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Questions and Answers
What role do APCs play in maintaining tolerance in the absence of infection?
What role do APCs play in maintaining tolerance in the absence of infection?
How can microbial antigens contribute to autoimmune responses?
How can microbial antigens contribute to autoimmune responses?
Which process describes how self antigens can be recognized as foreign?
Which process describes how self antigens can be recognized as foreign?
What can lead to the release of sequestered antigens into the immune system?
What can lead to the release of sequestered antigens into the immune system?
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What is a characteristic of cryptic self epitopes?
What is a characteristic of cryptic self epitopes?
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Which of the following correctly describes the role of haptens in altering self antigens?
Which of the following correctly describes the role of haptens in altering self antigens?
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Which statement best describes the outcome of APCs expressing B7 in response to infection?
Which statement best describes the outcome of APCs expressing B7 in response to infection?
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What is the main consequence of the breakdown of tolerance to self antigens?
What is the main consequence of the breakdown of tolerance to self antigens?
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Which mechanism involves the activation of T cells by self antigens without the presence of additional signals?
Which mechanism involves the activation of T cells by self antigens without the presence of additional signals?
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Which mechanism does NOT contribute to the recognition of self antigens as foreign?
Which mechanism does NOT contribute to the recognition of self antigens as foreign?
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What is molecular mimicry in the context of autoimmune diseases?
What is molecular mimicry in the context of autoimmune diseases?
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What happens to immature B cells that bind to self antigens during development?
What happens to immature B cells that bind to self antigens during development?
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Which mechanism involves the recognition of previously hidden or buried epitopes leading to autoimmune responses?
Which mechanism involves the recognition of previously hidden or buried epitopes leading to autoimmune responses?
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What role do Treg cells play in maintaining peripheral tolerance?
What role do Treg cells play in maintaining peripheral tolerance?
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Which of the following best describes altered self in the context of autoimmune disease development?
Which of the following best describes altered self in the context of autoimmune disease development?
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The display of sequestered antigens typically leads to which immune response?
The display of sequestered antigens typically leads to which immune response?
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What is the role of CD25 in T cell inhibition?
What is the role of CD25 in T cell inhibition?
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Which cytokines are secreted by Treg cells to inhibit immune responses?
Which cytokines are secreted by Treg cells to inhibit immune responses?
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What is the consequence for an immature B cell that binds to a self antigen with high avidity?
What is the consequence for an immature B cell that binds to a self antigen with high avidity?
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What happens to B cells that are regularly stimulated by self-antigens without T cell help?
What happens to B cells that are regularly stimulated by self-antigens without T cell help?
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Which receptor regulates B cell activation in response to self antigens?
Which receptor regulates B cell activation in response to self antigens?
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How do immature B cells that bind self antigens with low avidity respond?
How do immature B cells that bind self antigens with low avidity respond?
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What is a proposed mechanism of peripheral tolerance in B cells?
What is a proposed mechanism of peripheral tolerance in B cells?
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Which mechanism allows Treg cells to negatively regulate self-reactive lymphocytes?
Which mechanism allows Treg cells to negatively regulate self-reactive lymphocytes?
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What type of hypersensitivity mechanisms are primarily involved in organ-specific autoimmunities?
What type of hypersensitivity mechanisms are primarily involved in organ-specific autoimmunities?
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Which of the following diseases is classified as a systemic autoimmune disorder?
Which of the following diseases is classified as a systemic autoimmune disorder?
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What is the primary mode of action of fingolimod in treating Multiple Sclerosis?
What is the primary mode of action of fingolimod in treating Multiple Sclerosis?
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How do autoantibodies contribute to the development of systemic lupus erythematosus?
How do autoantibodies contribute to the development of systemic lupus erythematosus?
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Which immunotherapy is used in treating Rheumatoid Arthritis by targeting cytokines?
Which immunotherapy is used in treating Rheumatoid Arthritis by targeting cytokines?
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What differentiates organ-specific autoimmunities from systemic autoimmunities?
What differentiates organ-specific autoimmunities from systemic autoimmunities?
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Which immunotherapy is aimed specifically at treating systemic lupus erythematosus?
Which immunotherapy is aimed specifically at treating systemic lupus erythematosus?
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What is a major mechanism by which multiple sclerosis results in neurological damage?
What is a major mechanism by which multiple sclerosis results in neurological damage?
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What is the primary mechanism of cellular damage in Type 1 Diabetes Mellitus?
What is the primary mechanism of cellular damage in Type 1 Diabetes Mellitus?
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Which of the following best describes the role of autoantibodies in Multiple Sclerosis?
Which of the following best describes the role of autoantibodies in Multiple Sclerosis?
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What is a potential trigger for the autoimmune response in Type 1 Diabetes Mellitus?
What is a potential trigger for the autoimmune response in Type 1 Diabetes Mellitus?
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In Multiple Sclerosis, what is the role of the blood-brain barrier?
