Abnormal Immunity: Innate

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Questions and Answers

Within the framework of T cell development and selection, what critical mechanism prevents autoimmunity by inducing apoptosis in T cells that exhibit high-affinity binding to self-antigens presented on thymic epithelial cells, while simultaneously ensuring the survival of T cells with moderate affinity for self-MHC molecules?

Receptor editing in immature T cells, where the T cell receptor (TCR) undergoes rearrangement to alter its affinity for self-antigens, preventing strong autoreactive responses.
Peripheral tolerance induced by regulatory T cells (Tregs) that suppress autoreactive T cells in the periphery through the expression of CTLA-4 and secretion of immunosuppressive cytokines such as IL-10 and TGF-β.
Negative selection in the bone marrow, where autoreactive B cells are eliminated via receptor editing or clonal deletion, preventing their migration to the thymus for further T cell interactions.
Positive selection mediated by cortical thymic epithelial cells (cTECs), followed by negative selection mediated by medullary thymic epithelial cells (mTECs) expressing tissue-restricted antigens (TRAs) under the control of the autoimmune regulator (AIRE) gene. (correct)

In the intricate interplay of innate and adaptive immune responses, which cells are responsible for the critical transition of linking those responses by internalizing pathogens or antigens, processing them into smaller peptides, and presenting those peptides to T cells via MHC class II molecules, thereby initiating T cell activation and cytokine production?

Dendritic cells, which are specialized antigen-presenting cells that capture and process antigens, migrate to lymph nodes, and activate T cells, thereby bridging the innate and adaptive immune systems. (correct)
Neutrophils, which are the first responders in the innate immune system, engulfing and destroying pathogens through phagocytosis and degranulation, but lacking the ability to present antigens to T cells.
B cells, which recognize and bind to specific antigens, undergo receptor-mediated endocytosis, and present antigens to T cells, but primarily function in antibody production rather than initiating innate immune responses.
Macrophages, which reside in tissues and perform phagocytosis, clean up cellular debris, and present antigens to T cells, but do not migrate to lymph nodes to initiate adaptive immune responses.

Imagine that during a clinical trial B cells are rendered unable to undergo somatic hypermutation (SHM). How is this specifically going to impact an individual?

Impaired plasma cell differentiation, leading to a complete absence of antibody production and subsequent susceptibility to opportunistic infections.
Diminished affinity maturation, resulting in decreased antibody specificity and reduced ability to neutralize rapidly evolving pathogens. (correct)
Compromised isotype switching leading to unchecked Th1 polarisation owing to a lack of IgG production.
Disrupted central tolerance, causing systemic autoimmunity due to the uncontrolled survival of self-reactive B cells.

Consider an innovative therapeutic strategy that promotes immune tolerance by selectively upregulating the expression of FoxP3 in autoreactive CD4+ T cells that successfully evaded central tolerance mechanisms. What implications does this strategy have regarding control of peripheral tolerance?

It will convert autoreactive T cells into induced regulatory T cells (iTregs), fostering immune homeostasis and preventing autoimmune reactions. (B) Signup and view all the answers

Under circumstances of chronic viral infection, what phenomenon critically impairs T cell function and how does programmed cell death protein 1 (PD-1) directly contribute?

T cell exhaustion, defined by a progressive loss of effector function, increased expression of inhibitory receptors like PD-1, and altered transcriptional programming that limits the T cell's ability to clear the infection. (B) Signup and view all the answers

How does HLA class I downregulation by malignant cells specifically influence the balance between innate and adaptive immunity?

It primarily enhances NK cell-mediated cytotoxicity due to decreased inhibitory signaling via killer cell immunoglobulin-like receptors (KIRs), while concurrently impairing cytotoxic T lymphocyte (CTL) recognition and killing of tumor cells. (C) Signup and view all the answers

When considering the complexity of post-translational modifications of MHC molecules, how do alterations such as citrullination or glycosylation affect antigen presentation and the subsequent T cell response?

