11) Autoimmunity Flashcards
What is the underlying cause of autoimmune diseases?
Production of antibodies and cytotoxic T-cells that target normal body cells
Does genetic predisposition affect the onset of autoimmune diseases?
- They appear to develop spontaneously and at random
- The genetic component is not particularly strong
Which age group tends to develop autoimmune diseases?
Older individuals
Which gender group tends to develop autoimmune diseases?
Women
What are the two most common autoimmune diseases?
- Thyroid diseases (autoimmune)
- Type I diabetes
What is the primary characteristic of vitiligo?
Depigmentation of the skin
What are the primary antibodies of vitiligo associated with? What is it implicated in?
- Tyrosinase
- Melanin synthesis
What are the two autoimmune diseases that have a higher propensity in men than women?
- Diabetes mellitus
- Ulcerative collitus
What are the six most common autoimmune diseases? (6)
- Grave’s disease
- Type 1 diabetes
- Pernicious anemia
- Rheumatoid arthritis
- Hashimoto’s disease
- Vitiligo
1 in __ individuals develop Graves’ disease, type 1 diabetes, pernicious anemia, rheumatoid arthrititis, Hashimoto’s disease and vitiligo, forming __% of affected individuals.
30
93
What is Sjogren’s syndrome?
Autoimmune disease in which there is an inability to produce tears
Why do females have a greater risk to develop autoimmune diseases?
- Due to their hormones (estrogens)
- Immune system has to be depressed to allow implantation to occur during pregnancy
How do estrogens affect B-cell autoimmunity?
- Estrogens stimulate B-cell autoimmunity
- Associated with reproductive years
How do estrogens affect T-cell autoimmunity?
- Falling estrogens support T-cell autoimmunity
- Associated with post-menopausal years
Why do sex and specific stages of life influence the development of autoimmune diseases?
May be due to differences in hormones
What are three common theories to explain the etiology of autoimmunity?
1) T-cells may encounter self-antigens that are normally “hidden” from them
2) Triggered from infections
3) Diminished suppressor T-cell function
How may the encounter of T-cells with self-antigens that are normally “hidden” affect the development of autoimmunity?
- Physical damage or trauma may expose these tissues
- T-cells become reactive to self following exposure to these tissues
How may infections trigger autoimmunity?
An infectious agent has an antigenic determinant that is similar or identical to self-antigen
What are the three factors that are related to the etiology of autoimmune diseases?
- Genes
- Immune regulation
- Environment
What are examples of organ-specific autoimmune diseases?
- T1DM
- MS
- Grave’s disease
- Hashimoto’s
- Addison’s disease
- Myasthenia gravis
What are examples of systemic autoimmune diseases?
- Rheumatoid arthritis
- Scleroderma
- SLE
What gland does hypophysitis affect? What is the auto-antibody?
- Pituitary
- Anti-pituitary
What gland does Grave’s disease affect? What is the auto-antibody?
- Thyroid
- TSH-receptor or anti-TPO
What gland does Hashimoto’s disease affect? What is the auto-antibody?
- Thyroid
- Anti-TPO, anti-TG
What gland does autoimmune hypoparathyroidism affect? What is the auto-antibody?
- Parathyroid
- Anti-parathyroid
What gland does T1DM affect? What is the auto-antibody?
- Pancreas (B-cells)
- Anti-GAD, anti-insulin
What glands does type B insulin resistance with acanthosis affect? What is the auto-antibody?
- Adipocytes, muscle cells
- Insulin receptor blocking
What gland does Addison’s disease affect? What is the auto-antibody?
- Adrenal
- Anti-21-hydroxylase, anti-17a-hydroxylase, anti-P450scc
What are immunologically privileged sites? Provide examples.
- Parts of the body that EXCLUDE immune responses
- Brain, eye, testes, uterus
What is a possible consequence of an injury to an immunologically privileged site?
Injury leads to exposure of antigens, which may lead to autoimmunity
Which autoantibodies may cross the placenta to affect the fetus?
IgG
How may a pregnant women with Grave’s disease affect her fetus?
- Transfer of antibodies across the placenta to the fetus
- Newborn suffers from Grave’s disease
What is the treatment of a newborn with congenital Grave’s disease?
- Plasmapheresis
- Removes maternal anti-TSHR antibodies
What are the three factors that regulate the steady-state of osteoimmunology?
1) Cytokines
2) Receptors
3) Apoptosis
Where does the blood system originate from?
Hematopoietic stem cells in the bone marrow
Where does B-cells immunocompetency occur? Where does T-cells immunocompetency occur?
- B-cells: bone marrow
- T-cells: thymus
What are the two types of stem cells in the bone marrow?
- Hematopoietic stem cells
- Mesenchymal stem cell
What are the two progenitor cells that may differentiate from hematopoietic stem cells?
- Lymphoid progenitor
- Myeloid progenitor
What progenitor cell may differentiate from mesenchymal stem cells?
Multipotent progenitor
What stem cell do osteoclasts arise from?
Hematopoietic stem cells (myeloid progenitor)
What stem cell do osteoblasts arise from?
Mesenchymal stem cells (multipotent progenitor)
Dendritic cells, macrophages, osteoclasts, neutrophils, platelets and erythryocytes are formed from which progenitor cell?
Hematopoietic stem cells (myeloid progenitor)
T-cell progenitors, B-cells, NK cells and dendritic cells are formed from which progenitor cell?
Hematopoietic stem cells (lymphoid progenitor)
Adipocytes, chondrocytes, myocytes, stroma, and osteoblasts are formed from which progenitor cell?
