Autoimmunity Flashcards
1
Q
re-edit again after lecture
Define autoimmunity
A
- Breakdown in tolerance
- Ability to distinguish between ‘self’ and ‘non-self’
- Central
- Peripheral
- Specific adaptive response against self antigens
- Impossible to eliminate the antigen completely
- Sustained immune response
- Chronic inflammation involving target tissues
2
Q
Recap self tolerance
A
- Unresponsiveness to self antigens
- Mechanisms actively prevent either the maturation or activation of potentially self-reactive lymphocytes
-
Central tolerance
- Induction of tolerance in generative lymphoid organs
- Encounter antigen presented by thymic epithelial cells
-
Peripheral tolerance
- Induction of tolerance in mature lymphocytes in the peripheral tissues
3
Q
Recap layers of tolerance
A
- Central tolerance:
- Deletion
- Editing
- Site of Action
- Thymus
- Bone marrow- Antigen segregation
- Physical barrier to self-antigen access to lymphoid system
- Site of action: Peripheral organs (e.g., thyroid, pancreas)
- Peripheral anergy
- Cellular inactivation by weak signaling without co-stimulus
- Secondary lymphoid organ - Regulatory T cells
- Suppression by cytokines, intercellular signals
- Secondary lymphoid tissue and sites of inflammation - Functional deviation
- Differentiation of regulatory T cells that limit inflammatory cytokine secretion
- Secondary lymphoid tissue and sites of inflammation
- Antigen segregation
- Activation- induced cell death
- apoptosis
- secondary lymphoid tissue and sites of inflammation- Central tolerance:
- Deletion
- Editing
- Site of Action
- Thymus
- Bone marrow- Antigen segregation
- Physical barrier to self-antigen access to lymphoid system
- Site of action: Peripheral organs (e.g., thyroid, pancreas)
- Peripheral anergy
- Cellular inactivation by weak signaling without co-stimulus
- Secondary lymphoid organ - Regulatory T cells
- Suppression by cytokines, intercellular signals
- Secondary lymphoid tissue and sites of inflammation - Functional deviation
- Differentiation of regulatory T cells that limit inflammatory cytokine secretion
- Secondary lymphoid tissue and sites of inflammation
- Antigen segregation
- Activation- induced cell death
- apoptosis
- secondary lymphoid tissue and sites of inflammation
4
Q
Describe the factors influencing susceptibility to autoimmune disease
A
Factors influencing susceptibility to autoimmune disease
- Genetic factors
- Familial clusters, HLA association
- Sex
- Age
- Environmental factors
- Ultraviolet radiation, drugs, viruses, chronic infection, gliadin
- Loss of regulatory T cells
5
Q
Describe genetic and familial susceptibility to autoimmune disease
A
- Familial Clusters suggestive of a more generalised heritable defect as seen in:
- Type I diabetes mellitus
- Graves’ disease, Hashimoto’s thyroiditis, autoimmune gastritis, hypoadrenalism, vitiligo
- Systemic lupus erythematosus scleroderma
- Autoimmune polyendocrinopathy syndromes - HLA associations: specific HLA complexes are associated with incidence of autoimmune diseases
- HLA B27
- Ankylosing spondylitis
- Anterior uveitis
- Reactive arthritis
- HLA DR3
- Graves’ disease
- Myasthenia gravis
- Systemic lupus erythematosus
- HLA DR4
- Diabetes mellitus
- Rheumatoid arthritis
- Pemphigus vulgaris
- HLA B27
6
Q
Describe other factors that influence susceptibility to development to autoimmune disease
A
- Sex
- More common in female patients, particularly those of childbearing age
- Age
- Environmental exposures
- UV radiation
- Drugs - alpha methyldopa
- Certain viral and chronic infections - Chronic inflammation leads to greater chance of exposure to self antigens
- Gliadin
- Loss of regulatory T cells
- May be secondary to other medical conditions and exposures, or perhaps idiopathic.
