Case 23- Autoimmune diseases and Anatomy Flashcards
Articulations of the elbow joint
Radio-humeral: capitulum with the radial head
Ulno-humeral: trochlea with the trochlear notch of the ulna
Radio-ulnar: radial head with the radial notch of the ulna
Autoimmunity
- A state in which the body exhibits immunological reactivity to itself, leading to tissue damage and disease
- Responses to antigens associated with the microbiota. It is a form of xenoimmunity because the organisms from which the antigens derive are foreign and not encoded by the human genome
- Immune mediated disease directed against the commensal microbiota are often considered as part of the extended spectrum of autoimmune disease because ethe microbiota can be considered as part of the ‘superorganism.’
Autoimmune disease- Tolerance breakdown
- Tolerance prevents self-reactivity. Tolerance breakdown:
- Central → usually for genetic reasons
- Peripheral → can be caused by extrinsic factors e.g. infection
- Often multifactorial → >1 defective regulatory mechanisms for disease development i.e. autoimmunity may be triggered in genetically predisposed individuals as a result of failure of intrinsic tolerance mechanisms and or extrinsic triggers such as infections
Autoimmunity- Genetic factors
- Many autoimmune diseases have a familial component- affects the central tolerance mechanisms
- Genetic predisposition - HLA or human MHC haplotype
- Many autoimmune diseases are more common in females than males
- Many mutations identified - affect genes that encode immune systems components e.g. cytokines, co-receptors & apoptotic proteins. These are molecules involved in antigen-signalling cascades, co-stimulatory molecules, proteins involved in apoptosis and proteins that clear antigen or antigen:antibody complexes
- Deficiencies in complement proteins C2 and C4 and thus reduces ability to clear immune complexes are associated with a predisposition to systemic lupus erythematous (SLE)
- Predisposition to common autoimmune diseases- due to multiple genes and or extrinsic factors.
Monogenic autoimmune disease
There are some monogenic autoimmune diseases where a mutant allele confers a very high risk of disease but these variants are rare. The disease autoimmune polyendrinopathy syndrome (APECED) is a recessive autoimmune disease caused by a defect in the gene AIRE (autoimmune regulator gene).
Autoimmune disease Genetic predisposition- the role of HLA
- HLA allele that does not bind self-antigen with high affinity = self-reactive T cells not deleted in thymus
- Certain HLA haplotype does not automatically result in development of an autoimmune disease
- HLA- main genetic factors, involved in antigen presentation
- A mutant HLA allele will not bind to self antigens with high affinity, it will not present that self-reactive antigen and the self reactive T-cell will not be deleted in the thymus
Certain HLA alleles are linked to specific autoimmune processes
- HLA-DR4 - rheumatoid arthritis
- HLA-DQ8 - coeliac disease
- HLA-B27 - ankylosing spondylitis. Not a big link though most people with the condition have the mutation, most people with the mutation don’t have the condition
- HLA-DR3 – SLE & myasthenia gravis
Certain HLA alleles are linked to specific autoimmune processes
- HLA-DR4 - rheumatoid arthritis
- HLA-DQ8 - coeliac disease
- HLA-B27 - ankylosing spondylitis. Not a big link though most people with the condition have the mutation, most people with the mutation don’t have the condition
- HLA-DR3 – SLE & myasthenia gravis
Autoimmune disease- Loss of suppression
- Peripheral tolerance to self-epitopes can be induced by Treg cells. They suppress the action of T cells that are reacting to self antigens
- Treg cells may decline with age thus self-reactive cells may escape regulation and initiate autoimmune diseases
- Pattern of increasing risk with age seen with SLE
Autoimmune disease- Extrinsic factors
- Environmental factors i.e. geographical distribution, strong influence but poorly understood. Areas with low vitamin D levels, stress, occupation and a westernised diet
- Infections- molecular mimicry
- Drugs and toxins- can mimic autoimmune symptoms, hard to differentiate between a true SLE and drug induced lupus (DILE) especially if the patient is being treated with drugs i.e. TNF blockers for a pre-existing autoimmune disease
- Neoantigens- modified self antigens: Environmental agents (can modify self antigens causing a condition which mimics autoimmunity), Tissue injury and inflammation, Post-translational modifications
- Mimicked autoimmunity should cease upon removal of the agent but it can trigger true autoimmunity
Autoimmune disease- Extrinsic factors
- Environmental factors i.e. geographical distribution, strong influence but poorly understood. Areas with low vitamin D levels, stress, occupation and a westernised diet
- Infections- molecular mimicry
- Drugs and toxins- can mimic autoimmune symptoms, hard to differentiate between a true SLE and drug induced lupus (DILE) especially if the patient is being treated with drugs i.e. TNF blockers for a pre-existing autoimmune disease
- Neoantigens- modified self antigens: Environmental agents (can modify self antigens causing a condition which mimics autoimmunity), Tissue injury and inflammation, Post-translational modifications
- Mimicked autoimmunity should cease upon removal of the agent but it can trigger true autoimmunity
Autoimmune disease- enzyme PAD
Tissue injury and inflammation can induce activity of the enzyme PAD which converts the amino acid arginine into citrulline leading to structural alterations of self protein which causes the immune system to view it as non-self. Post translational changes I.e. oxidation, glycosylation of self proteins act as neoantigens.