They can introduce neo-epitopes that stimulate autoreactive T cells, driving autoimmune responses, or alter the repertoire of presented peptides in MHC molecules. (D) Signup and view all the answers

Supposing you're developing a novel class of adjuvants that aim to harness the power of innate immune sensors, how would triggering intracellular NOD-like receptors (NLRs) and specifically aim at amplifying adaptive immunity to a co-administered vaccine?

By promoting the secretion of IL-1β and activating the inflammasome pathway in antigen-presenting cells, leading to enhanced T cell priming and robust antibody responses. (C) Signup and view all the answers

How does chronic HIV infection lead to the progressive depletion of CD4+ T cells, and what are the specific mechanisms leading to CD4+ T cell death?

A combination of direct viral killing, increased susceptibility to apoptosis due to chronic immune activation, and immune-mediated killing by cytotoxic T lymphocytes that target HIV-infected cells. (D) Signup and view all the answers

In the pathogenesis of autoimmune diseases like rheumatoid arthritis (RA), what is the role of citrullinated proteins and how do they contribute to chronic inflammation and joint destruction?

Citrullinated proteins act as neoantigens, which break immune tolerance by activating autoreactive T and B cells, leading to the production of anti-citrullinated protein antibodies (ACPAs) and immune complex formation in the joints. (D) Signup and view all the answers

How does dysregulation in the signaling pathways of pattern recognition receptors (PRRs) on innate immune cells potentiate the development of inflammatory and autoimmune diseases?

It leads to chronic production of pro-inflammatory cytokines, amplifies the activation of autoreactive T and B cells, and impairs resolution of inflammation, perpetuating tissue injury and disease progression. (D) Signup and view all the answers

How do defects in the complement regulatory proteins (e.g., C1 inhibitor, factor H) contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) and atypical hemolytic uremic syndrome (aHUS)?

By impairing the clearance of immune complexes and apoptotic debris, leading to chronic activation of the complement system, inflammation, and tissue damage. (B) Signup and view all the answers

How can a breakdown in peripheral tolerance mechanisms, specifically those involving regulatory T cells (Tregs), lead to the development of autoimmune diseases?

By suppressing the activation and proliferation of autoreactive T cells, inhibiting cytokine production, and maintaining immune homeostasis. (D) Signup and view all the answers

What features of the cytokine milieu within the synovial microenvironment perpetuate chronic inflammation and joint destruction in rheumatoid arthritis (RA)?

An overabundance of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which drive the activation of synovial fibroblasts, promote angiogenesis, and stimulate osteoclast activity, leading to cartilage and bone destruction. (B) Signup and view all the answers

Considering the pathogenesis of systemic lupus erythematosus (SLE), how do plasmacytoid dendritic cells (pDCs) contribute to systemic autoimmunity and inflammation?

By producing copious amounts of type I interferons (IFN-α) in response to nucleic acid-containing immune complexes, thereby activating autoreactive lymphocytes and promoting inflammation. (B) Signup and view all the answers

In the development of type 1 diabetes (T1D), how do autoreactive T cells specifically recognize and destroy pancreatic beta cells, leading to insulin deficiency?

Autoreactive T cells recognize peptides derived from beta cell-specific proteins presented on MHC class I molecules, leading to targeted destruction of beta cells and insulin deficiency. (A) Signup and view all the answers

Considering the development of multiple sclerosis (MS), how does molecular mimicry contribute to autoreactive T cell activation and central nervous system (CNS) demyelination?

Molecular mimicry leads to the activation of autoreactive T cells that cross-react with myelin antigens in the CNS, causing inflammation and demyelination. (A) Signup and view all the answers

How would a genetic defect leading to impaired expression of the autoimmune regulator (AIRE) gene in thymic epithelial cells contribute to the pathogenesis of autoimmune diseases?

It impairs negative selection of autoreactive T cells, leading to their escape into the periphery and subsequent activation by self-antigens. (C) Signup and view all the answers

In the context of Type I hypersensitivity reactions, what is the mechanistic basis for the 'late phase' response that occurs several hours after initial allergen exposure?

