Infection and Immunity III B Exam Revision Flashcards
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With reference to a specific autoimmune condition, describe how tolerance can be broken to lead to the pathogenesis of that disease.
Type 1 diabetes is an example of an autoimmune condition caused by the loss of self-tolerance. Peripheral and central tolerance are lose due to genetic predisposition and environmental stresses. This causes for self reactive T-cells to survive T cell regulation, thus causing the overexpression of self reactive T-cells and allowing for the immune system mediated destruction of insulin producing cells.
Following infection with a virus, the germinal centre reaction results in high affinity antibody responses tailored to combat this type of pathogen. Discuss the molecular and cellular events required for high affinity class switched antibody responses that occur both within and prior to the germinal centre reaction.
The germinal centre is the where affinity maturation and somatic hypermutation occur. Affinity maturation is the antigen-induced process of selecting for B cells with high affinity. Somatic hypermutation produces individual point mutations in Ig heavy and light chains rearrangement. The B-cells must receive a co-stimulatory signal for CD40 and cytokine signaling determines the isotype produced.
Describe how inflammatory responses are initiated, amplified and resolved following pathogen recognition.
Inflammatory responses are initiated by the release of pro-inflammatory cytokines (IL-1, IL-6) by immune cells (macrophages, mast cells)at damaged/infected tissue. Pro-inflammatory cytokines recruit more cells (neutrophils) to the site of injury. These cells are able to release their own pro-inflammatory cytokines, resulting in a cytokine cascade and amplification of the inflammatory response. Cells recruited assist in destroying pathogens and dead cells. Once the threat has been eliminated, anti-inflammatory cytokines (IL-10, TGF-beta) are released to counteract the inflammatory response. This, along with immune cell apoptosis, phagocytosis and repair resolve the immune response to prevent chronic inflammation.
Outline the process of T cell development in the thymus and describe how this contributes to self tolerance.
T-cells undergo a double negative (DN) and double positive (DP) selection stage. Within the DN stage, a T-cell lineage is committed to, the T-cell receptor (TCR) undergoes beta-chain rearrangement and selection, and the alpha-TCR undergoes rearrangement. During the DP stage, CD4 and CD8 are upregulated by thymocytes. The TCR-alpha chain is rearranged and replaced by a functional TCR-alpha chain. T-cells must recognise self-MHC molecules to receive survival signals. Tolerance is also carried out, where self-reactive cells are prevented from function by apoptosis, clonal anergy and suppression to prevent autoimmunity.
Describe the different types of memory B cells and how these differ from naive follicular B cells.
- Memory B cells are specific for the antibody that activated them. They remain in the body after infection clearance to quickly recognise the same pathogen if reinfection occurs, providing a rapid, strong and affinity matured IgG antibody response to secondary infection.
- GC-independent B cells retain broad non-mutated affinity for the antigen so they can refresh affinity for new variant antigens.
- Naive B cells have a longer lag period and peak response time than memory B cells. They produce low affinity antibodies and the cells are short lived.
What does neutralising antibody responses mean and how can viruses escape these responses?
Neutralising antibodies affect viral infectivity in several ways. They can form non-infectious aggregates that cannot enter cells, block virion attachment to cells, and block endocytosis and uncoating. Viruses can avoid antibody and humoral immune responses if they mutate their surface glycoproteins. Therefore, the neutralising antibodies and humoral immune response will not be able to recognise them.
The immune response in pregnancy exerts a form of ‘immune-mediated quality control’ to either tolerate or reject implanting embryos. Summarise the factors and cellular mediators that determine which of these two outcomes will occur.
The immune system discriminates foreign from self, after which it commits to and implements an appropriate response (tolerogenic or effector). Lymphocytes can elicit tolerance (Treg, Th2) or rejection (Th1, Th2, Th17). APCs further support the tolerance (M2 macrophage, tolerogenic DCs) or rejection (M1 macrophage, immunogenic DCs). Seminal fluid induces recruitment of APCs with M2 and tDC phenotypes, thus supporting the tolerogenic route.
Describe the warning signs when suspecting a primary immunodeficiency disease.
Primary immunodeficiency disease (PID) has warning signs of increased severity, frequency and duration of infection. It also presents with repeated infections with no symptom free interval, unexpected or severe complications of infection and increased reliance on antibiotics.
Discuss the detection of viral infections based on viral genomes by innate immune receptors and outline important features that differentiate viral from host genetic materials.
Viral infections are detected through pattern recognition receptors (PRRs). PRRs recognise pathogen associated molecular patterns (PAMPs) found on microbes. Toll like receptors (TLR) subclasses are able to recognise viral double stranded and single stranded RNA. The binding of viral RNA to TLRs activates MyD88, leading to the production of interferons and cytokines. Viral genomes are typically much smaller than host genomes and can be single stranded, opposed to the double stranded nature of host genomes. Virus genome is also non-complex and relies on host machinery to replicate, where host genomes are complex and replicate independently with their cellular machinery.
