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Questions and Answers
What therapeutic strategy is primarily utilized in disease-modifying treatments for autoimmune disorders?
How do FcRn inhibitors exert their therapeutic effects in autoimmune conditions?
In the context of hypersensitivity reactions, what does autoimmunity specifically refer to?
Which population percentage is noted to have abnormal responsiveness to common environmental substances?
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What type of antibodies are produced by individuals who exhibit allergic reactions to environmental antigens?
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Which classification is NOT part of the Coombs and Gell hypersensitivity types?
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What abnormal reaction may occur in hypersensitivity to microbial antigens?
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Hypersensitivity diseases are primarily classified based on which criteria?
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What role does the immune synapse play in T cell signaling?
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How do corticosteroids primarily activate anti-inflammatory gene expression?
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What functions are associated with the immune synapse in relation to T cells?
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Which of the following is NOT a characteristic of the immune synapse?
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What is the outcome of the degradation of signaling proteins at the immune synapse?
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In the context of immune synapse signaling, what is the role of adaptors?
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Which of the following proteins is NOT typically involved in the anti-inflammatory actions mediated by corticosteroids?
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What process aids corticosteroids in promoting the transcription of anti-inflammatory genes?
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Which of the following mechanisms is NOT associated with T cell anergy?
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What is the primary role of CTLA-4 in the immune response?
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Which of the following is a mechanism by which regulatory T cells (Tregs) suppress immune responses?
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Which ligand does CTLA-4 primarily compete with for binding in T cells?
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How does TGF-β1 produced by Tregs influence T cell function?
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In which scenario is CTLA-4 expressed constitutively at high levels?
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What effect does the engagement of inhibitory receptors of the CD28 family have on T cells recognizing self antigens?
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What is the role of IL-2 in the context of regulatory T cells?
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What is a primary mechanism that leads to graft failure in chronic rejection?
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How does alloantibody binding affect endothelial function?
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What is graft vasculopathy characterized by?
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What role does IL-2 play in the immune response?
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What factor most significantly influences renal allograft survival?
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What commonly occurs after arterial lesions progress in graft arteriosclerosis?
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In the context of chronic rejection, which cytokine is primarily associated with the proliferation of vascular smooth muscle cells?
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Which of the following accurately describes the outcome of mismatched HLA alleles in live donor renal allografts?
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What is the primary mechanism of tissue injury in immune complex-mediated diseases (ICMD)?
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Which type of T lymphocytes are primarily responsible for inducing inflammation in T cell-mediated diseases?
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In which scenario might T lymphocyte-mediated tissue injury be observed?
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Which statement correctly describes the nature of immune complexes in immune complex-mediated diseases?
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What effect does complement fixation on the RBC surface have?
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What is commonly observed in the glomerulus of patients with systemic lupus erythematosus (SLE)?
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What triggers the inflammation associated with immune complex-mediated diseases?
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Which type of immune response is most directly associated with tissue injury in organ-specific autoimmune diseases?
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Study Notes
Novel Strategy for Autoimmune Disorders
- Disease-modifying therapies commonly modulate cytokine signaling and/or cellular functions.
- These therapies include kinase inhibitors, cytokine inhibitor monoclonal antibodies (mAbs), and B cell depleting mAbs.
- FcRn inhibitors emerged as a new therapeutic class due to the mechanism of IVIG efficacy, which involves FcRn saturation.
- Cellular therapies are being explored for autoimmune disorders, representing the next generation of treatment.
Hypersensitivity Disorders
- The four types of hypersensitivity reactions are categorized using the Coombs and Gell classification system.
- Hypersensitivity refers to harmful immune responses against foreign antigens, such as environmental antigens, drugs, or microbes.
- In healthy individuals, there is usually no reaction to common environmental substances, but 20% or more of the population has an abnormal response to these substances.
- Individuals with hypersensitivity may produce IgE (immunoglobulin E) antibodies which can cause allergic diseases.
Classification of Hypersensitivity Diseases
- Hypersensitivity diseases are classified based on the type of immune response and the effector mechanism responsible for cell and tissue damage.
Mechanisms of T Cell Anergy
- Anergy occurs when T cells are unable to respond to antigens they recognize.
- Several mechanisms contribute to inducing and maintaining anergy, including blocked TCR-induced signal transduction.
- Self-antigen recognition without costimulation can activate cellular ubiquitin ligases, leading to TCR-associated protein ubiquitination and degradation via proteasomes or lysosomes.
- T cell engagement of inhibitory receptors in the absence of innate immune responses can terminate T cell responses.
Mechanisms of Action of CTLA-4
- CTLA-4 acts as a competitive inhibitor of CD28, reducing the availability of B7 for CD28 binding.
- CTLA-4 is expressed constitutively on Tregs (regulatory T cells) and transiently on activated T cells, preventing T cell activation.
- CTLA-4 on one T cell (a Treg) can inhibit the responses of other T cells.
Actions and Functions of CTLA-4 and PD-1
- CTLA-4 and PD-1 are both immune checkpoint molecules that regulate T cell activation and function.
- PD-1 is expressed on activated T cells and interacts with its ligands PD-L1 and PD-L2, inhibiting T cell responses.
- Both CTLA-4 and PD-1 play critical roles in maintaining immune tolerance and preventing excessive inflammation.
Regulatory T Cells (Tregs)
- Tregs are a specialized population of T cells that suppress immune responses.
- Tregs play a vital role in preventing autoimmune diseases and maintaining immune homeostasis.
- They express the transcription factor FoxP3, which is essential for their development and function.
Role of Interleukin-2 in the Maintenance of Regulatory T Cells
- Tregs suppress immune responses through several mechanisms, including production of immunosuppressive cytokines (IL-10 and TGF-β), reduced ability of APCs to stimulate T cells, and consumption of IL-2.