It is characterized by the synthesis and release of newly generated mediators such as leukotrienes, prostaglandins, and cytokines from mast cells and recruited inflammatory cells, leading to sustained inflammation. (A) Signup and view all the answers

During antibody-mediated (Type II) hypersensitivity, how does the mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC) lead to tissue damage and cellular destruction?

Antibodies bind to antigens on target cells, and Fc receptors on NK cells recognize the bound antibodies, triggering the release of cytotoxic granules that induce apoptosis in the target cells. (B) Signup and view all the answers

In the context of Type III hypersensitivity reactions, what mechanistic processes determine the extent and location of tissue damage resulting from immune complex deposition?

The balance between pre-formed antibody affinity, immune complex size, receptor avidity, and the functional capacity of phagocytic cells responsible for immune complex clearance. (D) Signup and view all the answers

Within the complex landscape of Type IV hypersensitivity responses, what specific mechanisms govern the selective recruitment of immune cells to the site of antigen exposure, leading to the characteristic delayed-type hypersensitivity (DTH) reactions?

It is driven by the production of chemokines such as CXCL9, CXCL10, and CXCL11 by tissue cells and macrophages, selectively attracting antigen-specific T cells to the area, amplifying the cellular response. (D) Signup and view all the answers

Characterizing a theoretical immunodeficiency, you find increased B cell numbers in circulation but a marked lack of germinal centers within lymph nodes. Furthermore, in vitro stimulation reveals impaired B cell proliferation upon BCR crosslinking. Which signaling molecule is most likely deficient in these patients?

Bruton's tyrosine kinase (BTK) (C) Signup and view all the answers

In individuals presenting with hyper IgM syndrome due to a defect in CD40L, what additional immune deficiency would these individuals MOST likely present with?

Deficiencies in T cell dependent B cell activation and isotype switching. (A) Signup and view all the answers

Consider two patients, one diagnosed with Severe Combined Immunodeficiency (SCID) due to a mutation in the IL2RG gene (encoding the common \gamma chain) and another with DiGeorge syndrome. What immune defects and functional capabilities will be shared in BOTH of these patients?

Absence of T cells and defective B cell function (D) Signup and view all the answers

An experimental drug is designed to selectively deplete regulatory T cells (Tregs) in the tumor microenvironment to enhance anti-tumor immunity. However, clinical trials reveal severe autoimmune side effects in a subset of patients. What refinement to this drug is ideal?

Conjugate with a tumor-specific antibody to target only Tregs within the tumor microenvironment, preventing systemic Treg depletion. (A) Signup and view all the answers

Bone marrow transplantation is being considered for a nine month old infant. The transplantation team are in disagreement which source of hematopoietic stem cells (HSCs) has the best chance of generating immune self-tolerance and long-term-engraftment. Who should they choose?

Umbilical cord blood from a fully HLA-matched sibling (B) Signup and view all the answers

Following successful reconstitution of T cell populations following bone marrow transplantation for treatment of SCID, your patient develops chronic diarrhea, a maculopapular rash, and hepatosplenomegaly. Histological analysis of the involved tissues shows extensive lymphocyte infiltration and tissue destruction. What explains this constellation of symptoms?

A graft-versus-host disease (GVHD) reaction, in which donor-derived T cells recognize host tissues as foreign. (A) Signup and view all the answers

In Multiple Myeloma that is characterised by excessive production of monoclonal immunoglobulins, what would the MOST likely downstream defect be that contributes to renal damage?

Direct toxicity of the monoclonal light chains causing tubular damage and inflammation. (B) Signup and view all the answers

In HIV-infected individuals, what cellular mechanism accounts for the establishment and maintenance of viral reservoirs despite antiretroviral therapy (ART)?

Latency due to the infection of resting memory CD4+ T cells (B) Signup and view all the answers

You have a patient with HIV presenting with a constellation of symptoms indicative of progressive multifocal leukoencephalopathy (PML). What statement best explains this condition given the context of HIV-mediated immunosuppression?

Reactivation of the JC virus leads to lytic infection of oligodendrocytes. (C) Signup and view all the answers

In the complex interplay of T cell activation, what specific intracellular signaling event, subsequent to T cell receptor (TCR) engagement and co-stimulation, is indispensable for the induction of gene transcription required for T cell effector function and proliferation, and how might pharmacological targeting of this event modulate autoimmune responses?