In Multiple Sclerosis, what is the role of the blood-brain barrier?
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Which therapy modulates S1P receptors to treat Multiple Sclerosis?
Which therapy modulates S1P receptors to treat Multiple Sclerosis?
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What type of immune response primarily contributes to the cellular damage in both Type 1 Diabetes Mellitus and Multiple Sclerosis?
What type of immune response primarily contributes to the cellular damage in both Type 1 Diabetes Mellitus and Multiple Sclerosis?
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What is one of the roles of autoreactive T cells in the context of Multiple Sclerosis?
What is one of the roles of autoreactive T cells in the context of Multiple Sclerosis?
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Which cytokine profile is likely to be involved in the local inflammation seen in Type 1 Diabetes Mellitus?
Which cytokine profile is likely to be involved in the local inflammation seen in Type 1 Diabetes Mellitus?
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In the context of Multiple Sclerosis, what does the term 'CMI response' refer to?
In the context of Multiple Sclerosis, what does the term 'CMI response' refer to?
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What is a characteristic feature of the immune response in Type 1 Diabetes Mellitus?
What is a characteristic feature of the immune response in Type 1 Diabetes Mellitus?
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What is the primary immune response involved in Multiple Sclerosis?
What is the primary immune response involved in Multiple Sclerosis?
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Which autoantibody is primarily associated with Systemic Lupus Erythematosus (SLE)?
Which autoantibody is primarily associated with Systemic Lupus Erythematosus (SLE)?
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What type of autoimmune response characterizes Rheumatoid Arthritis?
What type of autoimmune response characterizes Rheumatoid Arthritis?
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What is one of the main outcomes of the immune response in SLE?
What is one of the main outcomes of the immune response in SLE?
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Which biological therapy is an anti-BLyS agent used for SLE?
Which biological therapy is an anti-BLyS agent used for SLE?
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What mechanism does Anifrolumab-fnia use to exert its effect?
What mechanism does Anifrolumab-fnia use to exert its effect?
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Which of the following diseases is associated with antibodies against thyroid peroxidase?
Which of the following diseases is associated with antibodies against thyroid peroxidase?
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What is the outcome of the immune response in pernicious anemia?
What is the outcome of the immune response in pernicious anemia?
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Which type of antibodies are typically produced in Type 1 diabetes mellitus?
Which type of antibodies are typically produced in Type 1 diabetes mellitus?
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What is the main cellular mechanism involved in the destruction of myelin in Multiple Sclerosis?
What is the main cellular mechanism involved in the destruction of myelin in Multiple Sclerosis?
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What does the presence of anti-CCP antibodies indicate?
What does the presence of anti-CCP antibodies indicate?
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What is the primary target of the immune response in Hashimoto thyroiditis?
What is the primary target of the immune response in Hashimoto thyroiditis?
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Which autoimmune disease features both Type II and Type IV immune responses?
Which autoimmune disease features both Type II and Type IV immune responses?
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What is the consequence of the autoantibodies in autoimmune diseases like SLE and RA?
What is the consequence of the autoantibodies in autoimmune diseases like SLE and RA?
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Study Notes
Tolerance
- In absence of infection, APCs present self-antigens but not B7, thereby maintaining tolerance.
- APCs express B7 when induced by a microbe, presenting both foreign and self-antigens in MHC molecules.
- Activated APCs provide B7 co-stimulation to both microbe-specific and self-reactive T cells.
- Activation of self-reactive T cells can result in autoimmunity.
Molecular Mimicry
- Microbial antigens similar to self-antigens can activate T and B cells, producing cross-reacting antibodies and/or CTLs (cytotoxic T lymphocytes).
Altered Self
- Self-antigens can be altered and recognized as foreign.
- Haptens can bind to self-antigens, creating a new antigen that can stimulate an autoimmune response.
- Enzymatic modifications like citrullination can change the original antigen structure and make it recognized as foreign.
Release of Sequestered Antigens
- Immune-privileged sites (brain, eye, ovary, testis) sequester self-antigens from the immune system.
- These sequestered antigens might not be exposed to developing lymphocytes, failing to induce central tolerance.
- Immune system exposure through tissue damage caused by injury or infection can lead to recognition of these newly revealed antigens as foreign.
Cryptic Self Epitopes
- Molecules can shield epitopes from contact with the immune system.
- Denaturation or conformational changes in the molecule can expose these epitopes, triggering an immune response.
Immune Response Against Self-Antigens
- Cell-mediated and humoral responses can occur against self-antigens when tolerance fails.
- Helper T cells activate macrophages and cytotoxic T cells, causing inflammation and tissue damage.
- Helper T cells assist B cell activation and antibody production, which can damage tissue.
Summary of Tolerance Mechanisms
- Tolerance is unresponsiveness to self-antigens.
- Central tolerance is negative selection in primary lymphatics.
- Immature B cells binding to self-Ag become anergic, undergo apoptosis, or receptor editing.