7
Q
Describe autoimmune disease, and classification
A
- Occur in 3-5% of the general population
-
Classification
- Sites of organ damage
- Location of the immune response
- Demonstrable autoantibodies (Ig’s) or autoreactive T cells
- Specificity for self antigens (autoantigens)
- Sites of organ damage
8
Q
Describe pathogenic autoantibodies, and pathogenic mechanisms of autoantibodies
A
Pathogenic Autoantibodies
- Introduction of antibodies into man/animal models results in the development of disease
- Able to cross the placenta causing disease in the foetus or newborn
- Identification of autoantibodies in the pathological lesion
- Correlation between antibody levels and disease activity
Pathogenic Mechanisms of Autoantibodies
- Complement lysis
- Antibody-dependent cellular cytotoxicity
- Binding of antibody to cell-surface/tissue antigens followed by complement activation and cell lysis/phagocytosis
- Formation of circulating immune complexes
- Deposition in capillary beds, activation of complement, localized inflammatory response
- Production of stimulating or blocking antibodies
9
Q
List and describe immunopathogenic mechanisms
A
-
Type I
- IgE mediated
-
Type II
- IgG or IgM mediated cytotoxic damage
- Autoimmune haemolytic anaemia, Goodpasture’s syndrome
-
Type III
- Immune complex diseases
- Circulating immune complexes deposit in capillary beds
- Systemic lupus erythematosus
-
Type IV
- Delayed type hypersensitivity
- Cell-mediated
- Type I diabetes mellitus
10
Q
List some organ-specific autoimmune diseases by systems
A
-
Endocrine
- Autoimmune thyroiditis
- Graves disease (hyperthyroidism)
- Type I diabetes mellitus
- Hypoadrenalism (Addison’s disease)
- Primary ovarian failure
-
Gastrointestinal
- Autoimmune gastritis (pernicious anaemia)
- Coeliac disease
-
Haematological
- Autoimmune haemolytic anemia
- Autoimmune idiopathic thrombocytopenic purpura
- Neutropenia
-
Renal
- Goodpasture’s syndrome
-
Hepatic
- Autoimmune hepatitis
- Primary biliary cirrhosis
-
Neurological
- Myasthenia gravis
- Guillain Barré syndrome
-
Skin
- Vitiligo
- Pemphigus
- Bullous pemphigoid
11
Q
List systemic autoimmune diseases
A
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Sjögren’s syndrome
- Scleroderma
- Polymyositis/Dermatomyositis
12
Q
Describe some mechanisms of organ-specific autoimmune disease
A
- Antibodies and lesions are organ-specific
- Clinical and serological overlap
- Antigens present in low concentrations
- Administration of the antigen evokes organ-specific antibodies and induction of the lesion
- Familial tendency - clustering of organ-specific autoimmune disease suggestive of a more generalized defect
- Production of antibodies, cell-mediated destruction
13
Q
List some diseases mediated by direct cellular damage
A
Direct cellular damage occurs via:
- Cellular lysis and/or inflammatory response in the target organ
- Autoimmune thyroiditis (Hashimoto’s)
- Autoimmune anaemia
- Goodpasture’s syndrome
- Type I diabetes mellitus
14
Q
Describe Hashimoto’s thyroiditis
A
- Autoimmune thyroiditis
- Predominantly middle-aged women
- Characterized by a lymphocytic infiltrate (thyroid gland)
- Progressive thyroid destruction and the development of hypothyroidism
- Up to 95% anti-thyroid peroxidase antibodies (high titre)
- Association with other autoimmune diseases
15
Q
Briefly describe T1DM
A
- Characterized by
- Pancreatic β cell destruction and ultimately absolute insulin deficiency
- T cell-mediated
- Presence of autoantibodies (directed against pancreatic islet cells)
- Glutamic acid decarboxylase (GAD), protein tyrosine phosphatase (IA2), zinc transporter 8 and insulin (IAA)
- Presence of one or more antibodies can precede clinical onset by many years (presence of all three close to 100% risk of developing clinical diabetes)
- No evidence that these autoantibodies are pathogenic
- Image - Link
- Inflammatory response within the pancreatic islet cells “insulitis”
- Mononuclear cell infiltrate with predominantly CD8+ cells (CD4 + T cells and macrophages)
- observed in early diabetes
- Increased expression of Class I MHC and aberrant expression of class II MHC on beta cells
- Mononuclear cell infiltrate with predominantly CD8+ cells (CD4 + T cells and macrophages)
- Progressive pancreatic β cell destruction (size and number)