The precise activation of phospholipase C-γ (PLC-γ), leading to the hydrolysis of phosphatidylinositol bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG), with IP3 inducing calcium release from the endoplasmic reticulum and DAG activating protein kinase C (PKC) isoforms, a process that can be modulated to fine-tune T cell responses. (A) Signup and view all the answers

What role does the interplay between central and peripheral tolerance mechanisms play in preventing autoimmune diseases, and how might disruptions in these processes, particularly concerning the regulation of autoreactive T cells, contribute to the pathogenesis of such conditions?

Central tolerance primarily involves negative selection of T cells in the thymus and B cells in the bone marrow, while peripheral tolerance relies on mechanisms like anergy, suppression by regulatory T cells (Tregs), and clonal deletion to control autoreactive lymphocytes that escape central tolerance; failure of either process can lead to autoimmunity. (C) Signup and view all the answers

Considering the multifaceted roles of cytokines in regulating the immune response, what are the implications for therapeutic interventions targeting specific cytokine pathways in autoimmune diseases, taking into account potential compensatory mechanisms and off-target effects?

Targeting specific cytokine pathways in autoimmune diseases carries the risk of triggering compensatory upregulation of other pro-inflammatory cytokines, potentially diminishing therapeutic efficacy and leading to unintended consequences; thus, combinatorial therapies may be necessary. (B) Signup and view all the answers

If a novel therapeutic approach aims to selectively inhibit the function of plasmacytoid dendritic cells (pDCs) in patients with systemic lupus erythematosus (SLE), what downstream immunological consequences would be anticipated, specifically regarding the production of type I interferons and the activation of autoreactive B cells?

A significant reduction in type I interferon production, leading to decreased activation of autoreactive B cells and subsequent reduction in autoantibody production, thereby ameliorating SLE symptoms. (C) Signup and view all the answers

Given the complexity of HLA gene polymorphism and its role in antigen presentation, how does the diversity of HLA alleles within a population influence susceptibility and resistance to infectious diseases and autoimmune disorders, and what are the implications for personalized medicine approaches?

HLA polymorphism results in differential antigen presentation capabilities, influencing the strength and specificity of immune responses, which can determine susceptibility or resistance to various diseases and can inform personalized medicine strategies. (C) Signup and view all the answers

How does the chronic activation of the innate immune system, particularly through pattern recognition receptors (PRRs), contribute to the development and perpetuation of autoimmune diseases, and what are the potential therapeutic strategies to modulate this persistent activation?

Persistent innate immune activation, via PRRs recognizing self-nucleic acids or other endogenous danger signals, amplifies inflammation and promotes autoimmunity; therapeutic strategies could involve blocking PRRs or inhibiting downstream signaling pathways. (C) Signup and view all the answers

In the context of T cell dysfunction, what specific molecular mechanisms lead to the impaired ability of cytotoxic T lymphocytes (CTLs) to effectively eliminate tumor cells, and how can this knowledge be leveraged to improve cancer immunotherapy strategies?

CTL dysfunction results from a combination of factors including inhibitory receptor expression (e.g., PD-1), metabolic exhaustion, and suppressive signals from the tumor microenvironment, which can be addressed through checkpoint inhibitors, metabolic modulators, and strategies to block suppressive signals. (A) Signup and view all the answers

Considering the different types of hypersensitivity reactions, how does the mechanism underlying Type IV hypersensitivity, specifically the role of sensitized T cells and macrophages, contribute to the pathogenesis of chronic contact dermatitis, and what targeted therapeutic interventions could disrupt this process?

Type IV hypersensitivity involves the activation of sensitized T cells upon re-exposure to an antigen, leading to cytokine release, macrophage activation, and chronic inflammation in contact dermatitis; targeted therapies could involve blocking T cell activation, cytokine signaling, or migration of immune cells to the skin. (D) Signup and view all the answers

In the context of autoimmune diseases and considering the mechanisms of molecular mimicry, how might microbial infections trigger autoimmune responses and what criteria must be met to definitively establish a causative link between a specific pathogen and an autoimmune condition?

