculitis, Nephritis, serum sickness, Extrinsic allergic alveolitis
Do patients with SLE have an increased risk of cardiovascular disease?
Yes
What is the pathogenesis of SLE?
1) Infection => Increased ROS production
2) Mutations in MAC 1 => Decreased phagocytosis and increased apoptosis
3) Apoptotic bodies degrade and release potential auto antigens
4) Autoreactive B cells (loss of tolerance) produce autoantibodies against nuclear antigens
5) Immune complex formation and deposition in vasculature => complement cascade activated => tissue damage
How are SLE managed?
Limit sun exposure Analgesia Hydroxychloroquinnie Prednisalone to decrease inflammation Immunosupressive agents to reduce the production of autoantibodies Agents to suppress B cell proliferation
Which drugs inhibit B cell proliferation used in SLE?
Belimumab
List immunosupressive agents used in SLE?
Azathioprine
Myeophenolate
Cyclosphosphamide
What is the hypersensitivity, autoantigen and consequences of Insulin dependent type 1 diabetes?
Type 4 hypersensitivity
Pancreatic beta cell antigen
Pancreatic beta cell destruction
What is the hypersensitivity, autoantigen and consequences of rheumatoid arthritis?
Type 4 hypersensitivity
Unknown synovial joint antigen
Joint inflammation and destruction
What is the hypersensitivity, autoantigen and consequences of Multiple Sclerosis?
Type 4 hypersensitivity
Myelin basic protein, proteolipid protein
Brain degeneration and paralysis
What is the hypersensitivity, autoantigen and consequences of celiac disease?
Type 4 hypersensitivity
Gluten modified by tissue transglutaminase
Malabsorption of nutrients Atrophy of intestinal villi
