Podcast
Questions and Answers
What is the primary role of rheumatoid factor in the immune response?
What is the primary role of rheumatoid factor in the immune response?
Which condition is commonly associated with the production of rheumatoid factor?
Which condition is commonly associated with the production of rheumatoid factor?
What process is involved in managing immature B cells that are self-reactive?
What process is involved in managing immature B cells that are self-reactive?
What causes the immune response to cross-react with self-antigens during an infection?
What causes the immune response to cross-react with self-antigens during an infection?
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Which of the following best describes the nature of autoimmunity?
Which of the following best describes the nature of autoimmunity?
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What can result from damage to certain barriers, such as the testes barrier?
What can result from damage to certain barriers, such as the testes barrier?
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Which mutation is typically linked to defective mechanisms that regulate T cell responses?
Which mutation is typically linked to defective mechanisms that regulate T cell responses?
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What role do cryptic antigens play in autoimmunity?
What role do cryptic antigens play in autoimmunity?
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What is a common genetic predisposition to autoimmunity mentioned?
What is a common genetic predisposition to autoimmunity mentioned?
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Which condition can result from a defect in the Fas/FasL apoptotic mechanism?
Which condition can result from a defect in the Fas/FasL apoptotic mechanism?
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What can trigger the misdirected immune response associated with normal (misdirected) response option 1?
What can trigger the misdirected immune response associated with normal (misdirected) response option 1?
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What role do MHC genes play in autoimmunity?
What role do MHC genes play in autoimmunity?
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In what way can molecular changes contribute to autoimmunity?
In what way can molecular changes contribute to autoimmunity?
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Which of the following conditions is associated with the presence of autoantibodies against liver membrane proteins?
Which of the following conditions is associated with the presence of autoantibodies against liver membrane proteins?
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What is an effect of selective breeding for rare dog breeds in relation to autoimmunity?
What is an effect of selective breeding for rare dog breeds in relation to autoimmunity?
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What occurs during a heart attack that can trigger an autoimmune response?
What occurs during a heart attack that can trigger an autoimmune response?
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Which statement accurately reflects the available treatment options?
Which statement accurately reflects the available treatment options?
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What phenomenon is demonstrated by a vaccinated patient gaining enhanced immunity against unrelated viruses?
What phenomenon is demonstrated by a vaccinated patient gaining enhanced immunity against unrelated viruses?
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Which of these is a common misconception about DNA synthesis inhibitors?
Which of these is a common misconception about DNA synthesis inhibitors?
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Which of the following is NOT a function of radiation as related to immune response?
Which of the following is NOT a function of radiation as related to immune response?
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Which of the following statements about folic acid antagonists is misleading?
Which of the following statements about folic acid antagonists is misleading?
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Which statement about autoimmune diseases is not true?
Which statement about autoimmune diseases is not true?
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The phenomenon where antibodies against a parasite attack host myocardial cells is an example of which process?
The phenomenon where antibodies against a parasite attack host myocardial cells is an example of which process?
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A cryptic epitope refers to which of the following?
A cryptic epitope refers to which of the following?
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In the case of a young Doberman displaying signs of obesity and hair loss due to suspected autoimmune disorder, which of the following is likely false?
In the case of a young Doberman displaying signs of obesity and hair loss due to suspected autoimmune disorder, which of the following is likely false?
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Which of the following best describes the role of molecular mimicry in autoimmune diseases?
Which of the following best describes the role of molecular mimicry in autoimmune diseases?
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Which of the following statements about cryptic epitopes is true?
Which of the following statements about cryptic epitopes is true?
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Which mechanism primarily contributes to tissue damage in autoimmune diseases?
Which mechanism primarily contributes to tissue damage in autoimmune diseases?
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In a patient with suspected autoimmune thyroiditis, which lab finding would most likely be observed?
In a patient with suspected autoimmune thyroiditis, which lab finding would most likely be observed?
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Which virus is known to cause bystander effects in autoimmunity?
Which virus is known to cause bystander effects in autoimmunity?