Discuss Human Immunodeficiency Virus (HIV) infection in terms of immune evasion and pathogenicity.
HIV transmission can occur through sexual contact, intravenous drug use, blood transfusions and such. The virus attaches to dendritic cells, which migrate to draining lymph nodes. The HIV virus is able to transfer from the DCs to T-cells, entering by receptor mediated surface fusion. It actively replicates in T-cells. HIV evades the immune system by rapidly mutating the proteins on its surface, thus antibodies cannot bind. They are also covered with immune evading glycans.
Outline the neutrophil defects in chronic granulomatous disease (CGD). What is the present approach to treating patients with this deficiency?
Neutrophils have a defective NADPH oxidase and therefore cannot undergo the respiratory burst to generate oxygen radicals. Bacteria engulfed cannot be killed through this method. Cytokine therapy for IFN-gamma is the current method to treating CGD.
Describe the biological mechanisms that provoke a maternal immune response to paternally-inherited fetal antigens in mammalian pregnancy, and explain the relevance to pregnancy success.
Seminal fluid exposure induces transient active tolerance to male transplantation antigens. It also induces many cytokine and chemokine genes. The cervical response induces APC recruitment with M2 and tDC phenotypes and T cell proliferation in the cervix.
Discuss 5 key characteristics of an ideal clinically accepted vaccine, and outline the protective efficacy of CD8+ T cell based vaccines.
Ideal vaccines must protect against illness, provide life-long protection (memory), cause no disease or side effects and maintain immunogenicity despite storage. It must also be easily administered, only require 1-2 doses and be affordable for global administration. CD8+ T-cell based vaccines activate such cells. Viral mutations would need to occur in all cytotoxic T-cell (CTL) epitopes to avoid CTL responses. This is incredibly unlikely, thus virus are unable to avoid CD8+ T-cell based vaccines.
Discuss strategies utilised by Ebola virus to evade antibody responses or to use these responses to enhance infections.
Ebola secretes glycoproteins (GP) to decoy antibody (Ab) responses. Three GP of different sizes are coded by the GP gene through transcriptional editing (full length GP = GP1,2, presecreted GP = pre-sGP, small secreted GP = ssGP). Ab-dependent enhancement occurs two ways. 1: Fc receptors (FcR), host Abs facilitate or enhance virus’s attachment to host cells. 2: Complement pathway, C1q component of complement system binds to the Ab-GP complex.
Describe the sequential gene rearrangements that B cell progenitors undergo as they develop in the bone marrow.
Early pro-B cells receive survival signals and express RAG to begin heavy chain DJ recombination. The Pro-B cells then undergo V-DJ recombination. Pre-B cells next have their Ig heavy chain complexed with a surrogate light chain. Pre-BCR expression inhibits further H-chain locus rearrangement. This initiates light chain rearrangement.
With 2 specific examples of each, describe the fundamental differences between organ-specific and systemic autoimmunity.
Organ specific auto immunities affect a specific organ/tissue. They occur due to an autoantibody or cell mediated response against tissue restricted antigens. For example; multiple sclerosis (CNS) and type 1 diabetes (pancreas). Systemic auto-immunities affect multiple organs/tissues. These occur due to the formation of circulating antigen:antibody (immune complexes), as well as autoantibody or cell mediated responses against widely expressed antigens. For example; Arthritis (joints) and Sjogren’s Syndrome (Salivary and other glands).
Discuss various factors that may contribute to the emergence of pandemic influenza and outline key parameters associated with severe pandemic influenza A virus infections.
The influenza virus has many factors aiding to its ability to cause pandemics. It has a segmented genome (high mutation rate), multiple subtypes, multiple hosts (zoonotic), different receptors it can bind, antigenic variations due to mutations and reassortment (associated with severe pandemic influenza A virus infections) and transmits through the respiratory system.
Major Histocompatibility Complex (MHC) molecules play a major role in our immune response to viral and bacterial infections. Discuss the structure and diversity of MHC molecules.
MHC I molecules contain a peptide binding cleft that can present small peptides (8-9 aa) derived from endogenous proteins. It contains an alpha1 and alpha2 membrane distal domain, as well as an alpha3 and beta2-microglobulin membrane proximal domain. The alpha3 domain anchors the molecule to the surface. MHC II molecules contain a binding cleft that can present larger antigens (12-17 aa) derived from exogenous proteins. They possess an alpha1 and beta1 membrane distal domain, as well as a alpha2 and beta2 membrane proximal domain. Both the alpha2 and beta2 domains anchor the molecule to the surface. All nucleated cells express MHC I, whereas only professional APCs express MHC II.
Outline the replication strategy/lifecycle for the hepatitis C virus and the molecular targets for direct acting antivirals (DAAs) in controlling chronic hepatitis C infections.