- Immature T cells binding to MHC+self-Ag are deleted via apoptosis or differentiate into Treg cells for peripheral tolerance.
- Peripheral tolerance mechanisms occur in secondary lymphatics.
- B and T cells: Absence of costimulation leads to anergy; self-antigen recognition can trigger apoptosis.
- B cells: May express inhibitory receptors when encountering self-antigens.
- Treg cells: Secrete immunosuppressive cytokines like IL-10 and TGF-β; perforin/granzymes; CD25 sequesters IL-2; and express inhibitory receptors like CTLA-4.
Breakdown of Tolerance: Autoimmunity
- Genetic susceptibility to AI development, including MHC alleles and other factors.
- Five proposed mechanisms for breaking tolerance: bystander T cell activation, molecular mimicry, altered self, release of sequestered antigens, and cryptic self epitopes.
- Autoreactive B and T cell immune responses against self-antigens cause tissue damage.
Treg Cells
- Treg cells inhibit the activation, activity, and survival of self-reactive lymphocytes.
- They inhibit T cell proliferation by CD25 binding and sequestering IL-2.
- They secrete inhibitory cytokines: IL-10, TGF-β, and IL-35.
- They down-modulate APCs by CTLA-4 binding to B7 (CD80/CD86).
B Cell Central Tolerance
- Central tolerance develops during B cell maturation.
- Immature B cells with high avidity binding to self-antigens can undergo receptor editing for a non-self-reactive BCR and complete maturation.
- If receptor editing fails, the B cell remains self-reactive and undergoes apoptosis.
- Immature B cells with low avidity binding to self-antigens become anergic (unresponsive) with downregulated BCRs or reduced signaling capacity upon release from the bone marrow.
B Cell Peripheral Tolerance
- Proposed mechanisms:
- B cells repeatedly stimulated by self-antigens without T cell help become anergic or deleted.
- Regulation by the inhibitory receptor CD22 sets a threshold for B cell activation.
- CD22 on B cells binds to sialic acids on host cells, inhibiting activation against self-antigens.
Autoimmune Disorders
- Autoimmune diseases are either organ-specific or systemic.
- Organ-specific autoimmune diseases affect certain organs, glands, tissues.
- Systemic autoimmune disorders create autoantibodies against antigens found in various tissues.
Organ-Specific Autoimmune Diseases
- Organ-specific immune responses may involve Type II or Type IV hypersensitivity mechanisms.
Type 1 Diabetes Mellitus (T1DM)
- Autoantibodies and autoreactive T cells damage pancreatic beta cells.
- Delayed-type hypersensitivity (DTH) represents a primary cytotoxic process in T1DM.
- Effector cytotoxic T lymphocytes (CTLs) destroy pancreatic beta cells.
- Effector T helper 1 (TH1) cytokines contribute to local inflammation.
- Various autoantibodies are detectable in T1DM patients.
- Antibodies can activate complement or trigger antibody-dependent cellular cytotoxicity (ADCC).
Multiple Sclerosis (MS)
- Autoantibodies and autoreactive T cells damage the central nervous system (CNS).
- Infections or tissue injury might disrupt the blood-brain barrier (BBB), leading to the release of CNS antigens or the entry of self-reactive T cells into the CNS.
- Cell-mediated immunity (CMI) involves T cells and macrophages infiltrating the CNS.
- These immune cells target self-antigens on nerves, such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG).
- Humoral immunity plays a role.
- Autoantibodies to MBP, or other antigens, activate complement or induce ADCC.
Immunotherapies for MS
- Fingolimod and Ozanimod: S1P receptor agonists that diminish S1PR1 expression.
- The downregulation of S1PR1 retains lymphocytes within lymphatic tissues.
Systemic Autoimmune Diseases
- Systemic autoimmune diseases primarily involve Type III hypersensitivity responses.
- They can also include Type II and/or Type IV responses.
Systemic Lupus Erythematosus (SLE)
- Autoantibodies against double-stranded DNA (dsDNA) and Sm antigen, a nuclear protein, are characteristic.
Rheumatoid Arthritis (RA)
- RA involves autoantibodies against immunoglobulin G (IgG) and citrullinated peptides.
- Rheumatoid factor, anti-citrullinated peptide antibodies (anti-CCP), and anti-modified citrullinated vimentin (anti-MCV) antibodies are prominent.
Immunotherapies for SLE and RA
- Belimumab (Benlysta®) is a monoclonal antibody that neutralizes B lymphocyte stimulator (BLyS), a B cell growth factor.
- Anifrolumab-fnia (Saphnelo®) is a humanized monoclonal antibody that binds to interferon alpha receptor 1 (IFNAR1) with high specificity and affinity.
- This binding blocks type I interferon activity.
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Description
This quiz explores concepts of immune tolerance including the role of antigen-presenting cells (APCs) and mechanisms leading to autoimmunity. It delves into molecular mimicry and how altered self-antigens can trigger immune responses. Test your understanding of these crucial immunological principles.