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What autoimmune disorder is triggered by Streptococcus pyogenes infection?
What autoimmune disorder is triggered by Streptococcus pyogenes infection?
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What is a common consequence of Myasthenia gravis?
What is a common consequence of Myasthenia gravis?
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Which of the following conditions is specifically linked to an autoimmune response involving antibodies against thyroid peroxidase?
Which of the following conditions is specifically linked to an autoimmune response involving antibodies against thyroid peroxidase?
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Which pathogen is associated with Equine Recurrent Uveitis?
Which pathogen is associated with Equine Recurrent Uveitis?
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Which autoimmune condition is associated with pemphigus vulgaris?
Which autoimmune condition is associated with pemphigus vulgaris?
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What type of hypersensitivity is associated with Insulin dependent diabetes mellitus in dogs?
What type of hypersensitivity is associated with Insulin dependent diabetes mellitus in dogs?
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What role do adjuvants play in vaccine-induced autoimmune reactions?
What role do adjuvants play in vaccine-induced autoimmune reactions?
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What clinical sign is related to Equine Polyneuritis resulting from autoimmune damage?
What clinical sign is related to Equine Polyneuritis resulting from autoimmune damage?
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Which specific autoimmune condition is linked to antibodies against keratinocytes?
Which specific autoimmune condition is linked to antibodies against keratinocytes?
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What condition is characterized by high T4 hormone levels in a dog?
What condition is characterized by high T4 hormone levels in a dog?
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Alopecia areata is primarily associated with which of the following?
Alopecia areata is primarily associated with which of the following?
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What is the mechanism of action of cyclophosphamide in cancer treatment?
What is the mechanism of action of cyclophosphamide in cancer treatment?
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Which autoimmune condition involves antibody destruction of collagen and laminin?
Which autoimmune condition involves antibody destruction of collagen and laminin?
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Which immunosuppressive drug acts by blocking calcineurin?
Which immunosuppressive drug acts by blocking calcineurin?
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Which vitamin is known for its immune-stimulating properties?
Which vitamin is known for its immune-stimulating properties?
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What is the primary effect of the BCG vaccine in trained immunity?
What is the primary effect of the BCG vaccine in trained immunity?
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What type of immunosuppression is characterized by blocking specific immune responses?
What type of immunosuppression is characterized by blocking specific immune responses?
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What common element is involved in the immune response and cell death regulation?
What common element is involved in the immune response and cell death regulation?
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Methotrexate has what primary role in cancer treatment?
Methotrexate has what primary role in cancer treatment?
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Study Notes
Autoimmunity & Immunomodulation
- This week's topic is autoimmunity and immunomodulation.
- Autoimmunity involves a chronic, progressive, and self-perpetuating immune response that targets the body's own tissues.
- It's often linked to hormonal and genetic factors, but rarely has obvious predispositions.
- Autoimmunity occurs via an immune reaction involving humoral or cell-mediated response.
- A key characteristic is the lack of tolerance induction or maintenance.
- Autoimmunity can be systemic or organ-specific.
- Genetic predispositions involve deletions or overexpression of genes, often related to MHC genes.
- Specific examples of genetic predisposition include selective breeding in dogs for certain traits which results in autoimmune susceptibility.
- A specific example of genetic conditions are mutations in DLA-A3, 7, 10 and B4 genes, which cause diabetes mellitus.
- Breed-specific aggressive phenotypes can lead to the expression of deleterious recessive genes, subsequently losing MHC polymorphism.
Autoimmunity
- Autoimmunity is a breakdown of self-tolerance.
- There are mechanisms of how the immune system attacks the self.
- Normal response vs. Abnormal response, Hormonal influences, Genetic predisposition.
- Previously hidden antigens are exposed (cryptic antigens) and the immune system reacts in response.
- Molecular changes where normal proteins develop new epitopes.
- Molecular mimicry where a pathogen's antigen triggers a response against a similar self-antigen.
Normal(Misdirected) Response- Option 1: Cryptic Antigens
- Hidden antigens, exposed by injury/breakdowns such as blood-testes barrier breaks.