HCV is a blood borne disease. It attaches to CD81 receptors primarily on the surface of hepatocytes. It undergoes endocytosis and uncoating within the cell. Viral RNA is translated by host machinery into a polyprotein. Viral and host proteases cleave this into viral proteins. The viral genome is replicated and transported to the ER and lipid droplets, where they are assembled into viral particles. The new virions enveloped and released into the bloodstream by exocytosis. Direct acting antivirals (DAAs) used for HCV control include; interferon alpha2b therapy, NS5a inhibitors, NS3/4a protease inhibitor and NS5B polymerase inhibitor.
The most prominent feature of the neutrophil is the ability to rapidly release oxygen-derived reactive species to kill bacteria confined to the phagocytic vacuole. Describe the mechanisms by which these molecules are generated, including the different proteins involved and their assembly. Outline the consequences of being born with mutations in the genes that lead to lack of expression or activity of these proteins.
Respiratory burst entails the production of reactive oxygen species (ROS) used to kill internalized pathogens. ROS is produced by membrane bound NADPH oxidases catalyzing the reduction of molecular oxygen to the reactive oxygen intermediate, superoxide (diatomic oxygen O2-). Superoxide dismutase (SOD) can convert the superoxide anion into hydrogen peroxide, followed by either hypochlorous acid by myeloperoxidase (MPO) or water by catalase. Mutations leading to lack of expression of these proteins can cause for chronic granulomatous disease (CGD), thus not being able to kill bacteria engulfed.
Arboviral infections cause significant morbidity and mortality worldwide. Select one arbovirus and briefly discuss its transmission cycle, viral replication and pathogenesis. Diagrams may help.
Ross River is a blood-borne arbovirus that is transmitted through mosquitos. It typically includes a cycle of mosquito to stable hosts (wild birds, chickens) to mosquito (repeats), however can infect dead-end hosts such as horses and humans, resulting in severe disease. It enters the cell through receptor-mediated endocytosis, where the release of the nucleocapsid core and viral genome occurs. The viral RNA genome is translated and processed into a replication complex. The RNA genome also undergoes replication to form new RNA and glycoproteins. The glycoproteins are processed and mature in the Golgi apparatus, after which they are transported to the plasma membrane. A nucleocapsid core is assembled with genome RNA packaged within. These exit the cell through budding and are attached to by the surface glycoproteins to form a mature virion.
Describe how cytotoxic T lymphocytes differentiate and then find and kill their target cells.
Cytotoxic T cells (CTL) undergo a 3 phase generation. Phase 1 includes recognition/priming by APCs, where co-stimulation from CD28/B7 must occur. This is followed by phase 2 of IL-2 dependent proliferation and cytokine-dependent differentiation (IFN-gamma). Phase 3 includes their effector function, where they recognise and bind to the virus infected cells. They program for cell death through cytotoxic proteins and granzymes (DNA fragmentation included), after which they move to a new target to repeat whilst the previous cell undergoes apoptosis.
Compare and contrast the homing patterns of naïve, effector and different subsets of memory T cells. In the context of providing protective immunity, describe why these cell types have these distinct migratory characteristics and discuss some of the receptors on the cell surface that control their migration.
Naive T cells enter lymph nodes (LN) through high endothelial venules (HEVs). This is dependent on CD62L and CCR7 on the naive T cells and CD34 and chemokine CCL21 on HEVs. In secondary lymphoid organs (LOs) they browse APCs for antigens. They will exit through efferent lymphatic vessels into the bloodstream and enter another secondary LO until death or antigen encounter. Upon activation (become effector T-cells), their homing capabilities change to enter inflamed tissues by CCR6, CCR5 and CCR2. Central memory T cells (CD44, CD62L, CCR7) reside in/travel between secondary lymphoid tissues and are rapidly reactivated by second Ag exposure. They can differentiate into several subset types depending on the cytokine environment. Effector memory T cells (CD44) travel to/between tertiary tissues. They contribute to first line defenses and return to effector functions on second Ag exposure.
Helper T cells can be divided into distinct functional subsets that govern how immune responses develop. Select 4 of these subsets and outline i) the cytokines that polarise their differentiation from naïve precursors, ii) the master transcriptional regulator(s) of these cells, iii) the cytokines that they produce in response to antigen receptor stimulation, and iv) their overall role in the immune response.
Naive CD4+ T cells can be polarized into Treg, Th1, Th2 and Th17 helper T cells. Treg is polarized by IL-2 and TGF-beta, FOXP3 is the master transcriptional regulator, they produce IL-10 and TGF-beta and they regulate and suppress the immune and inflammatory responses. Th1 is polarized by IL-12, IFN-gamma and IL-18, T-Bet is the master transcriptional regulator, they produce IFN-gamma and TNF and they are involved in cell-mediated immunity, macrophage activation and inflammation. Th2 is polarized by IL-4, GATA3 is the master transcriptional regulator, they produce IL-4, IL-5 and IL-13 and are responsible for allergic and anti-helminth responses. Th17 is polarized by IL-1, IL-6, IL-23 and TGF-beta, ROR-gamma-t is the master transcriptional regulator, they produce IL-17A, IL-17F and IL-22 and are involved in inflammation.