Microbial infections can trigger autoimmunity if microbial antigens share structural similarities with self-antigens, leading to cross-reactive immune responses; establishing a causative link requires fulfilling stringent criteria, including sequence homology, evidence of cross-reactivity, and disease induction in animal models. (D) Signup and view all the answers

Given the complexity of the immune response in graft rejection scenarios, what specific mechanisms underlie chronic rejection of solid organ transplants, focusing on the roles of alloantibodies, T cell-mediated inflammation, and the resulting vascular damage, and what strategies could be employed to mitigate these processes?

Chronic rejection involves a combination of alloantibody-mediated injury, T cell-mediated inflammation, and subsequent vascular damage leading to graft fibrosis and dysfunction; mitigation strategies include refined immunosuppression, B cell depletion, and interventions targeting vascular remodeling. (C) Signup and view all the answers

Within the classification of immunodeficiency disorders, what are the key distinctions between primary and secondary forms of immunodeficiency, focusing on their etiologies, typical clinical manifestations, and the implications for diagnostic strategies and therapeutic interventions?

Primary immunodeficiencies are genetic disorders affecting immune system development or function, often presenting in early childhood with recurrent infections, while secondary immunodeficiencies are acquired due to external factors like infections or immunosuppressive drugs, and diagnostic/therapeutic approaches must address the underlying cause. (A) Signup and view all the answers

How would you differentiate between leukocyte adhesion deficiency (LAD) type 1, caused by mutations in the ITGB2 gene encoding the CD18 subunit, and LAD type 2, resulting from defects in the SLC35C1 gene affecting the expression of sialyl-Lewis X, regarding their underlying molecular mechanisms, cellular phenotypes, and consequent clinical presentations?

LAD-1 results from impaired leukocyte migration due to defective CD18-dependent adhesion to endothelial cells, leading to neutrophilia and recurrent bacterial infections, whereas LAD-2 involves defective selectin-mediated rolling due to lack of sialyl-Lewis X, causing similar but potentially milder symptoms, further complicated by neurological defects. (C) Signup and view all the answers

If the development of a novel cancer immunotherapy involves the ex vivo expansion and adoptive transfer of tumor-infiltrating lymphocytes (TILs) with enhanced cytotoxic activity, what specific modifications to the TILs, such as genetic engineering or pharmacological pre-conditioning, would most effectively overcome immunosuppressive mechanisms within the tumor microenvironment and improve therapeutic efficacy?

Enhancing TILs could involve genetic engineering to express chimeric antigen receptors (CARs) specific for tumor-associated antigens, CRISPR-mediated knockout of inhibitory receptors (e.g., PD-1, CTLA-4), or pharmacological pre-conditioning with cytokines or metabolic modulators to enhance survival, proliferation and cytotoxicity within the suppressive TME. (B) Signup and view all the answers

Considering the complexities of HIV pathogenesis, what specific cellular and molecular mechanisms account for the establishment and long-term maintenance of latent viral reservoirs within infected individuals despite effective antiretroviral therapy (ART), and how might these reservoirs be specifically targeted for eradication?

HIV latency involves the integration of proviral DNA into the genome of long-lived cells, such as resting memory CD4+ T cells and macrophages, where the virus remains transcriptionally silent and protected from immune clearance; targeting these reservoirs requires strategies such as 'shock and kill' or 'block and lock'. (A) Signup and view all the answers

What are the distinct immunological mechanisms underlying the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), focusing on the specific roles of autoantibodies, T cell subsets, cytokines, and the characteristic features of synovial inflammation and joint destruction in each disease?

RA is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), Th17-mediated inflammation, and pannus formation, while PsA involves a more prominent role for the IL-23/IL-17 axis, enthesitis, and distinct patterns of joint involvement, though both involve TNF-α and synovial inflammation. (B) Signup and view all the answers

Flashcards

What is immunity?

The body's defense system against harmful agents and abnormal cells.

How does the immune system work?

Recognizing antigens on pathogens or damaged cells and responding to neutralize or destroy them