- Results in stimulation of autoimmunity.
- Examples include heart attack exposing mitochondria which causes autoimmunity against heart muscle.
- Bacterial induced damage can induce autoantibodies against normal tissue (non-self).
- Hepatitis causing liver membrane protein autoantibodies.
Normal(Misdirected) Response- Option 2: Molecular Changes
- Normal proteins can develop new epitopes.
- Autoantibodies directed against complement components C2, C4, and C3, upon their activation.
- The immune system doesn't recognize the protein anymore.
Rheumatoid Factor
- Rheumatoid factor (RF) are antibodies directed against other immunoglobulins (antibodies).
- RF is altered and new antigens are displayed when an immunoglobulin binds an antigen.
- Rheumatoid factor is only present in diseased states like lupus or arthritis.
Normal(Misdirected) Response-Option 3: Receptor Editing
- B cells can undergo central and peripheral tolerance.
- Not a perfect system.
- Receptor editing is supposed to handle immature B cells that are self-reactive and removes them if they are to recognize self.
- Mature B cells that recognize self undergo apoptosis.
Principle Causes of Autoimmunity
- Genetic condition: MHC gene variants strongly associated with autoimmunity.
- Abnormally display self antigens.
- Inflammation causes localized auto-immune reactions.
- Normally hidden antigens exposed during tissue damage.
- Lymphocytes are not tolerant to hidden antigens.
- Examples include damage to the testes barrier causing antigens against sperm.
- Myocardial infarction can lead to antibody formation against heart muscle mitochondria.
- During normal responses, response cross-reacts to a self-antigen when exposed to a pathogen. This includes physiological aging, such as RBCs shedding CD47.
Normal (Misdirected) Response-Option 4: Molecular Mimicry
- Pathogen antigens resembling host antigens induce an immune response.
- Immune response also targets similar host antigens.
- The response occurs only when B cells receive help from T cells.
- An example is Trypanosoma cruzi triggering cross-reaction to heart and neurons (Chagas disease).
Molecular Mimicry
- Self-antigens are bound at the same time as foreign antigens.
- Antibodies are created for both the foreign and self-antigen.
- Mycoplasma in swine and cattle cross-react with lung antigens.
- Lepto cross-reacts with eye antigens causing recurrent uveitis.
- Lyme cross-reacts with LFA-1 (leukocyte extravasation).
Abnormal Immune Response
- Lack of regulatory mechanisms.
- Defective AIRE (autoimmune regulator) gene.
- Associated with myasthenia gravis and thymic carcinoma.
- Rheumatoid arthritis is 4x more likely in malignant lymphoid tumor patients.
- Defect in Fas/FasL mechanism; no apoptosis.
- Mutation encoding apoptotic mechanism, T cells cannot recognize and destroy self.
Infection-Induced Autoimmunity
- Reovirus and Coxsackie B can produce antibodies against nucleic acid and red blood cells.
- Viruses can have molecular mimicry.
- Bystander effect means antigens induce an immune reaction of naive cells (not previously activated).
- These are non-specific.
- Streptococcus pyogenes have autoimmune response to the heart.
- Lepto and Lyme cross-react with eye antigens causing uveitis/arthritis.
Autoimmune Disorders
- Various autoimmune diseases exist.
Autoimmune Vaccine Reactions
- Influenza vaccine linked to Guillain-Barré syndrome.
- Rabies vaccine linked to anti-thyroglobulin antibodies (hypothyroidism) in beagles.
- Vaccination linked to immune-mediated hemolytic anemia in puppies.
- Adjuvants sometimes trigger antibody development.
Autoinflammatory Diseases
- Extensive and uncontrolled inflammation.
- Innate autoimmune initiated.
- Examples include lupus erythematosus, Sjogren's syndrome, polyarthritis, and immune vasculitis.
Endocrine-Specific Autoimmunity
- Autoimmune Lymphocytic Thyroiditis (a type 2 hypersensitivity reaction) is common in young Dobermans and chickens.
