Autoimmune and Hypersensitivity Disorders

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Questions and Answers

What therapeutic strategy is primarily utilized in disease-modifying treatments for autoimmune disorders?

Enhancing T cell proliferation

Directly eliminating pathogens

Modulating cytokine signaling and/or cell functions (correct)

Increasing antibody production

How do FcRn inhibitors exert their therapeutic effects in autoimmune conditions?

By preventing the degradation of immunoglobulins

By stimulating the production of autoantibodies

By enhancing T cell activation

By saturating the neonatal Fc receptor (FcRn) (correct)

In the context of hypersensitivity reactions, what does autoimmunity specifically refer to?

Harmful immune responses against one's own cells and tissues (correct)

Responses to pathogenic microbes

Excessive immune responses to non-microbial antigens

Reactions to environmental antigens

Which population percentage is noted to have abnormal responsiveness to common environmental substances?

20% or more Signup and view all the answers

What type of antibodies are produced by individuals who exhibit allergic reactions to environmental antigens?

IgE Signup and view all the answers

Which classification is NOT part of the Coombs and Gell hypersensitivity types?

Type V: Delayed-type hypersensitivity Signup and view all the answers

What abnormal reaction may occur in hypersensitivity to microbial antigens?

Persistent infections Signup and view all the answers

Hypersensitivity diseases are primarily classified based on which criteria?

Type of immune response and effector mechanism Signup and view all the answers

What role does the immune synapse play in T cell signaling?

It facilitates prolonged T cell signaling through stable interaction with APCs. Signup and view all the answers

How do corticosteroids primarily activate anti-inflammatory gene expression?

By binding to cytoplasmic glucocorticoid receptors and influencing histone modifications. Signup and view all the answers

What functions are associated with the immune synapse in relation to T cells?

It stabilizes contact for the transfer of granule contents and signaling molecules. Signup and view all the answers

Which of the following is NOT a characteristic of the immune synapse?

It serves as a primary site for T cell energy induction. Signup and view all the answers

What is the outcome of the degradation of signaling proteins at the immune synapse?

It contributes to the termination of T cell activation. Signup and view all the answers

In the context of immune synapse signaling, what is the role of adaptors?

They provide a scaffold for assembling signaling complexes. Signup and view all the answers

Which of the following proteins is NOT typically involved in the anti-inflammatory actions mediated by corticosteroids?

Cyclic AMP response element-binding protein (CREB) Signup and view all the answers

What process aids corticosteroids in promoting the transcription of anti-inflammatory genes?

Activation of coactivators with histone acetyltransferase activity. Signup and view all the answers

Which of the following mechanisms is NOT associated with T cell anergy?

Activation of CD28 in response to self antigens Signup and view all the answers

What is the primary role of CTLA-4 in the immune response?

Inhibiting T cell activation Signup and view all the answers

Which of the following is a mechanism by which regulatory T cells (Tregs) suppress immune responses?

Producing immunosuppressive cytokines like IL-10 Signup and view all the answers

Which ligand does CTLA-4 primarily compete with for binding in T cells?

CD80 Signup and view all the answers

How does TGF-β1 produced by Tregs influence T cell function?

Inhibits T cell proliferation and effector functions Signup and view all the answers

In which scenario is CTLA-4 expressed constitutively at high levels?

Regulatory T cells (Tregs) Signup and view all the answers

What effect does the engagement of inhibitory receptors of the CD28 family have on T cells recognizing self antigens?

Terminates T cell responses Signup and view all the answers

What is the role of IL-2 in the context of regulatory T cells?

Reduces availability for Treg function Signup and view all the answers

What is a primary mechanism that leads to graft failure in chronic rejection?

Intimal smooth muscle cell proliferation Signup and view all the answers

How does alloantibody binding affect endothelial function?

It induces intracellular signals that enhance adhesion molecule expression Signup and view all the answers

What is graft vasculopathy characterized by?

Development of intimal hyperplasia Signup and view all the answers

What role does IL-2 play in the immune response?

Promotes survival and differentiation of T lymphocytes Signup and view all the answers

What factor most significantly influences renal allograft survival?

MHC allele matching Signup and view all the answers

What commonly occurs after arterial lesions progress in graft arteriosclerosis?

Compromise of blood flow to the graft parenchyma Signup and view all the answers

In the context of chronic rejection, which cytokine is primarily associated with the proliferation of vascular smooth muscle cells?

IFN-γ Signup and view all the answers

Which of the following accurately describes the outcome of mismatched HLA alleles in live donor renal allografts?

Has minimal impact on survival rates Signup and view all the answers

What is the primary mechanism of tissue injury in immune complex-mediated diseases (ICMD)?

Inflammation within the walls of blood vessels due to complement activation Signup and view all the answers

Which type of T lymphocytes are primarily responsible for inducing inflammation in T cell-mediated diseases?

CD4+ Th1 and Th17 T cells Signup and view all the answers

In which scenario might T lymphocyte-mediated tissue injury be observed?

In response to intracellular microbes resisting phagocytosis Signup and view all the answers

Which statement correctly describes the nature of immune complexes in immune complex-mediated diseases?

They can be made up of antibodies bound to either self or foreign antigens Signup and view all the answers

What effect does complement fixation on the RBC surface have?

Results in complement-mediated lysis of the opsonized erythrocyte Signup and view all the answers

What is commonly observed in the glomerulus of patients with systemic lupus erythematosus (SLE)?

Thickening of the basement membrane due to immune complex deposition Signup and view all the answers

What triggers the inflammation associated with immune complex-mediated diseases?

Binding of leukocyte Fc receptors to antibodies in deposited complexes Signup and view all the answers

Which type of immune response is most directly associated with tissue injury in organ-specific autoimmune diseases?

Cytokine release and inflammation mediated by autoreactive T cells Signup and view all the answers

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.