Lecture 3- autoimmunity Flashcards
what is autoimmunity?
- If a person has an autoimmune disease, the immune system mistakenly attacks self, targeting the cells, tissues, and organs of a person’s own body.
- Breach in “Tolerance”
- There are more than 80 different kinds of diseases caused by autoimmunity
what can immune responses be?
beneficial or harmful, depending on the nature of the antigen.
*The immune system normally works to defend the body and eliminate infections caused by bacteria, viruses, and other invading microbes
what are features of autoimmune diseases?
- Fundamental problem: imbalance between immune activation and control
- Underlying causative factors: susceptibility genes + environmental influences
- Immune response is inappropriately directed or controlled; effector mechanisms of injury are the same as in normal responses to microbes
- Nature of disease is determined by the type of dominant immune response
- Many immunological diseases are chronic and self- perpetuating
what drives autoimmunity?
- Immune regulatory failure
- Loss of central tolerance
- Loss of peripheral tolerance
- Inappropriate activation-Immune privilege * Molecular mimicry
what is APECED?
Autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy or Autoimmune polyglandular syndrome type-1 (APS-1)
Loss-of-function mutations in the autoimmune regulator (AIRE) gene.
Classic triad of clinical manifestations:
-chronic mucocutaneous candidiasis (CMC) -hypoparathyroidism -primary adrenal insufficiency (Addison’s disease)
What is IPEX?
IPEX: Immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome
FACS and gene sequencing:
* Lack of both CD4CD25 cells and CD4Foxp3 positive cells.
* Mutation of FOXP3 gene Immunosuppressive therapy, Bone marrow transplantation
What is APLS
Autoimmune lymphoproliferative syndrome (ALPS)
A result of a mutation in Fas: loss of function, unable to drive cell apoptosis
*Splenomegaly
*Lymphadenopathy (enlargement of lymph nodes)
*Increased lymphocytes and immunoglobulins in blood
*Family history: father, grandfather
Autosomal Dominant
What do MHC genes do?
have an important role in controlling susceptibility to autoimmune diseases
what re types of environmental changes?
- Smoking
- Air pollution * Drugs
- etc…
- Infectious agents * EBV
- Mycoplasma.
what are autoantibodies?
- Oftenpresent
- Mayormaynotbepathogenic
- Specificexamplesapparently significant
- Maybeassociatedwithspecific disease states
what is graves disease?
- Thyroidhormonesregulatedbythyroid- stimulating hormones (TSH)
- TSHbindtoreceptor&stimulatessynthesisof thyroid hormones
- Grave’sDiseaseresultsinnon-regulated “activating” auto-antibodies that bind to the TSH receptor, leading to overstimulation of the thyroid hormones
- Theauto-antibodiesarecalledlong-acting thyroid stimulating hormones
what is myasthenia graves?
- Antibodies against Acetyl Choline receptors, bind to receptors and block binding of Ach Neurotransmitter in the synapses
- Weakness and rapid fatigue of the muscles
- In more than 50% of people who develop Myasthenia gravis, their first sign involves eye problems, such as:
-Drooping of one or both eyelids (ptosis)
-Double vision (diplopia) - In about 15% of people with Myasthenia gravis, the first symptoms involve face and throat muscles, which can:
-Impair the sound of speech, Cause difficulty swallowing, Affect chewing, Change facial expressions - Myasthenia gravis can also cause weakness in neck, arms and legs.
what is Antibody Dependent Cytotoxicity: Hemolytic anemia?
Autoimmune destruction of red cells.
The hemolysis can be intravascular or extravascular.
In general, IgG mediates warm antibody–induced hemolysis, and IgM cold antibody–induced hemolysis.
Immunosuppression is the main treatment
what is Neutrophil activation: Lupus?
Immunisation against intra cellular components such as DNA
Hence multi system disease
Importance of NETs and antigen spreading
what is Acantholysis: Pemphigus vulgaris?
*Antibodies against Desmogleins, proteins which attach epidermal cells together
* Bullous lesions of the skin
what are the cellular mechanisms?
T cell specific for auto-antigens may ‘help’ to generate anti- host response
* Gravesdisease–Tcellstothyroidfollicularepithelial cells
* MyastheniaGravis–Tcellstoacetylcholinereceptor Aberrant effector T cells – Th1 vs Th17 vs Th2
Deficiency of Treg cells
Macrophage / Neutrophils / NK cells / Dendritic cells all implicated via
* Cytokine release
* Effector pathways e.g. MMPs / ROIs / RNIs
what is rheumatoid arthritis?
Autoimmune disease affecting mainly the joints
Immunisation against citrulline + immune complexes
Damage to the bones and cartilage
what is Guillain–Barré syndrome?
Example of molecular mimicry
* Auto-antibody mediated autoimmune disease of the peripheral nerves
* Triggered by infections including Campylobacter jejuni
* Common cause of acute paralysis * Pathogenesis incompletely
understood, however……
what is negative selection?
The expression of some, but not all, tissue-specific proteins in the thymic medulla is controlled by a gene called AIRE (autoimmune regulator).
AIRE is expressed in medullary stromal cells
what type of processes are present to limit the risk of immunity in the central (thymic) area?
positive and negative
what type of processes are present to limit the risk of immunity in the peripheral area?
- regulatory T & B cells
- dendritic cells & ʻdanger
- co-stimulation
- ignorance
- privilege
what are organ specific vs non organ specific diseases example?
Organ specific
*Hashimoto thyroiditis *Thyrotoxicosis
*Addison’s disease *Atrophic gastritis *Juvenile diabetes mellitus *Multiple sclerosis *Guillain-Barre Syndrome
Non-organ specific
*Systemic lupus (SLE) *Rheumatoid arthritis (RA) *Scleroderma *Dermatomyositis
*Mixed connective tissue disease (MCTD)
*Sjögren’s syndrome
what symptoms do organ specific diseases have?
- Autoimmune attack vs. self- antigens of given organ
- It results in a damage of organ structure and function
what symptoms do non-organ specific diseases have?
- Widespread self-antigens are targets for autoimmune attack
- Damage affects such structures as blood vessels, cell nuclei etc.
why does dysregulation occur?
But most AID are multifactorial
* Several AID have a genetic susceptibility