- Antibodies against thyroid peroxidase or thyroglobulin block T4 and T3 release, leading to hypothyroidism. Symptoms include obesity, hair loss, and hyperpigmentation.
- Thyroid tissue is infiltrated by lymphocytes leading to damage.
- Easily missed in early stages.
- Biopsy for diagnosis and levothyroxine (fake TH4) for treatment.
- Insulin dependent diabetes (type 1) mellitus involves antibodies against islets (beta cells), the production of lymphocytes infiltration in pancreas and NK cell damage via ADCC.
Nerve-Specific Autoimmunity
- Equine polyneuritis, caused by Adenovirus type 1 infection, results in antibodies against myelin in sacral and coccygeal nerves.
- Myasthenia gravis in dogs and cats (like Jack Russells), is hereditary in some breeds.
- Antibodies against acetylcholine receptors in neuromuscular junction cause weak muscles and exercise fatigue rapidly.
- Other conditions include necrotizing meningoencephalitis, degenerative myelopathy, and cerebellar degeneration,.
Eye-Specific Autoimmunity
- Recurrent uveitis, retinitis, and vasculitis are potentially blinding conditions, with antibodies against retinoids and proteins causing deposits of fibrin and collagen.
- Viral molecular mimicry plays a role (Borrelia burgdorferi and Onchocerca).
- Uveodermatological syndromes cause uveitis, retinitis, and skin depigmentation with lymphocyte infiltration.
- Macrophages in the uveal tract eat melanin causing retina detachment and blindness.
- Immune-mediated keratoconjunctivitis is another condition.
Skin-Specific Autoimmunity
- Antibodies against hair follicles, causing hypotrichosis (e.g., alopecia areata).
- Antibodies against keratinocytes, causing pemphigus (vulgaris and foliaceous).
- Vulgaris targets desmoglein 3 adhesion molecule.
- Foliaceous targets desmoglein 1 adhesion molecule.
- Diseases result in skin separation, bullous (blister) formation and either dermis (middle) or epidermis (top) sloughing.
- Bollous pemphigoid antibodies react to collagen and laminin in basement membranes causing inflammation and separation at basement membrane layers
Non-Specific Immunosuppression
- Cytotoxic drugs like alkylating agents (cyclophosphamide) cross-link DNA to stop cell division.
- Toxic to resting and dividing cells, especially cells of the immune system (T and B), leading to bone marrow suppression.
- Folic acid antagonist methotrexate inhibits tetrahydrofolate needed to make thymidine and purine nucleotides for DNA synthesis.
- Treats conditions like rheumatoid arthritis, and in chemotherapy for cancer.
- DNA synthesis inhibitors (azathioprine) suppress lymphocyte activity, inhibit DNA and RNA synthesis, and have a toxic effect on bone marrow, pancreas, and GIT.
- Radiation stops cell division and causes collateral DNA damage.
- Corticosteroids stimulate IkBa to block cytokine synthesis but inhibit inflammation and have immunosuppressive activity
Selective Immunosuppression
- Calcineurin inhibitors (cyclosporine, tacrolimus) block calcineurin, which results in inhibition of IL-2 and other cytokines from T-cells, and signal transduction.
- Suppresses macrophages and inhibits other cell responses (leukocytes)
- Rapamycin blocks mTOR (mechanistic target of rapamycin) to regulate T-cell activation.
- JAK inhibitors (such as oclacitinib) block the JAK-STAT signaling pathway to control cytokines like IL-2,IL-4, IL-6, IL-13, IL-31
Immune Stimulating
- Bacterial products (PAMPs), TLR stimulation, and cytokine synthesis activate macrophages.
- Complex carbohydrates activate macrophages.
- Vitamins A, D, and E are immune stimulatory.
- Cytokines IL-2 and recombinants interferons alpha and gamma stimulate the immune response.
Trained Immunity
- BCG vaccination enhances pro-inflammatory cytokines (IL-1β, TNFα, IL-6) and has transcriptional, epigenetic, and metabolic reprogramming of myeloid cells.
- Effects include increased responsiveness to other pathogens.
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