- mediated by autoreactive CD4+ T cells
- lysis by cytotoxic T cells
- local production of pro-inflammatory cytokines and ROS
- evidence for defects in Treg function
- overt diabetes only occurs once most of these cells have been destroyed
16
Q
Describe Grave’s disease
mediated by stimulating antibodies
A
- Grave’s disease
- Present with thyrotoxicosis, diffuse goitre
- Ophthalmopathy, dermopathy
- Female predominance
- Weak HLA association - HLA DR3 (Caucasians)
- Thyroid-specific autoantibodies including those with stimulating properties
- Directly involved in the pathogenic process
- Transplacental transfer can result in neonatal hyperthyroidism
- autoimmune B cells synthesise and secrete antibodies against thyroid-stimulating hormone receptor that subsequently cause elevated thyroid hormone production
- Normally, a negative feedback loop would cause a shutdown in the production of thyroid-stimulating hormone to ensure that an appropriate level of thyroid activity is maintained, but no mechanisms exist to shut down the production of auto-antibodies that mimic the effect of thyroid-stimulating hormone.
- Excessive thyroid hormone production hence causes the symptoms of Graves’ disease.
17
Q
Describe myasthenia gravis
mediated by blocking antibodies
A
- Fatiguability of muscles leading to profound weakness
- Association with thymoma, thymic hyperplasia, other autoimmune diseases (including thyroid)
- HLA association
- Female preponderance
- Autoantibodies to the acetylcholine (Ach) receptor on the motor end plates of muscles
- Blocks binding of ACh leading to complement-mediated destruction
- Transplacental transfer - neonatal myasthenia
18
Q
Describe some systemic polyendocrine syndromes
A
- Autoimmune polyendocrine syndrome type 1 (APECED)
- Mutations in AIRE (autoimmune regulator) gene
- Deletion of autoreactive T cells does not occur in the thymus, mature and exported to the periphery leading to organ-specific autoimmune disease
- Onset in early childhood, male predominance
- Major manifestations
- Mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency
- Other associated manifestations
- Other autoimmune endocrineopathies, chronic active hepatitis, hypogonadism, alopecia, pernicious anemia
- Autoimmune polyendocrine syndrome type 2 (Schmidt’s syndrome)
- Females (peak age of onset 20 - 40 years)
- Addison’s disease and
- Autoimmune thyroid disease, type I diabetes mellitus
- Pernicious anemia, chronic active hepatitis, vitiligo, hypogonadism
19
Q
Describe IPEX
A
- X-linked polyendocrinopathy, immune dysfunction, and diarrhea
- Rare, lethal disorder
- Early onset diarrhea, villous atrophy and lymphocytic infiltrates, failure to thrive
- Early onset (usually neonatal) type I diabetes mellitus
- Autoimmune cytopenias, eczematous skin rash, recurrent infections
- Mutations in FOXP3
- Mediates CD4+CD25+ regulatory T cell development within the thymus
- In absence, generation of autoreactive T cells responsible for disease manifestations observed in IPEX
20
Q
Describe features of systemic autoimmune disease
A
- Antibodies and lesions non-organ specific
- Overlap of systemic autoimmune features possible
- Higher levels of antigen present
- Reflect generalised immune dysfunction
- Cell-mediated destruction
- Direct cellular damage mediated by autoantibodies
- Deposition of immune complexes
21
Q
Describe the features of SLE
A
- Wide-ranging effects, multiorgan involvement
- Rash
- Cytopenias
- Glomerulonephritis
- Sicca symptoms
- Neurological syndromes
- Thrombosis, recurrent miscarriage
- Neonatal syndromes (photosensitivity rash, congenital heart block)
- Presence of autoantibodies
22
Q
Describe the pathogenic mechanisms of SLE
A
- Multiple factors
- Genetic and environmental influences
- Abnormal responses to self-antigens
- Production of autoantibodies - play a role in complement fixation and activation, deposition of immune complexes
- Defects in clearance of immune complexes (related to complement deficiency)
- Defects in apoptosis
23
Q
Recall mechanisms of T cell tolerance
A
- Central tolerance in T cells: normally induced in the thymus
- Newly formed immature T cells migrate to the thymus
- There, they encounter self-antigens presented by thymic epithelial cells.