Molecular mimicry
- Infections can mimic self antigens
- Microbe infects bearing antigen with epitopes similar to some found on host cells
- Response (e.g. Abs) generated against microbial epitope
- Anti-microbial Abs can bind to cross-reactive epitopes on host cells causing injury to host tissues. Will only bind if the microbial and self epitopes are sufficiently similar in structure
- Examples: T1DM – Cocksackie virus & CMV cross-react with glutamate decarboxylase which is a main target for autoreactive T cells. Myasthenia gravis – polio virus, the affected acetylcholine receptor shares structural similarities with poliovirus proteins
Causes of autoimmune disease
Auto-immune disease tends to be multi-factorial and is likely caused by a series of random events.
A breakdown in central tolerance is usually due to genetics such as HLA haplotype, certain mutations in immune components and gender
A breakdown in peripheral tolerance is more likely due to extrinsic factors such as environmental agents, certain drugs and tissue injury and inflammation which can trigger autoimmunity
Tolerance
Failure to respond in an aggressive way against an epitope recognised by the immune system i.e. the mechanisms preventing T and B cell from responding to self antigens. T and B cells randomly recombine genes for receptors and so there is a risk of producing receptors that react with self-antigen. These must be eliminated to make the host more tolerant to itself.
Central tolerance
Elimination of self-reactive T cells (in the thymus) and B cells (in the bone marrow) during early development by the process of negative selection (also known as early clonal deletion).
Peripheral tolerance
Results from mechanisms that inactivate (via anergy) or eliminate B and T cells that are in the circulation:
• Anergy: Inactivation of B and T cells when naïve lymphocytes bind via their B or T cell receptor (first signal) but fail to receive a second activation signal (provided by a T cell for a B cell and a professional APC (antigen presenting cell) for a T cell).
• Suppression: Tolerance to self-epitopes can be induced by regulatory T (Treg) cells, who can a bit like the police and are able to suppress immune responses to self antigens.
• Sequestration of antigens behind a physical barrier: T cells entering immune privileged sites, e.g. the testis, brain and anterior chamber of the eye, undergo apoptosis, e.g. via Fas.
Autoimmune disease classification
- Organ specific- Autoantigens specific to the organ i.e. diabetes
- Systemic- more ubiquitous autoantigens i.e. SLE
- Depends on how widespread the autoantigens are which are causing the response
- Difficult to classify autoimmune diseases
Autoimmune disease classification- type II hypersensitivity
Antibody mediated. ADCC (Antibody Dependent Cell-mediated Cytotoxicity), complement activation, phagocytosis or direct effect on the receptor. Tend to be organ specific autoimmune diseases i.e. Grave’s where autoantibodies stimulate the receptor or MG where autoantibodies block the receptor
Autoimmune disease- type III hypersensitivity
Immune complex-mediated. Ag-Ab lattices form and deposit i.e. in blood vessels and trigger inflammation when not cleared. Associated with systemic autoimmune diseases i.e. SLE which causes increased immune complex formation or decreased immune complex clearance
Autoimmune disease- type IV hypersensitivity
Cell-mediated. Slow onset, tissue damage from persistent T cell (CD4) mediated cytokine release which activate Macrophages for phagocytosis i.e. in rheumatoid arthritis. Can be direct tissue damage from CD8 T-cells i.e. in diabetes
Antibody mediated immune response
- Immune cells engaged to destroy pathogen.
- Pathogen eliminated
- Immune response stops
- Most effector cells die off
- Small number of memory cells persist
Autoantibody mediated tissue damage
- Self-antigen not easily eliminated due to vast quantity in body
- B cells bind to self-antigens and release autoantibodies. The autoantibodies will bind to further self antigens, you will get persistent antigen-antibody binding as well as immune complex formation (type III hypersensitivity) which will trigger an inflammatory response causing more cell injury and death.
- This attracts non-specific effector cells such as Macrophages and Neutrophils which respond to the release of cytokines from dying tissue. Creates a positive feedback loop as more B cells react to more self-antigens amplifying the cycle of tissue damage
Phases of tissue damage in Autoantibody mediated tissue damage
- Early activation phase – few autoantigens involved
* Chronic stage – constant presence of autoantigen due to tissue damage - chronic autoantibody-mediated inflammation
Cell mediated tissue damage
- Inflammation and infection leads to cytokine release which can activate autoreactive T cells, normally these T cells are anergic till they receive activation
- Type IV hypersensitivity
- Site of infection and inflammation- local cytokine levels may be sufficient to activate autoreactive T cells when they are binding to the self-epitopes on non-antigen presenting cells. The activates T cells can then cause direct damage or further cytokine production