- IL-2 is crucial for the survival and function of Tregs.
Inhibitory Cytokines Produced by Regulatory T Cells
- TGF-β1 is a key inhibitory cytokine produced by Tregs, activated macrophages, and other cell types.
- TGF-β1 inhibits T cell proliferation and effector functions, as well as macrophage activation.
- It also plays a role in IgA antibody production by promoting B cell class switching and promotes tissue repair following inflammation.
Sequence of Immunologic Responses in Experimental Acute Serum Sickness
- Immune complex-mediated disease occurs when antigen-antibody complexes are deposited in tissues, triggering inflammation and damage.
- Complement activation and leukocyte Fc receptor binding to antibodies in the deposited complexes contribute to the inflammatory response.
Human Immune Complex-Mediated Diseases
- Immune complex-mediated diseases are caused by circulating antigen-antibody complexes that deposit in multiple tissues, leading to systemic disorders.
- These complexes may involve antibodies bound to self or foreign antigens.
- The majority of these diseases are systemic, but a few are restricted to the kidneys.
Mechanisms of T Cell-Mediated Diseases
- T cells injure tissues by producing cytokines that promote inflammation or by directly killing target cells.
- The Th1 and Th17 subsets of CD4+ T cells are primarily responsible for eliciting inflammatory reactions.
- CD8+ CTLs are involved in cell killing in some T cell-mediated disorders.
- T cells that cause tissue injury can be autoreactive or specific for foreign antigens that are present in or bound to cells or tissues.
- T cell-mediated tissue injury can accompany robust protective immune responses against persistent microbes, especially intracellular ones that resist eradication.
T Cell-Mediated Diseases
- Many organ-specific autoimmune diseases arise from autoreactive T cell activation triggered by self antigens, leading to cytokine release and inflammation.
- Alloantibodies can engage Fc receptors on neutrophils and NK cells, leading to endothelial cell killing.
- Alloantibody binding to endothelial surfaces can directly alter endothelial function by inducing proinflammatory and procoagulant molecule expression.
Chronic Rejection
- Arterial occlusion, caused by intimal smooth muscle cell proliferation, is a dominant lesion of chronic rejection in vascularized grafts.
- This leads to graft failure due to ischemic damage and is known as graft vasculopathy or accelerated graft arteriosclerosis.
- Graft vasculopathy is common in failing cardiac and renal allografts and can develop within 6 months to a year after transplantation.
- Activation of alloreactive T cells and secretion of IFN-γ and other cytokines contribute to the occlusive vascular lesions.
- As the arterial lesions progress, blood flow to the graft is compromised, and the parenchyma is replaced by nonfunctioning fibrous tissue.
Influence of MHC Matching on Graft Survival
- Matching MHC alleles between donor and recipient significantly improves renal allograft survival.
- HLA matching has a lesser impact on survival of renal allografts from live donors.
- Some MHC alleles are more impactful than others in determining graft survival.
Biologic Actions of IL-2
- IL-2 stimulates T lymphocyte survival, proliferation, and differentiation, acting as an autocrine growth factor.
- It also promotes the survival and function of regulatory T cells, controlling immune responses.
- IL-2 exhibits autocrine, paracrine, and endocrine actions.
The Immune Synapse
- The immune synapse forms a stable contact between an antigen-specific T cell and an APC.
- It facilitates the assembly of signaling machinery in the T cell, including TCR complex, coreceptors, costimulatory receptors, and adaptors.
- The immune synapse provides a platform for TCR triggering, ensuring prolonged and effective T cell signaling.
- The synapse also facilitates specific delivery of secretory granule contents and cytokines from a T cell to APCs or targets.
- The synapse is involved in the turnover of signaling molecules, contributing to the termination of T cell activation.
T Cell Signaling
- T cell activation is a complex process involving multiple signaling pathways, including TCR signaling and costimulatory signaling.
- TCR signaling involves the interaction of the TCR with MHC-peptide complexes on APCs, triggering a cascade of intracellular events.
- Costimulatory signaling is essential for T cell activation and survival and is mediated by interactions between costimulatory receptors (CD28, ICOS) and their ligands (B7-1, B7-2).
- The integration of TCR and costimulatory signals results in T cell activation, clonal expansion, and differentiation into effector T cells.
Mechanisms of Action of Immunosuppressive Drugs
- Immunosuppressive drugs are crucial for preventing graft rejection following transplantation.
- They work by interfering with various immune processes, including T cell activation, proliferation, and cytokine production.
- Examples of immunosuppressive drugs include calcineurin inhibitors (cyclosporine, tacrolimus), antiproliferative agents (azathioprine, mycophenolate mofetil), corticosteroids (prednisolone), and mAbs targeting specific immune molecules (anti-IL-2R, anti-CD3).
Corticosteroids Switch on Anti-Inflammatory Gene Expression
- Corticosteroids bind to cytoplasmic glucocorticoid receptors (GRs), which translocate to the nucleus and bind to glucocorticoid response elements (GREs).
- This binding activates gene expression of anti-inflammatory proteins.
- Corticosteroids induce acetylation of histone H4, leading to activation of genes encoding anti-inflammatory proteins, such as secretory leukoprotease inhibitor (SLPI), mitogen-activated protein kinase phosphatase (MKP)-1, inhibitor of nuclear factor-κB (IκB-α), and glucocorticoid-induced leucine zipper protein (GILZ).
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Description
This quiz covers the latest strategies and therapies for managing autoimmune disorders, including novel treatments like FcRn inhibitors and cellular therapies. Additionally, it explores hypersensitivity reactions and classification systems, shedding light on immune responses to various antigens. Test your understanding of these complex medical concepts.