- At the thymus, naïve T cells that are unable to recognise MHC are removed from the repertoire, as such T cells will be unable to confer immunologic advantage.
- Next, naïve T cells that are strongly auto-reactive (as determined by self-antigen expression through the action of the AIRE gene) are removed from the repertoire, with some of these autoreactive T cells exposed to signals that encourage their differentiation into regulatory T (Treg) cells.
- Peripheral tolerance: normally induced after central tolerance to limit the effect of autoreactive T cells.
- Immature dendritic cells collect self-antigens and present them to naïve T cells.
- If self-reactive naïve T cells recognise the self-antigens presented by dendritic cells, they may once again be converted into regulatory T (Treg) cells, or may be deleted.
- Another method of peripheral tolerance is the suppression of self-reactive T cells by Treg cells, or the induction of anergy, where self-reactive T cells are made non-responsive.
24
Q
Recall mechanisms of B cell tolerance
A
B cell tolerance
- Central tolerance for B cells:
- Immature B cells in the bone marrow are negatively selected when they recognise self antigen. Initially, they undergo further light chain rearrangement to express a new receptor specificity, but those B cells that remain self-reactive after this point:
- Undergo apoptosis
- Are made anergic
- Peripheral B cell tolerance
- B cells that have migrated to the periphery, yet recognise self-antigen in the absence of T cell help are made non-responsive.
25
Q
Revise Type I hypersensitivity reactions
A
- IgE mediated
- Soluble antigen
- Mechanism: allergen specific IgE antibodies bind to mast cell via their Fc receptor. When the specific allergen binds to IgE, cross-linking of IgE results in degranulation of mast cells
- local and systemic aaphyalaxs, hayfever, food and drug allergies
26
Q
Revise type II hypersensitivity reactions
A
- IgG or IgM mediated cytotoxic damage
- Cell bound antigen
- Autoimmune haemolytic anaemia, Goodpasture’s syndrome
- Mechanism: IgG or IgM binds to cellular antigen, leading to complement activation and cell lysis. IgG can also mediate ADCC with cytotoxic T cells, NK cells, macrophages and neutrophils
27
Q
Revise type III hypersensitivity reactions
A
- Immune complex diseases
- IgG and IgM
- Soluble antigen
- Circulating immune complexes deposit in capillary beds. Complement activation provides inflammatory mediators and recruits neutrophils. Enzymes are released from neutrophils and damage tissue
- Systemic lupus erythematosus, PSGN, RA
28
Q
Revise type IV hypersensitivity reactions
A
- Delayed type hypersensitivity
- Cell-mediated (T cells)
- Soluble or cell-bound antigen
- Th1 cells secrete cytokines, activating macrophages and cytotoxic T cells
- Type I diabetes mellitus, MS and contact dermatitis