Mesenchymal stem cells (multipotent progenitor)
What controls the development of B-cells?
A hierarchy of transcription factors
_-cells conduct humoral immunity.
B
_-cells conduct cellular immunity.
T
How do B-cells complete their maturation?
Upon binding to non-self antigens and destroying infected cells
What occurs to macrophages following phagocytosis? How are helper T-cells and cytotoxic T-cells implicated?
- Macrophages present non-self antigens on their membranes
- Helper T-cells recognize non-self antigens and recruit cytotoxic T-cells
What are two mechanisms by which the immune system is capable of recognizing virtually any foreign molecule?
1) Somatic recombination of the antibody light-chain and heavy-chain, producing 10^12 different types of antibodies
2) Recombination of genes encoding T-cell and B-cell receptor
What is a downside of random rearrangements of DNA to produce a large number of T-cell and B-cell receptors?
May produce receptors that recognize “self”
Developing lymphocytes express a large number of antigen receptors, which are (biased/not biased) by specificity.
not biased
Are individuals capable of producing lymphocytes with the ability to recognize self antigens?
Yes, because antigen receptors on lymphocytes are not biased by specificity
What must occur to prevent lymphocytes from reacting to self?
Self-reactive lymphocytes must be selected against (eliminated or inactivated) to prevent autoimmunity
Define immunological tolerance.
Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen
How does immunological tolerance differ from non-specific immunosuppression?
Immunological tolerance implies antigen specificity
Define self-tolerance.
All individuals are tolerant of their own antigens
What results from the breakdown of self-tolerance?
Autoimmunity
What are possible therapeutic potentials of inducing tolerance?
- Prevent graft rejection
- Treat autoimmune and allergic diseases
- Prevent immune responses in gene therapy (e.g. stem cell transplantation)
What does central tolerance refer to?
- Generative lymphoid organs
- Thymus (T-cells) and bone marrow (B-cells)
What are the two possibilities of B-cells following the recognition of self-antigen (central tolerance)?
1) Apoptosis (deletion)
2) Receptor editing (change in receptor specificity)
What are the two possibilities of T-cells following the recognition of self-antigen (central tolerance)?
1) Apoptosis (deletion)
2) Differentiation into regulatory (suppressor) T-cells
What does peripheral tolerance refer to? What is its function?
- Peripheral tissues
- Serves as a backup system (if a lymphocyte escapes central tolerance)
What are the three possibilities of mature T-cells in peripheral tissues?
1) Anergy
2) Apoptosis (deletion)
3) Suppression
Define anergy.
Neutralization of the cell (non-reactive)
What occurs to self-reactive lymphocytes during central tolerance?
Immature self-reactive lymphocytes that recognize self-antigens in central lymphoid organs die by apoptosis
What occurs to self-reactive lymphocytes during peripheral tolerance?
Mature self-reactive lymphocytes that recognize self-antigens in peripheral tissues are inactivated (anergy), killed (deletion) or suppressed
Which cells are positively selected for?
Cells with very weak (to none) self-recognition
What occurs if a stromal cell is capable of binding to an immature B-cell?
The stromal cell sends out a death ligand, causing apoptosis in the B-cell
What occurs if there is no cross-linking between a stromal cell and an immature B-cell?
The B-cell survives
What are the two conditions that may cause tolerance to fail, generating autoimmune diseases?
1) Wrong environment (e.g. viral infection)
2) Wrong genes or mutations
What may a weakly stimulating self-antigen lead to?
- Lymphoproliferative disorder (T-cell)
- Antibody-mediated systemic autoimmunity
What may a stimulating self-antigen lead to?
Organ-specific autoimmunity (multi-organ)
What may cross-reactivity with self due to a foreign antigen lead to?
Organ-specific autoimmunity
What are the factors that may lead to the failure of central or peripheral self-tolerance?
- Genetics
- Environment
- Diet (controversial)
- Aging
- Stress
- Pregnancy
- Trauma
- Disease
How are genetics related to autoimmunity?
- Complex and polygenic, but significant
- Increased incidence in monozygotic twins in contrast to dizygotic twins
Provide an example of how environment may affect autoimmunity.
Up to 20% of children prenatally infected with rubella develop T1DM
Why may pregnancy be associated with an increased risk of autoimmune diseases?
The harbouring of a foreign object for a substantial period of time
Describe the pathogenesis of T1DM throughout childhood.
- B-cell pathology: autoantibodies
- Pre-diabetes: loss of first phase of insulin response
- Diabetes: loss of glucose tolerance
Which antibodies are found in 90% of individuals with T1DM?
- Anti-glutamic acid decarboxylase (GAD)
- Anti-IA-2
Which antibody is found in 50% of individuals with T1DM?
Anti-insulin
Which antibodies are found in individuals with Grave’s disease?
- Anti-TSHR
- Anti-TPO
Which antibodies are found in individuals with Hashimoto’s disease?
- Anti-TPO
- Anti-TG
Which antibody is found in individuals with Addison’s disease?
Anti-21-hydroxylase
Rheumatoid arthritis is more susceptible in (women/men).
women
How is rheumatoid arthritis associated with bone erosion?
Rheumatoid arthritis may lead to bone erosion by activating osteoclasts
What is the target tissue of T1DM?
Islet B-cells of the pancreas
What is the target tissue of multiple sclerosis?
Myelin-producing cells in the central nervous system
What is the target tissue of rheumatoid arthritis?
Collagen-producing cells of the joints
How does vitamin D3 affect the development of autoimmune diseases?
- Reduced incidence of autoimmune diseases
- In areas of increased sunshine and/or rich diet in vitamin D3
